atrial-natriuretic-factor and Body-Weight

Natriuretic peptides are involved in the regulation of volume homeostasis. Their levels generally are increased in the setting of volume expansion and act on multiple effector systems to cause vasodilation and natriuresis in an effort to return volume status back to normal. In patients with end-stage renal disease, the natriuretic capabilities of these peptides are limited. However, there has been much interest in the potential applicability of measurement of these peptides as a surrogate marker of volume status and in the determination of dry weight. Furthermore, atrial natriuretic peptide and brain natriuretic peptide can serve as markers of left ventricular dysfunction and may have utility in determining cardiac prognosis in patients on long-term dialysis therapy.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Volume; Body Weight; Cohort Studies; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Natriuresis; Natriuretic Peptide, Brain; Natriuretic Peptides; Peritoneal Dialysis; Prognosis; Rats; Receptors, Neuropeptide; Ventricular Dysfunction, Left; Water-Electrolyte Balance

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Volume; Body Fluids; Body Weight; Body Weights and Measures; Cardiac Output; Electric Impedance; Hematocrit; Humans; Monitoring, Physiologic; Reference Values; Renal Dialysis; Vena Cava, Inferior

The hydration state of a hemodialysis patient reflects the balance between fluid overload, normovolemia and underhydration. Since chronic volume overload enhances the cardiac mortality, and chronic underhydration carries the risk for dialysis-associated hypotension, treatment for the deranged water homeostasis of hemodialysis patients needs to focus on an accurate assessment of dry body weight. Non-invasive methods such as echocardiography of the inferior caval vein diameter (ICVD) or conductivity measurements are considered as reliable techniques to estimate the hydration state of hemodialysis patients. The value of biochemical parameters for an adequate assessment of dry body weight remains controversial. In our study we have determined cyclic guanosine 3'5'-monophosphate (cGMP) serum levels in 125 patients undergoing regular hemodialysis. Predialytic cGMP significantly decreased from 46.1 +/- 26.0 to 17.0 +/- 9.3 pmol/liter post-dialysis (P < 0.001). In 35 patients cGMP level after hemodialysis remained > 20 pmol/liter, but non of these patients displayed any clinical signs of fluid overload. In a group of patients with normal heart function (N = 29) additional sonography of the ICVD revealed normovolemia in 16 patients, underhydration in 5 patients and fluid overload in 4 patients. The respective post-dialytic mean cGMP level was significantly higher in the overhydrated group compared to normovolemic and underhydrated patients (25.3 +/- 10.8 vs. 14.7 +/- 6.4 and 11.4 +/- 5.3 pmol/liter, P < 0.02). However, there was no significant correlation between cGMP level and ICVD (r = 0.5, NS). We conclude that there is no single parameter to define the adequate dry body weight of a hemodialysis patient. Our own data demonstrate the limitations using cGMP, particularly in estimating underhydration. ICVD and bioimpedance offer non-invasive methods for both volume overload and underhydration, and seem to be reliable in the routine assessment of dry body weight.

Topics: Atrial Natriuretic Factor; Body Water; Body Weight; Cyclic GMP; Humans; Proteins; Renal Dialysis

Topics: Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Humans; Renal Dialysis

The effects of long-term high calcium diet and physical exercise and their combined effects on the development of hypertension, plasma and tissue atrial natriuretic peptide, and arterial function were studied in spontaneously hypertensive rats with Wistar-Kyoto rats serving as normotensive controls. Hypertensive rats were made to exercise by running on a treadmill up to 900 m/day. Calcium supplementation was instituted by increasing the calcium content of the chow from 1.1% to 2.5%. During the 23-week study, calcium supplementation attenuated the rise in blood pressure in both trained and nontrained hypertensive animals, whereas exercise training had no significant effect on blood pressure. The high calcium diet alone was associated with reduced plasma and ventricular tissue contents of atrial natriuretic peptide, both of which were increased by exercise. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Neither increased dietary calcium nor endurance training affected the contractile sensitivity of endothelium-intact preparations to potassium chloride or norepinephrine. However, a high calcium diet enhanced the arterial relaxation induced by the return of potassium to the organ bath upon precontraction with potassium-free solution, and also moderately augmented relaxations to acetylcholine, sodium nitrite, and isoproterenol. Exercise training did not affect the potassium relaxation rate, but enhanced responses to acetylcholine, isoproterenol, and sodium nitrite. In conclusion, enhanced arterial potassium relaxation, a response reflecting the function of the vascular sodium pump, paralleled well the long-term blood pressure lowering action of increased dietary calcium intake in exercised and nonexercised hypertensive rats. However, augmented arterial relaxation to agonists could also be observed in the absence of reduced blood pressure following regular physical exercise.

Topics: Animals; Arteries; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium; Calcium, Dietary; Electrolytes; Heart Rate; Hypertension; Intracellular Membranes; Male; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstrictor Agents; Vasodilator Agents

Topics: Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Electric Conductivity; Humans; Renal Dialysis; Ultrasonography; Vena Cava, Inferior; Water-Electrolyte Balance; Water-Electrolyte Imbalance

GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR).. Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment.. Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration.. Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypertension; Liraglutide; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Receptors, Glucagon; Sodium

Randomized trials have shown that icodextrin reduces the volume of extra-cellular fluid (ECFv) with variable effects on residual renal function. To explore this fluid shift and its possible mechanisms in more detail, prospectively collected data from one such trial, including measures of inflammation (C-reactive protein, tumour necrosis factor-alpha, albumin and low and high molecular weight hyaluronan) ANP (atrial naturetic peptide), an indirect marker of intra-vascular volume, plasma concentrations of icodextrin metabolites and alpha-amylase activity were analysed.. 50 patients were randomized to either 2.27% glucose or icodextrin (n = 28) for a long exchange following a month run in. Blood samples were obtained at -1, 0, 3 and 6 months, coincident with measurements of urine volume and fluid status.. In both randomized groups, a significant correlation between the fall in ECFv and the decline in urine volume was observed (P = 0.001), although the relative drop in urine volume for patients randomized to icodextrin tended to be less. At baseline, ANP was higher in patients with proportionately more ECFv for a given body water or height. Icodextrin patients had non-significantly higher ANP levels at baseline, whereas by 3 (P = 0.026) and 6 months (P = 0.016) these differed between groups due to divergence. There was a correlation between increasing ANP and reduced ECF at 3 months, r = -0.46, P = 0.007, in patients randomized to icodextrin, but not glucose. There were no relationships between fluid status and any inflammatory markers at any point of the study, with the exception of albumin at baseline, r = -0.39, P = 0.007. Amylase activities at -1 month and baseline were highly correlated, r = 0.89, P < 0.0001. Within patients, concentrations of icodextrin metabolites were highly correlated; the only predictor of between-patient variability on multivariate analysis was body weight. There was no relationship between plasma concentrations of icodextrin metabolites and any of the other clinical parameters, including change in daily ultrafiltration, urine volume, fluid or inflammatory status.. This analysis supports observational data that changes in fluid status are associated with changes in urine volume. Icodextrin was not associated with a greater fall in urine output despite its larger effect on ECFv. Changes in fluid status could not be explained or did not appear to influence systemic inflammation. Nor can they be explained by individual variability in plasma concentrations of icodextrin that are in turn inversely proportional to the volume of distribution.

Topics: Amylases; Atrial Natriuretic Factor; Body Weight; C-Reactive Protein; Extracellular Fluid; Glucans; Glucose; Hemodialysis Solutions; Humans; Hyaluronic Acid; Icodextrin; Kidney Failure, Chronic; Multivariate Analysis; Osmolar Concentration; Peritoneal Dialysis; Serum Albumin; Tumor Necrosis Factor-alpha; Ultrafiltration; Urine

Thyroid dysfunction is associated with several abnormalities in intermediary metabolism, including impairment of lipolytic response to catecholamines in subcutaneous abdominal adipose tissue (SCAAT). Atrial natriuretic peptide (ANP) is a powerful lipolytic peptide; however, the role of ANP-mediated lipolysis in thyroid disease has not been elucidated. The aim of this study was to investigate the role of thyroid hormones in the regulation of ANP-induced lipolysis as well as in the gene expression of hormone-sensitive lipase, phosphodiesterase 3B (PDE3B), uncoupling protein-2 (UCP2), natriuretic peptide receptor type A, and beta(2)-adrenergic receptor in SCAAT of hyperthyroid and hypothyroid patients. Gene expression in SCAAT was studied in 13 hypothyroid and 11 hyperthyroid age-matched women before and 2-4 mo after the normalization of their thyroid status. A microdialysis study was performed on a subset of nine hyperthyroid and 10 hypothyroid subjects. ANP- and isoprenaline-induced lipolyses were higher in hyperthyroid subjects, with no differences between the groups following treatment. Hormone-sensitive lipase gene expression was higher in hyperthyroid compared with hypothyroid subjects before treatment, whereas no difference was observed following treatment. No differences in gene expression of other genes were observed between the two groups. Following treatment, the gene expression of UCP2 decreased in hyperthyroid, whereas the expression of PDE3B decreased in hypothyroid subjects. We conclude that thyroid hormones regulate ANP- and isoprenaline-mediated lipolysis in human SCAAT in vivo. Increased lipolytic subcutaneous adipose tissue response in hyperthyroid patients may involve postreceptor signaling mechanisms.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Weight; Catecholamines; Energy Metabolism; Female; Gene Expression Regulation; Humans; Hyperthyroidism; Hypothyroidism; Isoproterenol; Lipolysis; Middle Aged; Regional Blood Flow; Subcutaneous Fat, Abdominal

Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period.. We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH.. The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 +/- 26.4 vs. 9.8 +/- 7.4 ml/session, p < 0.05), frequency (0.60 +/- 0.26 vs. 0.10 +/- 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 +/- 56.4 vs. 104.8 +/- 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 +/- 0.9 vs. 7.9 +/- 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods.. The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Topics: Aged; Anemia; Antihypertensive Agents; Appointments and Schedules; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetic Nephropathies; Echocardiography; Erythropoietin; Female; Ferritins; Humans; Hypertension, Renal; Hypotension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Quality of Life; Recombinant Proteins; Renal Dialysis; Uremia

To study the effects of microgravity on the mechanisms involved in the regulation of body hydrous status, total body water (TBW), plasma volume (PV), and its main regulating hormones (plasma renin, aldosterone, atrial natriuretic peptide (ANP), anti-diuretic hormone (ADH)) were determined, by isotopic dilution, Dill and Costill's formula, and radio-immunologic dosages, in 9 male subjects submitted to a 90-d head-down bed rest (HDBR). ADH was determined in 24 h urinary collection as well as osmolality, sodium, and potassium. Body mass decreased (-2.8 +/- 0.8 kg) as well as TBW(-7.2% +/- 0.9%, i.e., -2.6 +/- 0.7 kg) and PV (-4.7% +/- 1.8%). Renin and aldosterone were enhanced (+109.0% +/- 15.4% and +87.2% +/- 38.9%, respectively). Simultaneously, we observed a decrease in ANP (-33.2% +/- 20.4%). Other variables, including ADH, were not affected by HDBR. Body mass and TBW decrease (and consequently lean body mass) are associated with muscle atrophy. Renin, aldostrerone, and ANP modifications are well explained by the decrease in PV, which was not enough to induce ADH changes. It suggests that in man, the main regulatory factor for ADH secretion is osmolality, when PV is modestly and progressively decreased without arterial pressure modification, which was the case in the present protocol.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Atrophy; Body Water; Body Weight; Head-Down Tilt; Hormones; Humans; Male; Osmolar Concentration; Plasma Volume; Radioisotope Dilution Technique; Renin-Angiotensin System; Vasopressins; Water-Electrolyte Balance; Weightlessness; Weightlessness Simulation

In heart failure patients, diuretics cause renin-angiotensin-aldosterone system (RAS) activation, which may lead to increased morbidity and mortality despite short-term symptomatic improvement.. To determine changes in RAS activation and clinical correlates following furosemide withdrawal in elderly heart failure patients without left ventricular systolic dysfunction.. We performed clinical assessments and laboratory determinations of aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP), norepinephrine, and endothelin in 29 heart failure patients [aged 75.1+/-0.7 (mean+/-S.E.M.) years], before, 1 and 3 months after placebo-controlled furosemide withdrawal. Recurrent congestion occurred in 2 of 19 patients withdrawn, and in 1 of 10 patients continuing on furosemide. Three months after withdrawal, PRA had decreased -1.61+/-0.71 nmol/l/h (P<0.05). Decreases in aldosterone levels did not reach significance (-0.17+/-0.38 nmol/l). The decreases in PRA after withdrawal correlated with decreases in systolic (r(s)=0.61, P=0.020) and diastolic blood pressure (r(s)=0.80, P=0.01). Successful withdrawal was associated with increases in norepinephrine (+0.58+/-0.22 nmol/l) and ANP (+3.5+/-1.3 pmol/l) (P<0.05) after 1 month, but these changes did not persist after 3 months. Endothelin levels did not change in both groups.. Successful furosemide withdrawal in elderly heart failure patients causes persistent decreases in RAS activation.

Topics: Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuretics; Double-Blind Method; Echocardiography; Epinephrine; Female; Follow-Up Studies; Furosemide; Heart Failure; Heart Rate; Humans; Male; Neurotransmitter Agents; Norepinephrine; Patient Compliance; Renin; Renin-Angiotensin System; Statistics as Topic; Stroke Volume; Substance Withdrawal Syndrome; Systole; Time Factors; Treatment Outcome; Ventricular Function, Left

Despite many advances in the treatment of hypertension, adequate blood pressure (BP) control in elderly patients continues to be a challenge. Optimal control of BP remains elusive because of issues relating to drug dosage and proper choice of therapeutic agents, including questions regarding the role of diuretics.. We examined the effect of diuretic treatment on BP in 12 elderly hypertensive patients whose hypertension was poorly controlled on previous drug regimens. We also evaluated the relationship of systolic, diastolic, and mean arterial BP (SBP, DBP, MAP, respectively) to changes in plasma renin activity (PRA), serum aldosterone (SA), atrial natriuretic peptide (ANP), and serum chemistries both before and after adding furosemide to the prior antihypertensive agents.. At baseline, 83% of patients had low PRA (< 1 ng/mL/h). After furosemide, in 67% of patients, decreases in SBP (166 +/- 5 to 134 +/- 5 mm Hg; P <.001), DBP (82 +/- 4 to 71 +/- 4 mm Hg; P =.004), and MAP (111 +/- 3 to 92 +/- 3 mm Hg; P <.001), were associated with increases in PRA (2.1 +/- 1.2 to 5.1 +/- 1.8 ng/mL/h; P =.01) and SA (4.8 +/- 1.0 to 9.4 +/- 1.4 ng/dL; P =.01) and with decreases in ANP (101 +/- 28 to 58 +/- 11 pg/mL; P =.01) and body weight (77.5 +/- 3.6 to 76.4 +/- 3.3 kg; P =.02), findings consistent with volume mediated/salt sensitive hypertension. In the remaining 33% of patients, BP also decreased significantly, but there was no increase in PRA (0.15 +/- 0.05 to 0.10 +/- 0 ng/mL/h) or SA (9.2 +/- 2.2 to 7.0 +/- 0.8 ng/dL) and no decrease in ANP (66 +/- 5 to 75 +/- 18 pg/mL) (P = ns for all), suggesting alternate mechanisms for their responses.. Many of the elderly hypertensive patients in our study had decreased PRA levels and showed significant reductions in BP after furosemide administration. Despite the associated increases in PRA and SA and decreases in ANP in 67% of patients, diuretic use remains important in the control of hypertension in this population.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuretics; Female; Furosemide; Humans; Hypertension, Renal; Male; Renin; Treatment Outcome

The simultaneous time courses of hydromineral hormones (renin-aldosterone system, arginine vasopressin, and atrial natriuretic peptide) and renal responses were examined during and after the completion of hyperhydration induced by glycerol and fluid ingestion. Eight healthy young male Caucasian subjects participated in two separate trials, each including three consecutive phases in a thermoneutral environment. Phases 1 and 3 involved a 90-min period at rest, while phase 2 involved a 120-min period at rest designed to provide either (i) euhydration (control trial) or (ii) hyperhydration induced by ingestion of glycerol (1.1 g/kg body mass) and fluid (21.4 mL/kg body mass). During the 2-h time period of glycerol and fluid ingestion, urine flow, urine osmolality, and plasma levels of hydromineral hormones remained at basal values. In contrast, after hyperhydration completion during phase 3, the diuresis increased markedly together with a dilution of the urine (p < 0.05) while hormonal responses did not change. These results indicate significant differences in renal responses during and after hyperhydration completion and suggest that these changes are independent of fluid-regulating hormonal responses.

Topics: Adult; Aldosterone; Algorithms; Arginine Vasopressin; Atrial Natriuretic Factor; Body Weight; Electrolytes; Glomerular Filtration Rate; Glycerol; Hormones; Humans; Kidney; Male; Osmolar Concentration; Renin; Urodynamics; Water Intoxication; Water-Electrolyte Balance

Abnormal responses of heart rate (HR) and oxygen uptake (VO2) during exercise characterize patients after right ventricular outflow tract reconstruction (RVOTR) for congenital heart defects. However, little is known about the postexercise dynamics.. We evaluated postexercise cardiovascular dynamics in 52 patients after closure of an atrioventricular septal defect (group A), 79 patients after RVOTR (group B), and 44 control subjects. HR variability, arterial baroreflex sensitivity (BRS), plasma norepinephrine, and hemodynamics were measured. Although there was no difference between group A and control subjects, declines in HR and VO2 after light and peak exercise and in systolic blood pressure (SBP) after peak exercise were delayed in group B. Age, low-frequency component of HR variability, and plasma norepinephrine were independent determinants of early HR decline. Peak SBP and VO2 had a great impact on the corresponding recoveries. When the peak values were excluded, body weight, BRS, and right ventricular ejection fraction were independent determinants of early SBP decline. BRS and the pulmonary artery resistance were independent determinants of VO2 decline throughout recovery, and age and right systolic ventricular pressure also determined the early VO2 decline. BRS and low-frequency component of HR variability were determined independently by the number of surgical procedures.. In RVOTR patients, in addition to metabolic and autonomic maturation, surgery-related abnormal cardiac autonomic nervous activity and impaired hemodynamics have a great impact on delayed postexercise cardiovascular recovery.

Topics: Atrial Natriuretic Factor; Autonomic Nervous System; Baroreflex; Blood Pressure; Body Weight; Cardiac Surgical Procedures; Cardiovascular Physiological Phenomena; Exercise Test; Heart Defects, Congenital; Heart Rate; Heart Septal Defects; Heart Ventricles; Hemodynamics; Humans; Linear Models; Natriuretic Peptide, Brain; Norepinephrine; Oxygen Consumption; Postoperative Period; Recovery of Function; Reference Values; Respiratory Function Tests; Stroke Volume; Ventricular Outflow Obstruction

Effects of hypobaric hypoxemia on endocrine and renal parameters of body fluid homeostasis were investigated in eight normal men during a sojourn of 8 days at an altitude of 4,559 m. Endocrine and renal responses to an osmotic stimulus (5% hypertonic saline, 3.6 ml/kg over 1 h) were investigated at sea level and on day 6 at altitude. Several days of hypobaric hypoxemia reduced body weight (-2.1 +/- 0.4 kg), increased plasma osmolality (+5.3 +/- 1.4 mosmol/kgH(2)O), elevated blood pressure (+12 +/- 1 mmHg), reduced creatinine clearance (122 +/- 6 to 96 +/- 10 ml/min), inhibited the renin system (19.5 +/- 2.0 to 10.9 +/- 0.9 mU/l) and plasma vasopressin (1.14 +/- 0.16 to 0.38 +/- 0.06 pg/ml), and doubled circulating levels of norepinephrine (103 +/- 16 to 191 +/- 35 pg/ml) and endothelin-1 (3.0 +/- 0.2 to 6.3 +/- 0.6 pg/ml), whereas urodilatin excretion rate decreased from day 2 (all changes P < 0.05 compared with sea level). Plasma arginine vasopressin response and the antidiuretic response to hypertonic saline loading were unchanged, but the natriuretic response was attenuated. In conclusion, chronic hypobaric hypoxemia 1) elevates the set point of plasma osmolality-to-plasma vasopressin relationship, possibly because of concurrent hypertension, thereby causing hypovolemia and hyperosmolality, and 2) blunts the natriuretic response to hypertonic volume expansion, possibly because of elevated circulating levels of norepinephrine and endothelin, reduced urodilatin synthesis, or attenuated inhibition of the renin system.

Topics: Adaptation, Physiological; Adult; Aldosterone; Altitude; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatinine; Endothelin-1; Epinephrine; Heart Rate; Humans; Hypertonic Solutions; Hypoxia; Infusions, Intravenous; Kidney; Kidney Function Tests; Male; Norepinephrine; Osmolar Concentration; Peptide Fragments; Renin; Sodium Chloride

Body weight (BW) reductions of more than 4 kg have been observed during diving with the open hot water suit, a technique in which heated seawater (SW) continuously floods the skin surface. To test the hypothesis that osmotic effects may be involved in these fluid-loss processes, head-out immersion experiments in 38 degrees C freshwater (FW) and SW for 4 h were performed. Average BW reduction was 2.5 and 1.9 kg in SW and FW head-out immersion, respectively (P < 0.01). Atrial natriuretic peptide increased during the first 30 min of SW immersion (5.6-13.4 pmol/l, P < 0.01) followed by a reduction to 7.6 pmol/l (P < 0.01). This paralleled an initial decrease in aldosterone (from 427 to 306 pmol/l, P < 0.05) followed by an increase to 843 pmol/l (P < 0.01). The effects of temperature on fluid loss were studied in thermoneutral (34.5 degrees C) and 38 degrees C SW for 2 h. In thermoneutral SW, calculated sweat production was negligible (0.05 kg) compared with 1.2 kg in warm SW. We recommend that, if a dive is planned to last for more than 4 h, a mandatory break for fluid intake should be incorporated in the diving regulations.

Topics: Adult; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Body Fluids; Body Weight; Dehydration; Diuresis; Fresh Water; Hormones; Humans; Immersion; Male; Osmolar Concentration; Seawater; Sweating; Water-Electrolyte Balance

The mechanisms underlying the reduction in blood pressure that occurs with a severe energy-restricted diet were evaluated in 12 obese subjects during 8 days on a very-low-calorie diet (1.67 MJ/d) with a constant intake of 17 mmol sodium per day. The relationship between changes in blood pressure, sodium balance, plasma volume, renin-aldosterone and sympathetic nervous system activities, plasma C-terminus and N-terminus of the atrial natriuretic factor (ANF) prohormone, brain natriuretic peptide (BNP), and endothelin-1 (ET-1) concentrations was investigated. A negative sodium balance was present throughout the diet and was associated with a moderate reduction in plasma volume, a marked activation of the renin-aldosterone system, and a concomitant reduction in C- and N-terminal ANF prohormone levels. Moreover, the postural changes in N-terminal proANF and ANF secretion documented before the diet, disappeared after 8 days of dieting, in contrast to a greater postural stimulation of aldosterone and renin. A negative correlation was found between the changes of C- and N-terminal ANF prohormone levels and those of aldosterone. Urinary catecholamine excretion, BNP, and ET-1 remained unchanged. These results indicate that the decrease in blood pressure occurring during severe caloric restriction was essentially due to the reduction in the effective blood volume, as reflected by the stimulation of the renin-aldosterone system and the decrease in ANF levels. The lack of any changes in catecholamine excretion and endothelin levels suggests that peripheral vascular resistance did not change significantly in these circumstances.

Topics: Adolescent; Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Urea Nitrogen; Body Weight; Catecholamines; Creatinine; Data Interpretation, Statistical; Diet, Reducing; Electrolytes; Endothelin-1; Female; Food Deprivation; Heart Rate; Hormones; Humans; Hydrocortisone; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Obesity; Plasma Volume; Renin; Sodium; Starvation; Uric Acid

This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibitors with and without a sulfhydryl group on intracellular production of cGMP, forearm blood flow, and neurohormonal factors during continuous transdermal application of nitroglycerin in patients with chronic heart failure. Platelet cGMP level and forearm blood flow were measured before and 5 min after sublingual administration of nitroglycerin (NTG) in 20 patients with chronic heart failure during the following 4 phases: (1) baseline phase; (2) NTG phase (1 week after NTG tape 10 mg/day); (3) CPT phase (1 week after both captopril 37.5 mg/day and NTG tape 10 mg/day); and (4) ENL phase (1 week after both enalapril 5 mg/day and NTG tape 10 mg/day). The platelet GMP level before sublingual NTG and forearm blood flow were significantly higher during the 3 phases with NTG tape than during the control phase. The percent increases in platelet cGMP level and forearm blood flow after sublingual NTG were significantly lower during the NTG phase than during the baseline phase. In contrast, concomitant application of ACE inhibitors maintained the percent increase in platelet cGMP level and forearm blood flow. These results indicate that concomitant therapy with ACE inhibitors may be helpful in preventing the attenuation of intracellular cGMP production in patients with chronic heart failure during continuous transdermal application of NTG.

Topics: Administration, Cutaneous; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Platelets; Blood Pressure; Body Weight; Chronic Disease; Cyclic GMP; Drug Tolerance; Female; Forearm; Heart Failure; Heart Rate; Hematocrit; Humans; Male; Middle Aged; Nitrates; Nitroglycerin; Norepinephrine; Regional Blood Flow; Renin; Systole; Vasodilator Agents

Patients with heart failure have abnormal neurohormonal regulation during orthostatic stress, and abnormal arterial baroreflex function. This study investigated the effects of alacepril, a new angiotensin-converting enzyme inhibitor with sulfhydryls, on changes in neurohormonal factors during tilt and on the arterial baroreflex control of heart rate.. Plasma concentrations of noradrenaline, adrenaline, renin activity, angiotensin II, and atrial natriuretic peptide were measured at supine rest and after 30 degrees head-up tilt with measurements of central venous pressure and cardiac dimensions in seven patients with congestive heart failure (65 years, ejection fraction = 34%). Arterial baroreflex control of heart rate was assessed by phenylephrine bolus. The arterial baroreflex test was re-examined 3 h after oral alacepril (37.5 mg). The tilt and arterial baroreflex tests were repeated 12 weeks after alacepril treatment (50 mg x day(-1)).. Heart rate, blood pressure, and neurohormonal factors did not differ before and after chronic alacepril, except for a trend toward an increase in renin activity (2.0 vs 4.9 ng x ml(-1) x h(-1)). Head-up tilt decreased central venous pressure (-2.5 mmHg) with a decrease in cardiac dimensions in the pre-alacepril phase. These changes were accompanied by increases in noradrenaline, adrenaline, and angiotensin II and a decrease in atrial natriuretic peptide. After chronic alacepril, the increase in noradrenaline during head-up tilt tended to be smaller (84 vs 30 pg x ml(-1)), with similar changes in central venous pressure (-3.4 mmHg) and cardiac dimensions. Both acute (3.6 vs 4.8 ms mmHg(-1)) and chronic (3.6 vs 6.7 ms mmHg(-1)) alacepril treatment was associated with a trend towards an increase in the arterial baroreflex control of heart rate.. These results suggest that treatment with alacepril may cause a reduction of sympathetic activation during orthostatic stress and may enhance arterial baroreflex function in patients with mild to moderate heart failure.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Arteries; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Body Weight; Captopril; Dose-Response Relationship, Drug; Epinephrine; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Renin; Tilt-Table Test; Ventricular Function, Left

The objective of this investigation was to study both the pharmacokinetics and renal pharmacodynamic properties of intravenously infused urodilatin in human beings.. Twelve healthy subjects received a short-term infusion (90 minutes) of urodilatin and placebo with a graded infusion rate (from 7.5 to 15 to 30 ng.kg body weight-1.min-1) in a randomized, double-blind, crossover study design. The renal parameters were evaluated by clearance technique with the use of 51Cr-ethylenediaminetetraacetic acid, 125I-hippuran, and lithium. Urodilatin concentrations were determined by a radioimmunoassay with a urodilatin-specific antibody.. Kinetics were characterized by a high apparent volume of distribution (43.7 +/- 11.2 L), a high total body clearance (5383 +/- 581 ml/min), and a short plasma half-life (5.57 +/- 0.8 minutes). The maximal plasma urodilatin level was 177.2 +/- 25.8 pmol/L. Less than 1% of total infused urodilatin was recovered in urine. Urodilatin significantly increased glomerular filtration rate (urodilatin, 7.0%, versus placebo, -1.9%; p < 0.05), reduced effective renal plasma flow (urodilatin, -17%, versus placebo, -3%; p < 0.01), increased fractional excretion of sodium (urodilatin, 137%, versus placebo, 27%; p < 0.05), and increased urine flow rate (urodilatin, 46%, versus placebo, -15%; p < 0.01). Fractional excretion of lithium did not change. Mean blood pressure decreased and vasoactive hormone levels remained unchanged or increased.. The natriuretic and diuretic effects of urodilatin closely followed the profile of urodilatin concentration in plasma. A major part of the synthetic urodilatin was removed from circulation by a route other than filtration through the glomeruli.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cross-Over Studies; Cyclic GMP; Diuretics; Double-Blind Method; Heart Rate; Hematocrit; Humans; Infusions, Intravenous; Kidney; Lithium; Male; Metabolic Clearance Rate; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Renin; Sodium

In this study we investigated the interactions between volume changes (body weight), plasma atrial natriuretic peptide (pANP) and ambulatory blood pressure (BP) in 10 patients with end-stage renal disease undergoing regular hemodialysis (HD) treatment three times weekly. Most patients retained their diurnal BP variation when their BP was adequately controlled. Interdialytic weight gain was 1.3 +/- 0.2 kg and the day-time systolic BP increased 12.5 +/- 4.8 mm Hg on the second interdialytic day. pANP did not correlate (r = -0.07, p = 0.85) with this BP elevation, but there was a fairly strong positive correlation (r = 0.61, p = 0.06) between interdialytic weight gain and systolic BP. The mean pANP level decreased from 149.7 +/- 18.2 to 117 +/- 0.1 ng/l during HD and continued its decrease to 83 +/- 12.2 ng/l at 20 h after an HD session. The total decrease from 149.7 +/- 18.2 to 83 +/- 12.2 ng/l was statistically significant (p = 0.001). Since the lowest pANP value was found 20 h after completion of the dialysis session, body weight is a more reliable indicator of volume reduction during HD than pANP. The results indicate that in HD patients weight gain between two dialysis sessions increases the day-time systolic BP but not the diastolic BP. Diurnal BP variation is maintained as long as BP is adequately controlled either by volume control or by drug treatment.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Weight; Circadian Rhythm; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Dialysis

beta-Receptor blockers may exert a spectrum of metabolic and humoral effects, which might differ depending on the specific adrenoreceptor characteristics of the individual agents. We investigated the influence of celiprolol, a beta 1-blocker with beta 2-agonistic and, possibly, additional weak alpha-receptor antagonistic properties, on insulin sensitivity (SI), glucose homeostasis, and lipid profile in 20 young, healthy, normotensive individuals. SI, fasting plasma glucose and insulin, serum total triglycerides (TG), lipoprotein cholesterol (C) fractions, lipoprotein a [Lp(a)], and plasma atrial natriuretic factor (ANF) levels were determined before and after acute glucose loading under placebo conditions and after 3 weeks of celiprolol administration. The participants were instructed to follow a 3-day standard diet (2,500 kcal/day, 45% carbohydrates, 40% fat, and 15% protein) and an overnight fast before measurements were recorded. As compared with control values, SI, fasting plasma glucose and insulin, the areas under the glucose and insulin curves, the k value of glucose disappearance after glucose load, and serum cholesterol fractions, TG, and Lp(a) were unchanged during celiprolol administration. However, celiprolol significantly reduced plasma ANF levels (p < 0.02). The latter increased in response to acute hyperglycemia/hyperinsulinemia with placebo (p < 0.05) but not with celiprolol. Although diastolic blood pressure (DBP) decreased slightly during the first and second week of celiprolol administration, BP and heart rate (HR) did not differ significantly after 3 weeks on celiprolol treatment as compared with placebo conditions. Our findings demonstrate that in healthy lean humans beta-receptor modulation with celiprolol is neutral with regard to SI and lipoprotein metabolism. Moreover, glucose loading stimulates whereas celiprolol decreases plasma ANF levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adult; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Celiprolol; Creatinine; Female; Glucose; Humans; Insulin; Insulin Resistance; Lipoproteins; Male; Patient Compliance; Receptors, Adrenergic, beta-2; Sensitivity and Specificity; Sodium

An elevated plasma atrial natriuretic peptide (ANP) concentration was observed in patients with chronic renal failure, and it was significantly (P < 0.01) decreased by hemodialysis with or without fluid removal. The ANP concentration was decreased by dialysis without fluid removal and the decrease was significantly (P < 0.01) correlated with the pre-dialysis value. The decrease in this peptide during fluid removal without diffusion was significantly (P < 0.05) correlated with the decrease in the circulating plasma volume measured by dye dilution. The decrease in the ANP level was therefore considered to be related to a fall in right atrial pressure caused by the decline in the circulating plasma volume. The circulating plasma volume, osmotic pressure, and blood pressure were not changed by hemodialysis without fluid removal. Moreover, the filtrate concentration of ANP (mean: 5.5 pg/ml) during fluid removal without dialysis was only about 8% of the plasma level, so filtration of ANP from the dialyzer was negligible. The decrease in ANP during hemodialysis without fluid removal may therefore have been caused by the removal of or a change in the level of substances, for example electrolytes, epinephrine, and uremic toxins. In addition to volume expansion, such a substance(s) might influence plasma ANP levels in patients with chronic renal failure.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Body Weight; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plasma Volume; Renal Dialysis; Time Factors

Blood pressure responses to 1 week of low-salt (20 mmol sodium/d) and high-salt (300 mmol sodium/d) intake were investigated in a single-blind randomized study in 163 white, nonobese normotensive subjects (65 women and 98 men; mean age, 38 +/- 1.2 years). The individuals were classified as salt sensitive when mean arterial blood pressure rose by at least 5 mm Hg during high-salt intake, as salt resistant when mean arterial blood pressure changed by less than 5 mm Hg, and as "counterregulator" when mean arterial blood pressure fell by at least 5 mm Hg during the high-salt diet. Reexamination of 31 subjects showed that this approach to the testing of salt sensitivity was reliable and reproducible. Thirty subjects (18.4%) were classified as salt sensitive, 108 (66.3%) as salt resistant, and 25 (15.3%) as counterregulators. Multiple regression analysis revealed that age, body weight, and family history of hypertension contributed significantly to the change in blood pressure after the diets. Salt sensitivity was more frequent in older subjects and in those with a positive family history of hypertension. An increase in blood pressure after salt restriction was more likely in younger individuals and in those with a negative family history of hypertension. Plasma renin activity and plasma aldosterone concentrations were lower in salt-sensitive compared with salt-resistant and counterregulating subjects. The rise in plasma renin activity during salt restriction was most pronounced in counterregulating subjects. Plasma norepinephrine concentrations were not different among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Family Health; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Renin; Reproducibility of Results; Single-Blind Method; Sodium Chloride; Sodium, Dietary

Sodium retention and symptoms and signs of fluid retention are commonly recorded during GH administration in both GH-deficient patients and normal subjects. Most reports have however, been casuistic or uncontrolled. In a randomized double blind placebo-controlled cross-over study we therefore examined the effect of 14-day GH administration (12 IU sc at 2000 h) on plasma volume, extracellular volume (ECV), atrial natriuretic peptide (ANP), arginine vasopressin, and the renin angiotensin system in eight healthy adult men. A significant GH induced increase in serum insulin growth factor I was observed. GH caused a significant increase in ECV (L): 20.45 +/- 0.45 (GH), 19.53 +/- 0.48 (placebo) (P less than 0.01), whereas plasma volume (L) remained unchanged 3.92 +/- 0.16 (GH), 4.02 +/- 0.13 (placebo). A significant decrease in plasma ANP (pmol/L) after GH administration was observed: 2.28 +/- 0.54 (GH), 3.16 +/- 0.53 (placebo) P less than 0.01. Plasma aldosterone (pmol/L): 129 +/- 14 (GH), 89 +/- 17 (placebo), P = 0.08, and plasma angiotensin II (pmol/L) levels: 18 +/- 12 (GH), 14 +/- 7 (placebo), P = 0.21, were not significantly elevated. No changes in plasma arginine vasopressin occurred (1.86 +/- 0.05 pmol/L vs. 1.90 +/- 0.05, P = 0.33). Serum sodium and blood pressure remained unaffected. Moderate complaints, which could be ascribed to water retention, were recorded in four subjects [periorbital edema (n = 3), acral paraesthesia (n = 2) and light articular pain (n = 1)]. The symptoms were most pronounced after 2-3 days of treatment and diminished at the end of the period. In summary, 14 days of high dose GH administration caused a significant increase in ECV and a significant suppression of ANP.

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Body Weight; Electrolytes; Extracellular Space; Growth Hormone; Humans; Male; Reference Values; Renin-Angiotensin System

To elucidate the effect of natriuretic and antinatriuretic factors on the excretion of an intravenous sodium load, we observed the natriuretic responses of 12 patients with essential hypertension (EHT) and 7 age- and sex-matched normotensive (NT) subjects following the intravenous administration of 1500 mL of normal saline over a 3 h period. After saline infusion, both groups showed increases in urinary sodium excretion (UNaV). The increases in glomerular filtration rate (GFR), atrial natriuretic peptide (ANP) and urinary dopamine excretion (UDAV) and the suppression of plasma renin activity (PRA) were similar in both groups. However, no significant change in blood pressure (BP) was seen in either group. Since significant negative linear correlations between the basal level of PRA and percent change in UNaV or GFR were seen only in EHT, we observed the influence of suppressing the renin-angiotensin system with a converting enzyme inhibitor. After a 7 day treatment with enalapril, GFR and UNaV in EHT after saline infusion were comparable to data obtained in the absence of enalapril, despite a reduction in preexpansion BP. Furthermore, a significant positive correlation between the basal BP and the percent increase in UNaV was seen among EHT after enalapril treatment. These results suggest that the state of the renin-angiotensin system is important in renal sodium excretion in EHT.

Topics: Adult; Aging; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatine; Dopamine; Enalapril; Female; Glomerular Filtration Rate; Hematocrit; Humans; Hypertension; Infusions, Intravenous; Kidney; Male; Middle Aged; Natriuresis; Norepinephrine; Prostaglandins; Regional Blood Flow; Renin; Renin-Angiotensin System; Sodium Chloride; Water-Electrolyte Balance

We studied, under outpatient conditions, nine patients with autosomal dominant polycystic kidney disease who were hypertensive on their usual diet, and nine normotensive healthy probands. The subjects were examined in random order on the 7th day after equilibration on a low-sodium diet (20 mmol/day) and again on the 7th day after equilibration on the same diet but with added sodium to yield a final intake of 200 mmol/day (or vice versa). Blood pressure was monitored non-invasively for 2 h at 4-min intervals using an automatic system. In healthy probands, mean arterial pressure (MAP) was similar on the low- and the high-sodium diets (92.7 versus 91.9 mmHg). In hypertensive patients, a significant (P less than 0.02) increase in mean MAP (107.2 versus 111.2 mmHg) and in systolic blood pressure (140.6 versus 148.7 mmHg) was observed irrespective of whether the glomerular filtration rate (GFR) was normal or reduced. The natriuresis pressure curve showed an upward shift (resetting) and a positive slope (sodium sensitivity). Patients with a reduced GFR as shown by inulin clearance differed from probands and patients with a normal GFR, by showing greater proportional changes in GFR and body weight. In hypertensive patients, atrial natriuretic factor (ANF) levels were higher at baseline and showed an exaggerated response to sodium loading. Changes in angiotensin II (Ang II) or in Ang II binding sites on platelets were similar in patients and controls and changed appropriately with the sodium intake. These data show a resetting of the natriuresis-blood pressure relationship and an increased blood pressure sensitivity to sodium in hypertensive patients with adult, dominant, polycystic kidney disease.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Natriuresis; Polycystic Kidney Diseases; Receptors, Angiotensin; Sodium, Dietary

We have studied the effect of xipamide on plasma alpha-atrial natriuretic peptide and the renin-aldosterone-kallikrein system in twelve healthy men, using a double-blind cross-over design. After a run-in period on placebo for 1 week the subjects were treated with either placebo (n = 6) or xipamide 20 mg once daily (n = 6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The plasma concentration of alpha-atrial natriuretic peptide fell after 1 week of xipamide administration and increased during prolonged xipamide administration but remained suppressed. The changes in plasma alpha-ANP observed after 1 week of xipamide were negatively correlated with the changes in haematocrit and haemoglobin. Plasma renin activity (PRA), aldosterone concentration (PAC), and urinary excretion of aldosterone and kallikrein increased after 1 week of xipamide administration, levelled off during the second and fourth weeks, but remained elevated during further prolonged xipamide administration for 16 weeks. The xipamide-induced changes in PRA and PAC were positively correlated with the changes in the haematocrit and haemoglobin. Our data suggest that the changes in plasma renin, aldosterone, and alpha-atrial natriuretic peptide during xipamide administration may be related to diuretic-induced volume contraction.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuretics; Double-Blind Method; Heart Rate; Humans; Kallikreins; Male; Regression Analysis; Renin; Renin-Angiotensin System; Time Factors; Xipamide

1. gamma-L-glutamyl-L-dopa (gludopa) and placebo were given by intravenous infusion to 12 healthy salt replete men for 10 h in a single-blind randomised fashion. 2. Gludopa caused a cumulative natriuresis of 46.5 mmol compared with placebo with a biphasic pattern and this was associated with a small reduction in body weight. 3. A small fall in arterial blood pressure and rise in pulse rate was seen with gludopa. 4. Plasma renin activity, atrial natriuretic peptide and urine kallikrein excretion were unchanged by gludopa but a small fall in urine aldosterone excretion, urine flow rate and free water clearance occurred. 5. The renal effects of gludopa are modest and last for only a few hours after the start of infusion.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Dihydroxyphenylalanine; Dopamine; Electrolytes; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Kallikreins; Kidney; Male; Potassium; Renin; Sodium

This study observed the effects of treadmill running on adipose tissue browning and lipolysis in rats with induced heart failure and elucidated the possible mechanism. Rats underwent abdominal aortic constriction as a model of heart failure. Cardiac function was detected by echocardiography. We detected serum levels of norepinephrine and interleukin 6, cardiac atrial natriuretic peptide and brain natriuretic peptide and marker genes of browning, white adipose tissue (WAT), and lipolysis in adipose tissue. Rats with heart failure showed typical symptoms such as increased heart weight and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide and decreased left ventricular ejection fraction. Exercise partially improved left ventricular diastolic function and significantly decreased atrial natriuretic peptide expression. Rats with heart failure showed significantly reduced body weight and ratios of muscle and fat weight to body weight. Exercise significantly increased body weight and the ratio of muscle weight to body weight. Heart failure stimulated the expression of proliferator-activated receptor-gamma coactivator-1-alpha and uncoupling protein 1 in epididymal WAT, inguinal WAT, and brown adipose tissue but decreased that of adiponectin and leptin in inguinal WAT. Lipolysis, characterized by high adipose triglyceride lipase and hormone-sensitive lipase expression, was activated in all adipose tissues. Exercise reduced browning and lipolysis in adipose tissues. Rats with heart failure had abnormally high levels of serum norepinephrine and interleukin 6, which could be suppressed by exercise. Exercise may improve cardiac cachexia and inhibit the browning and lipolysis of adipose tissue by downregulating sympathetic nervous system activity and inflammation.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Atrial Natriuretic Factor; Body Weight; Heart Failure; Interleukin-6; Lipolysis; Natriuretic Peptide, Brain; Norepinephrine; Physical Conditioning, Animal; Rats; Running; Stroke Volume; Ventricular Function, Left

The cardiac atria secrets polypeptide hormones usually called natriuretic peptides (NPs). These substances play a relevant role in the blood pressure regulation. The objective of the study was to estimate the effects of aging on the secretory apparatus of NPs in cardiomyocytes of the right atrium. Twenty male Wistar rats were studied: 10 young animals aged 3 months old (237 ± 27 g; mean ± SD) and 10 old animals aged 20 months old (450 ± 68 g; mean ± SD). The systolic blood pressure was verified instants before the moment of the euthanasia. Electron micrographs were prepared to quantify the area and density of the NP granules and the relative volumes of the endoplasmic reticulum, Golgi complex, and mitochondria. In addition, the number of pores per 10 μm of karyotheca was another variable evaluated. The significance of the results between the two groups evaluated was analyzed by the Student's t test (p < 0.05). The cardiomyocytes obtained from animals of the old group showed decreased in sectional area and density of secretory granules of NP and lower relative volume of endoplasmic reticulum, Golgi complex, and mitochondria compared with the young rats. Moreover, the quantitative density of nuclear pores was significantly lower compared with the youngers. CONCLUSION: Aging causes hypotrophy of the cardiomyocytes of right atrium, similar to what occurs in ventricular cardiomyocytes.

Topics: Aging; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart Atria; Heart Ventricles; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Rats; Rats, Wistar

Cardiac hypertrophy is a risk factor which can intrigue heart failure. In the present study, we explored whether AdipoRon attenuates isoprenaline (ISO) or l-thyroxine-induced cardiac hypertrophy in Sprague-Dawley (SD) rats and whether the anti-hypertrophy effect is mediated by AMPK-related pathway. Here, cardiac hypertrophy was induced by injection of l-thyroxine or ISO in SD rats. In the treatment group, AdipoRon was co-administered. We examined the effects of AdipoRon on cardiac hypertrophy and hypertrophy signaling pathway. The weight of SD rats was recorded every day. Rats were killed for collection of blood and heart under anesthesia. The left heart weight and heart weight were weighed. Paraffin-embedded heart tissue regions (4 μm) were stained with hematoxylin and eosin or Masson to detect left heart hypertrophy and myocardial fibrosis. The serum BNP levels were determined by using an enzyme-linked immunosorbent assay. The mRNA levels of ANP, BNP, PGC-1α, and ERRα were evaluated by real-time PCR analysis. The protein expression levels of PGC-1α, ERRα, and pAMPK/AMPK were determined by western blot analysis. The results showed that AdipoRon significantly reversed heart weight (HW)/body weight (BW) ratio, left ventricular (LV)/BW ratio, serum BNP level and the mRNA level of ANP and BNP induced by ISO or l-thyroxine. ISO or l-thyroxine reduced both the mRNA level and protein level of ERRα and PGC-1α, and also reduced the protein level of pAMPK/AMPK. However, AdipoRon reversed ISO or l-thyroxine-induced changes of pAMPK/AMPK, ERRα, and PGC-1α. Our data indicated that the effects of AdipoRon are mediated partly by activating AMPK-related pathway, and AdipoRon plays a potential role in the prevention of cardiac hypertrophy.

Topics: AMP-Activated Protein Kinases; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Gene Expression; Isoproterenol; Male; Natriuretic Peptide, Brain; Organ Size; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; Rats, Sprague-Dawley; Signal Transduction; Thyroxine

Diabetes mellitus (DM) has been demonstrated to have a strong association with heart failure. Conventional echocardiographic analysis cannot sensitively monitor cardiac dysfunction in type I diabetic Akita hearts, but the phenotype of heart failure is observed in molecular levels during the early stages.. Male Akita (Ins2WT/C96Y) mice were monitored with echocardiographic imaging at various ages, and then with conventional echocardiographic analysis and speckle-tracking based strain analyses.. With speckle-tracking based strain analyses, diabetic Akita mice showed changes in average global radial strain at the age of 12 weeks, as well as decreased longitudinal strain. These changes occurred in the early stage and remained throughout the progression of diabetic cardiomyopathy in Akita mice. Speckle-tracking showed that the detailed and precise changes of cardiac deformation in the progression of diabetic cardiomyopathy in the genetic type I diabetic Akita mice were uncoupled.. We monitored early-stage changes in the heart of diabetic Akita mice. We utilize this technique to elucidate the underlying mechanism for heart failure in Akita genetic type I diabetic mice. It will further advance the assessment of cardiac abnormalities, as well as the discovery of new drug treatments using Akita genetic type I diabetic mice.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Disease Models, Animal; Echocardiography; Female; Heart; Heart Rate; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocardium; Natriuretic Peptide, Brain; Severity of Illness Index; Ventricular Dysfunction, Left

The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen-deficient rats has not been reported.. We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-β-estradiol (E), OVX-treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days.. Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-β-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions.. Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women.

Topics: Active Transport, Cell Nucleus; Animals; Atrial Natriuretic Factor; Body Weight; Estrogens; Female; Heart; Hemodynamics; Myocardium; NF-kappa B; Organ Size; Ovariectomy; Raloxifene Hydrochloride; Rats; Selective Estrogen Receptor Modulators; Tamoxifen; Uterus

Although white adipose tissue mass and distribution correlates with cardiovascular disease, the fat cell-specific perturbations underlying this association are not known. We determined the relationship between adipocyte size and lipid metabolism with cardiovascular risk.. Adipocyte size as well as spontaneous (basal) and hormone-stimulated effects on adipocyte lipid metabolism (lipolysis and lipogenesis) were investigated in abdominal subcutaneous adipose tissue of 304 men and 775 women. Subjects were classified into five categories according to Adult Treatment Panel III (ATPIII) metabolic syndrome criteria.. Adipocyte size increased with increasing ATPIII score (P < 0.0001). For lipolysis, there was a gradual increase in basal and catecholamine-stimulated lipolysis and a decrease in insulin-mediated inhibition of stimulated lipolysis with ATPIII (P < 0.0001). In contrast, the lipolytic action of atrial natriuretic peptide was similar between ATPIII classes. Basal and insulin-stimulated lipogenesis decreased with increasing score (P < 0.0001). Circulating free fatty acid levels were 50% higher in the top risk category (4-5) compared with the lowest score (P < 0.0001). Fat cell size correlated positively with increasing ATPIII score and lipolysis but negatively with lipogenesis. All these differences were independent of age, sex and body weight status (P < 0.0001 to 0.02 after correction). When all functional measures were put together, maximum insulin-stimulated lipogenesis, insulin-antilipolytic sensitivity and basal lipolysis together explained about 20% in the variation of ATPIII in score.. Independently of sex, age and body weight status, a high cardiovascular risk score associates with increased circulating free fatty acid levels and hormone-specific alterations of lipolysis/lipogenesis in enlarged subcutaneous fat cells.

Topics: Adipocytes; Adult; Age Factors; Atrial Natriuretic Factor; Body Mass Index; Body Weight; Cardiovascular Diseases; Cell Size; Fatty Acids, Nonesterified; Female; Humans; Insulin; Isoproterenol; Lipogenesis; Lipolysis; Male; Middle Aged; Norepinephrine; Risk Assessment; Sex Factors

Renin-angiotensin system is involved in the pathophysiology of colonic inflammation. However, there are a few reports about modulation of natriuretic peptide system.. This study investigates whether a local atrial natriuretic peptide (ANP) system exists in rat colon and whether ANP plays a role in the regulation of colonic motility in experimental colitis rat model.. Experimental colitis was induced by an intake of 5 % dextran sulfate sodium (DSS) dissolved in tap water for 7 days. After rats were killed, plasma hormone concentrations and mRNAs for natriuretic peptide system were measured. Functional analysis of colonic motility in response to ANP was performed using taenia coli.. DSS-treated colon showed an increased necrosis with massive infiltration of inflammatory cells. The colonic natriuretic peptide receptor-A mRNA level and particulate guanylyl cyclase activity in response to ANP from colonic tissue membranes were higher, and the mRNA levels of ANP and natriuretic peptide receptor-B were lower in DSS-treated rats than in control rats. ANP decreased the frequency of basal motility in a dose-dependent manner but did not change the amplitude. The inhibitory responses of frequency of basal motility to ANP and 8-bromo-cGMP were enhanced in DSS-treated rat colon.. In conclusion, augmentation of inhibitory effect on basal motility by ANP in experimental colitis may be due an increased expression of colonic natriuretic peptide receptor-A mRNA. These data suggest that local natriuretic peptide system is partly involved in the pathophysiology of experimental colitis.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Motility; Guanylate Cyclase; Male; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Renin; Renin-Angiotensin System

Preeclampsia (PE) is a major cause of mortality of mothers, fetuses and newborns around the world. The etiology of preeclampsia has not yet been clarified, but many studies indicate a multifactorial basis of PE. Aldosterone synthase (CYP11B2) is responsible for synthesis of aldosterone responsible for regulating blood pressure. Similarly, natriuretic peptide (ANP) regulates blood pressure through a variety of mechanisms affecting the sodium concentration and the amount of extracellular fluid. Currently, attention is paid to the role of the polymorphisms in the expression level of these genes. The aim of the study was to determine the frequencies of genotypes and alleles for polymorphisms of -344C>T CYP11B2 gene and 2238T>C ANP gene in women with preeclampsia and healthy pregnant women from the Caucasian population.. The study included a group of 165 pregnant women (59 women with preeclampsia and 109 healthy pregnant women). DNA was extracted from peripheral blood. Determination of the polymorphism of -344C>T CYP11B2 gene and 2238T>C ANP gene was performed by PCR-RFLP method.. The results showed that the frequencies of the TC and CC genotypes of 2238T>C polymorphism in ANP gene were significantly higher in patients with PE compared to control group. For -344C>T polymorphism of CYP11B2 gene, the frequency of TT genotype was significantly higher in patients with hypertension than in controls (32.2% vs. 23.58%).. Our findings showed that gene polymorphism of CYP11B2 (-344C>T) and ANP (2238T>C) may be associated with developing PE during pregnancy.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Case-Control Studies; Cytochrome P-450 CYP11B2; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension, Pregnancy-Induced; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Pre-Eclampsia; Pregnancy; White People

This study examined the sex differences for physical, morphological, histological, mRNA, and protein expression levels changes for interleukins and natriuretic peptides in left ventricle (LV) of two groups of adult FVB/N mice; males (WM) and females (WF). LV morphological, histological, reverse transcription and quantitative real-time PCR (RT-PCR), and immunohistochemical (IHC) alterations were determined in FVB/N mice at 34-35 weeks on gender basis. Confirming the gender dimorphism, FVB/N males (WM) illustrated a significant reduction in ANP and IL1-A levels as well as significantly increased body weight (BW (gm)), tibia length (TL (mm)), heart weight (HW (mg)), heart weight-to-body weight (HW/BW (mg/gm)) ratio, heart weight-to-tibia length (HW/TL (mg/mm)) ratio, left ventricle weight (LV (mg)), left ventricle-to-body weight (LV/BW (mg/gm)) ratio, and left ventricle-to-tibia length (LV/TL (mg/mm)) ratio, left ventricular (LV) cardiomyocyte diameter, high BNP, NPRA, IL-1B, and IL1R1 expression in comparison with FVB/N females (WF). Gender differences in relation to left ventricle (LV) may be due to differences in the interleukins and natriuretic peptides levels as an outcome of sex related hormones.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Female; Heart Ventricles; Interleukins; Male; Mice; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organ Size; Real-Time Polymerase Chain Reaction; Receptors, Atrial Natriuretic Factor; Receptors, Interleukin-1 Type I; Sex Characteristics; Tibia

Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [(3)H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Cells, Cultured; Glucosides; Male; Myocardium; Myocytes, Cardiac; NADPH Oxidases; Organ Size; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Superoxides; Ventricular Myosins

Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Arterial Pressure; Atrial Natriuretic Factor; Biphenyl Compounds; Body Weight; Endothelin B Receptor Antagonists; Endothelin-1; Irbesartan; Kidney; Myocardium; Myocytes, Cardiac; Neprilysin; Oligopeptides; Organ Size; Piperidines; Protease Inhibitors; Rats; Receptor, Angiotensin, Type 1; Receptor, Endothelin B; Renin-Angiotensin System; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Tetrazoles; Thiorphan; Up-Regulation; Vasoconstriction; Vasodilation

In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1α is involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa). We evaluated the expression of ANP, HIF-1α, and transforming growth factor (TGF-β1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP and UVNa levels and enhanced renal immunostaining of ANP, HIF-1α, and TGF-β1. The administration of tempol together with the sodium overload increased the natriuresis further and prevented the elevation of blood pressure and the increased expression of ANP, TGF-β1, and HIF-1α compared to their control. These findings suggest that HIF-1α and ANP, synthesized by the kidney, are involved in an adaptive mechanism in response to a sodium overload to prevent or attenuate the deleterious effects of the oxidative stress and the hypoxia on the development of fibrosis.

Topics: Animals; Arterial Pressure; Atrial Natriuretic Factor; Blotting, Western; Body Weight; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Kidney Cortex; Male; Rats, Sprague-Dawley; Sodium; Sodium Chloride, Dietary; Transforming Growth Factor beta1

Abdominal and lower body fat mass tissues exhibit particular metabolic profiles at rest and during exercise. However, data are missing in normal weight women during exercise. The purpose of this study was to investigate the effect of low (LA/LB) and high (HA/LB) abdominal to lower body (A/LB) fat mass ratio on metabolic and hormonal responses during exercise in premenopausal normal weight women.. After preliminary testing (V˙O2max and body composition assessment), substrate oxidation (RER, lipid, and carbohydrate oxidation rates), metabolic response (glycerol, free fatty acids, and glucose), and hormonal response (insulin, growth hormone, atrial natriuretic peptide, adrenaline, and noradrenaline) were determined during exercise (45 min at 65% of V˙O2max) in 21 premenopausal normal weight women (10 HA/LB women vs 11 LA/LB women).. Waist circumference was significantly higher in HA/LB women compared with LA/LB women (P < 0.01). No difference in other anthropometric characteristics, V˙O2max, and resting blood values was observed between the two groups. LA/LB subjects exhibited greater lipid oxidation rates compared with HA/LB women during exercise (P < 0.01). This occurred with lower plasma insulin (P < 0.05) and glucose (P < 0.05) concentrations and higher plasma free fatty acids (P < 0.05), glycerol (P < 0.05), growth hormone (P < 0.05), and atrial natriuretic peptide levels (P < 0.01) during exercise in the LA/LB group compared with the HA/LB group.. The present study demonstrated that LA/LB women exhibited an increase in whole-body lipid mobilization and use during exercise compared with HA/LB counterparts. This greater reliance on lipid as fuel metabolism during exercise could be explained by substrate availability and metabolic and hormonal responses. It appeared that LA/LB women exhibited greater metabolic flexibility during an exercise bout of 45 min at 65% of V˙O2max on cycle ergometer.

Topics: Abdominal Fat; Adult; Atrial Natriuretic Factor; Blood Glucose; Body Fat Distribution; Body Weight; Energy Metabolism; Exercise Test; Fatty Acids, Nonesterified; Female; Glycerol; Growth Hormone; Humans; Insulin; Lipid Metabolism; Oxidation-Reduction; Oxygen Consumption; Physical Exertion; Premenopause; Waist Circumference; Young Adult

The purpose of this study was to compare the effects of conjugated equine estrogens (CEE) and estradiol benzoate on the blood pressure and body weight of spontaneously hypertensive rats (SHRs) and the associated changes in several components of the natriuretic peptide system.. The blood pressure of randomly distributed female SHRs and Wistar rats was determined by tail plethysmography. The rats were ovariectomized and, after 3 weeks, injected daily for 4 days with estradiol benzoate (5 μg/100 g/d), CEE (50 μg/100 g/d), or vehicle (corn oil 0.1 mL/100 g/d). One day after the last injection, the rats were decapitated, and their blood was collected to measure atrial natriuretic peptide (ANP) and estradiol. The atria were removed to measure ANP levels using radioimmunoassay and to quantify ANP messenger RNA expression using real-time polymerase chain reaction. The kidneys and adipose tissue were removed to analyze the expression of natriuretic peptide clearance receptor messenger RNA.. A reduction in blood pressure was observed in estradiol-treated SHRs, but CEE treatment had no effect. Estradiol decreased the body weight and parametrial adipose tissue mass of SHRs. Estradiol-induced alterations in SHRs were accompanied by increased synthesis and release of ANP. CEE had no effect on body weight but increased the mesenteric adipose tissue mass of SHRs.. These results indicate that estradiol and CEE have different effects on the reduction in body weight and blood pressure. These results are correlated with changes in plasma ANP levels.

Topics: Adipose Tissue; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Estradiol; Estrogens; Estrogens, Conjugated (USP); Female; Gene Expression; Heart Atria; Kidney; Mesentery; Ovariectomy; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger

Anthracyclines are used to treat cancers during the second and third trimester of pregnancy. The chemotherapeutic effect of anthracyclines is associated with a dose- and time-dependent cardiotoxicity that is well described for infants and adults. However, data regarding fetal anthracycline-related cardiotoxicity after administration of chemotherapeutics during pregnancy are limited. In this study, we analyzed the acute effect of doxorubicin, an anthracycline derivative, on fetal and maternal rat myocardium. We injected 10 or 20 mg/kg i.v. doxorubicin to pregnant Wistar rats at day 18 of pregnancy; age-matched pregnant rats injected with physiologic saline served as controls. Maternal echocardiography and fetal Doppler scanning were performed before the injection and before sacrifice. Cesarean operation was performed at day 19 or 20, and maternal and fetal blood samples and heart biopsies were collected to measure apoptosis, the impact on cell proliferation, and structural cardiac damage. Acute maternal cardiotoxicity is associated with loss of body weight, moderately deteriorated left ventricular function, induction of apoptosis, and a decrease in cell turnover. Despite a 30% lower fetal body weight and elevated plasma B-type natriuretic peptide concentrations after doxorubicin administration, the fetal hearts had intact microstructure, an unaltered number of apoptotic cells, and preserved cell proliferation compared with controls. Our study suggests that acute treatment using anthracyclines during pregnancy impairs maternal cardiac function, whereas fetal hearts are protected.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Atrial Natriuretic Factor; Body Weight; Cell Proliferation; DNA Fragmentation; Doxorubicin; Echocardiography; Female; Fetal Heart; Heart Diseases; In Situ Nick-End Labeling; Injections, Intravenous; Maternal-Fetal Exchange; Myocardium; Myosins; Organ Size; Pregnancy; Rats; Rats, Wistar; RNA; Transcription, Genetic

A positive association between air pollution exposure and increased human risk of chronic heart disease progression is well established. In the current study, we test two hypotheses: (1) the cardiac compensatory changes in response to air pollution are dependent on its composition and (2) specific cardiac adaptations are regulated by atrial natriuretic peptide (ANP). We address these hypotheses by initially examining the exposure effects of ozone (O(3)) and/or particulate matter (PM) on cardiac function in C57Bl/6J (B6) mice. Subsequently, the results are compared with cardiac functional changes to the same exposures in Nppa (the precursor gene for ANP) knockout (KO) mice. Separate groups of mice underwent 3 consecutive days of the same exposure sequence for 3h each consisting of the following: (1) 6h of filtered air (FAFA), (2) O(3) then FA (O(3)FA), (3) FA then carbon black (FACB), or (4) O(3) then CB. Cardiac function was assessed using a conductance catheter to generate cardiac pressure-volume loops 8-10h following each exposure sequence. As compared with FAFA, each sequence led to a substantial drop (as much as 33%) in stroke volume and cardiac output. However, these losses of cardiac function occurred by different compensatory mechanisms dependent on the pollutant composition. For example, O(3)FA exposure led to reductions in both end-systolic and end-diastolic left ventricular (LV) volumes, whereas FACB exposure led an increase in end-diastolic LV volume. These same cardiac compensatory changes were largely abolished in Nppa KO mice following O(3)FA or FACB exposure. These results suggest that cardiac functional changes in response to air pollution exposure are strongly dependent on the pollutant constituents, especially related to O(3) and/or PM. Furthermore, ANP regulation appears to be crucial to these cardiac compensatory mechanisms induced by air pollution.

Topics: Air Pollutants; Animals; Atrial Natriuretic Factor; Body Weight; Bronchoalveolar Lavage Fluid; Gene Expression; Gene-Environment Interaction; Heart Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Natriuretic Peptide, C-Type; Organ Size; Ozone; Particulate Matter; Pneumonia; Protein Precursors; Ventricular Function, Left; Ventricular Function, Right

We have previously shown that isoprenaline-induced cardiac hypertrophy causes significant changes in the expression of cytochromes P450 (CYP) and soluble epoxide hydrolase (sEH) genes. Therefore, it is important to examine whether the inhibition of sEH by 1-(1-methanesulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) will protect against isoprenaline-induced cardiac hypertrophy.. Male Sprague-Dawley rats were treated with TUPS (0.65 mg kg(-1) day(-1), p.o.), isoprenaline (5 mg kg(-1) day(-1), i.p.) or the combination of both. In vitro H9c2 cells were treated with isoprenaline (100 μM) in the presence and absence of either TUPS (1 μM) or 11,12 EET (1 μM). The expression of hypertrophic, fibrotic markers and different CYP genes were determined by real-time PCR.. Isoprenaline significantly induced the hypertrophic, fibrotic markers as well as the heart to body weight ratio, which was significantly reversed by TUPS. Isoprenaline also caused an induction of CYP1A1, CYP1B1, CYP2B1, CYP2B2, CYP4A3 and CYP4F4 gene expression and TUPS significantly inhibited this isoprenaline-mediated effect. Moreover, isoprenaline significantly reduced 5,6-, 8,9-, 11,12- and 14,15-EET and increased their corresponding 8,9-, 11,12- and 14,15-dihydroxyeicosatrienoic acid (DHET) and the 20-HETE metabolites. TUPS abolished these isoprenaline-mediated changes in arachidonic acid (AA) metabolites. In H9c2 cells, isoprenaline caused a significant induction of ANP, BNP and EPHX2 mRNA levels. Both TUPS and 11,12-EET significantly decreased this isoprenaline-mediated induction of ANP, BNP and EPHX2.. TUPS partially protects against isoprenaline-induced cardiac hypertrophy, which confirms the role of sEH and CYP enzymes in the development of cardiac hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Cardiotonic Agents; Cell Line; Cytochrome P-450 Enzyme System; Drug Antagonism; Epoxide Hydrolases; Gene Expression Regulation; Heart; Humans; Isoproterenol; Kidney; Liver; Natriuretic Peptide, Brain; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction

Mouse parathyroid hormone-related peptide (PTHrP) is a peptide hormone consisting of 139 amino acids. It is target of proteolysis resulting in circulation of N- and C-terminal peptides. C-terminal PTHrP peptides act in a PTH/PTHrP receptor-independent way with a minimal peptide sequence required to exert these effects covering amino acids 107-111 also known as osteostatin. Although effects of osteostatin on cardiac hypertrophy have been described in vitro, the in vivo relevance of these findings remained to be defined. The study was performed in two experimental series. In the first series, mice were randomly distributed into placebo or treatment group (each n=7) and osteostatin was administered via osmotic minipumps. In the second series, mice underwent a banding of the thoracic aorta to induce pressure overload and were again randomly distributed into placebo or treatment group (n=9 each). After 14 days, mice were anaesthetized and cardiac function, ECG, and cardiac hypertrophy were determined. Osteostatin increased the expression of ANF and reduced P-wave duration with little effects on cardiac performance in mice without pressure overload. In TAC banded mice, however, osteostatin significantly reduced TAC-induced loss of body weight, induced right ventricular hypertrophy, and reduced P-wave duration again. In osteostatin treated mice with pressure overload, the protein kinase C-dependent phosphorylation of connexin 43 was preserved. In summary, osteostatin attenuated pressure-overload-dependent loss of body weight without affecting left ventricular hypertrophy or left ventricular function but preserved atrial conduction. Osteostatin exerts moderate cardioprotective effects in mice under hemodynamic stress.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Connexin 43; Heart; Male; Mice; Mice, Inbred C57BL; Parathyroid Hormone-Related Protein; Peptide Fragments; Phosphorylation; RNA, Messenger; Ventricular Function, Left

To identify cardiac mechanisms that contribute to adaptation to high altitudes in Tibetan antelope (Pantholops hodgsonii).. 9 male Tibetan antelope and 10 male Tibetan sheep (Ovis aries).. Tibetan antelope and Tibetan sheep inhabiting a region with an altitude of 4,300 m were captured, and several cardiac variables were measured. Expression of genes for atrial natriuretic peptide, brain natriuretic peptide, and calcium-calmodulin-dependent protein kinase II δ was measured via real-time PCR assay.. Ratios of heart weight to body weight for Tibetan antelope were significantly greater than those of Tibetan sheep, but ratios of right-left ventricular weights were similar. Mean ± SD baseline heart rate (26.33 ± 6.15 beats/min) and systolic arterial blood pressure (97.75 ± 9.56 mm Hg) of antelope were significantly lower than those of sheep (34.20 ± 6.57 beats/min and 130.06 ± 17.79 mm Hg, respectively). The maximum rate of rise in ventricular pressure in antelope was similar to that in Tibetan sheep, but after exposure to air providing a fraction of inspired oxygen of 14.6% or 12.5% (ie, hypoxic conditions), the maximum rate of rise in ventricular pressure of the antelope increased significantly to 145.1% or 148.1%, respectively, whereas that of the sheep decreased to 68.4% or 70.5%, respectively. Gene expression of calcium-calmodulin-dependent protein kinase II δ and atrial natriuretic peptide, but not brain natriuretic peptide, in the left ventricle of the heart was significantly higher in antelope than in sheep.. Hearts of the Tibetan antelope in this study were well adapted to high-altitude hypoxia as shown by higher heart weight ratios, cardiac contractility in hypoxic conditions, and expression of key genes regulating cardiac contractility and cardiac hypertrophy, compared with values for Tibetan sheep.

Topics: Adaptation, Biological; Altitude; Animals; Antelopes; Atrial Natriuretic Factor; Blood Cell Count; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Heart; Hemoglobins; Male; Natriuretic Peptide, Brain; Organ Size; Real-Time Polymerase Chain Reaction; Sheep; Tibet; Ventricular Pressure

The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear.. Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca(2+) transient in response to isoprenaline when stimulated concomitantly with angiotensin II.. The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart.

Topics: Angiotensin II; Animals; Animals, Newborn; Atrial Natriuretic Factor; bcl-2-Associated X Protein; Blood Pressure; Body Weight; Calcium; Cardiotonic Agents; Gene Expression; Heart; Immunoblotting; In Vitro Techniques; Isoproterenol; Mice; Mice, Knockout; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Reverse Transcriptase Polymerase Chain Reaction; Sarcomeres; Signal Transduction; Time Factors; Vasoconstrictor Agents

Cardiac hypertrophy, a major determinant of heart failure, is associated with heat shock proteins (HSPs). HSP75 has been reported to protect against environmental stresses; however, its roles in cardiac hypertrophy remain unclear. Here, we generated cardiac-specific inducible HSP75 transgenic mice (TG) and cardiac hypertrophy was developed at 4 weeks after aortic banding in TG mice and wild-type littermates. The results revealed that overexpression of HSP75 prevented cardiac hypertrophy and fibrosis as assessed by heart weight/body weight ratio, heart weight/tibia length ratio, echocardiographic and hemodynamic parameters, cardiomyocyte width, left ventricular collagen volume, and gene expression of hypertrophic markers. Further studies showed that overexpression of HSP75 inhibited the activation of TAK/P38, JNK, and AKT signaling pathways. Thus, HSP75 likely reduces the hypertrophy and fibrosis induced by pressure overload through blocking TAK/P38, JNK, and AKT signaling pathways.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Cell Size; Collagen; Fibrosis; Heart Ventricles; HSP90 Heat-Shock Proteins; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle Cells; Myocardium; Myosin Heavy Chains; Organ Size; Phosphorylation; Recombinant Proteins; Transcription, Genetic; Ventricular Pressure; Ventricular Remodeling

We investigated the effects of tolvaptan, a vasopressin V(2)-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.. CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220-240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.. Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.. Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin-angiotensin-aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Atrial Natriuretic Factor; Benzazepines; Blood Pressure; Body Weight; Chlorides; Disease Models, Animal; Diuretics; Dogs; Furosemide; Heart Failure; Kidney; Male; Potassium; Renin; Sodium; Tolvaptan

atrial natriuretic peptide (ANP) is released from the heart in response to hypoxia and helps mitigate the development of pulmonary hypertension. However, the mechanism of hypoxia-induced ANP release is not clear. The cardiac atria are the primary source of ANP secretion under normal conditions, but right ventricular ANP expression is markedly up-regulated during adaptation to hypoxia. We sought to better understand mechanisms of cardiac ANP release during adaptation to hypoxia.. we measured hypoxia-induced ANP release from isolated perfused rat hearts obtained from normoxia and hypoxia-adapted rats before and after removal of the atria.. in both normoxia- and hypoxia-adapted hearts, ANP levels in the perfusate increased within 15 min of hypoxia. Hypoxia-induced ANP release was greater from hypoxia-adapted than normoxia-adapted hearts. Baseline and hypoxia-induced ANP release were considerably greater with the atria intact (213±29 to 454±62 and 281±26 to 618±87 pg/ml for normoxia- and hypoxia-adapted hearts respectively, P<0.001 for both) than with atria removed (94±17 to 131±32 and 103±26 to 201±55 pg/ml, respectively, P<0.002 for both). Hypoxia-induced ANP release was reduced over 80% by removing the atria in both normoxia- and in hypoxia-adapted hearts. Acute hypoxia caused a transient increase in lactate release and reductions in pH and left ventricular generated force, but no differences in pH or left ventricular generated force were seen between normoxia- and hypoxia-adapted rats.. we conclude that the right ventricle is not a major source of cardiac ANP release in normoxia- or hypoxia-adapted rats.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Calcium; Glucose; Heart Atria; Hydrogen-Ion Concentration; Hypertrophy, Right Ventricular; Hypoxia; Lactic Acid; Male; Myocardium; Perfusion; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Ventricular Dysfunction, Left; Ventricular Pressure

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Body Weight; Cardiomegaly; Eating; Echocardiography; Glucosyltransferases; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Glycoproteins; Hemodynamics; Hypoglycemic Agents; Lipoprotein Lipase; Male; Myofibrils; Natriuretic Peptide, Brain; Proteasome Endopeptidase Complex; Protein Kinases; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones; TOR Serine-Threonine Kinases; UTP-Glucose-1-Phosphate Uridylyltransferase

Extracellular osmolarity is known as an important factor for the regulation of natriuretic peptide receptors (NPRs). We investigated the intra-renal osmoregulation of NPRs using renal medullectomized rats with bromoethylamine hydrobromide (BEA, 200mg/kg). The administration of BEA caused the decreased food intake and body weight. Water intake was decreased on the first day and then increased from the second day. Urine volume was persistently increased from the first day and free water clearance was also increased from the second day. Urinary excretions of sodium and potassium were decreased on the second day and then recovered to control level. Plasma levels of atrial natriuretic peptide (ANP) and Dendroaspis natriuretic peptide (DNP) in BEA-treated rats were not different from control rats. The inactive renin was increased. The maximum binding capacities of (125)I-ANP as well as (125)I-DNP decreased in glomeruli and medulla of BEA-treated rat kidneys but the binding affinity was not changed. In renal cortex, the gene expressions of ANP, NPR-A, and NPR-B were not changed but that of NPR-C decreased. In renal medulla, the gene expressions of NPR-A, -B, and -C decreased without change in ANP mRNA. Both renal medullary osmolarity and sodium concentration by BEA treatment were lower than those in control kidney. The cGMP concentrations in renal medulla and urine in BEA-treated rats were higher than those in control rats. These results suggest that the increased cGMP production may be partly involved in the decrease in NPRs mRNA expression and their binding capacities by BEA-induced medullectomy.

Topics: Animals; Atrial Natriuretic Factor; Binding Sites; Body Weight; Cyclic GMP; Eating; Elapid Venoms; Ethylamines; Intercellular Signaling Peptides and Proteins; Kidney; Male; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Water-Electrolyte Balance

Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular mortality and is commonly caused by hypertension. In rodents, transverse aortic constriction (TAC) is a model regularly employed in mechanistic studies of the response of the LV to pressure overload. We previously reported that inbred strains of male mice manifest different cardiac responses to TAC, with C57BL/6J (B6) developing LV dilatation and impaired contractility and 129S1/SvImJ (129) males displaying concentric LVH. In the present study, we investigated sex and parent-of-origin effects on the response to TAC by comparing cardiac function, organ weights, expression of cardiac hypertrophy markers, and histology in female B6 and female 129 mice and in F1 progeny of reciprocal crosses between B6 and 129 mice (B6129F1 and 129B6F1). Five weeks after TAC, heart weight increased to the greatest extent in 129B6F1 mice and the least extent in 129 and B6129F1 mice. Female 129B6F1 and B6 mice were relatively protected from the increase in heart weight that occurs in their male counterparts with pressure overload. The response to TAC in 129 consomic mice bearing the B6 Y chromosome resembled that of 129 rather than 129B6F1 mice, indicating that the B6 Y chromosome does not account for the differences in the reciprocal cross. Our results suggest that susceptibility to LVH is more complex than simple Mendelian inheritance and that parental origin effects strongly impact the LV response to TAC in these commonly used inbred strains.

Topics: Animals; Aortic Diseases; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Disease Models, Animal; Epigenesis, Genetic; Female; Fibrosis; Genes, Y-Linked; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Myosin Heavy Chains; Natriuretic Peptide, Brain; Organ Size; Sex Factors; Species Specificity

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may prevent development of heart failure through alterations in cardiac phospholipids that favorably impact inflammation and energy metabolism. A high-fat diet may block these effects in chronically stressed myocardium. Pathological left ventricle (LV) hypertrophy was generated by subjecting rats to pressure overload by constriction of the abdominal aorta. Animals were fed: (1) standard diet (10% of energy from fat), (2) standard diet with EPA+DHA (2.3% of energy intake as EPA+DHA), (3) high fat (60% fat); or (4) high fat with EPA+DHA. Pressure overload increased LV mass by approximately 40% in both standard and high-fat diets without fish oil. Supplementation with fish oil increased their incorporation into cardiac phospholipids, and decreased the proinflammatory fatty acid arachidonic acid and urine thromboxane B(2) with both the standard and high-fat diet. Linoleic acid and tetralinoloyl cardiolipin (an essential mitochondrial phospholipid) were decreased with pressure overload on standard diet, which was prevented by fish oil. Animals fed high-fat diet had decreased linoleic acid and tetralinoloyl cardiolipin regardless of fish oil supplementation. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-beta and atrial natriuetic factor). These beneficial effects of fish oil were absent in animals on the high-fat diet. In conclusion, whereas treatment with EPA+DHA prevented tetralinoloyl cardiolipin depletion, LV hypertrophy, and abnormal genes expression with pressure overload, these effects were absent with a high-fat diet.

Topics: Animals; Aorta, Abdominal; Arachidonic Acid; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiolipins; Cardiotonic Agents; Constriction; Dietary Fats; Docosahexaenoic Acids; Echocardiography; Eicosapentaenoic Acid; Fish Oils; Hypertrophy, Left Ventricular; Linoleic Acid; Male; Myocardium; Myosin Heavy Chains; Organ Size; Phospholipids; Rats; Rats, Wistar; Thromboxane B2

Whether a high plasma aldosterone concentration induced by strict salt restriction promotes cardiac remodeling remains controversial. Male Sprague-Dawley rats at 10weeks of age were given normal salt (NS) (1.5% NaCl) or low salt (LS) (0.05% NaCl) diets. Each animal underwent aortocaval fistula creation for volume-overloaded heart failure or sham surgery. All rats with a fistula received either vehicle or a non-hypotensive dose of spironolactone (200mg/kg/day) by gavage. Two weeks later, the LS diet significantly increased the plasma aldosterone level in the sham-operated and fistula-created rats (2677+/-662pg/ml and 2406+/-422pg/ml) compared with that in rats given the NS diet (518+/-18pg/ml and 362+/-45pg/ml, respectively). In sham-operated rats, the difference in plasma aldosterone level did not affect the extent of myocardial fibrosis (1.8+/-0.1% with LS diet vs. 1.5+/-0.3% with NS diet). However, the increase in myocardial fibrosis in fistula-created rats was more prominent with the LS diet than with the NS diet (4.7+/-0.3% vs. 3.4+/-0.1%). In addition, the fistula-created rats on the LS diet expressed significantly increased oxidative stress and transforming growth factor-beta compared with those on the NS diets (P<0.05). These increases in the fistula-created rats on the LS diet were significantly suppressed by the non-hypotensive dose of spironolactone (P<0.05). These results suggest that increased plasma aldosterone level with strict salt restriction activated the mineralocorticoid receptor signaling in volume-overloaded condition, resulting in increased myocardial fibrosis.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Body Weight; Cell Size; Contraindications; Diet, Sodium-Restricted; Endomyocardial Fibrosis; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Signal Transduction; Spironolactone; Transforming Growth Factor beta; Tyrosine; Ventricular Remodeling

Topics: Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Diabetes Mellitus; Dietary Fats; Energy Metabolism; Homeostasis; Humans; Lipid Peroxidation; Mitochondria; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Signal Transduction

Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Myosins; Cardiac Output; Cardiomegaly; Caspase 3; Cell Size; Chronic Disease; Collagen; Disease Models, Animal; Hypertrophy; Hypoxia; Male; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Myosin Light Chains; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Research Design; RNA, Messenger; Ventricular Dysfunction, Left; Ventricular Pressure; Ventricular Remodeling

Torasemide is a long-acting loop diuretic that combines the effects of both furosemide and spironolactone. It has been reported that torasemide may block the renin-angiotensin-aldosterone system and therefore it might attenuate myocardial remodeling accompanied by left ventricular dysfunction. However, nothing is known about the effect of torasemide on myocardial remodeling in a rat model in which myosin-induced experimental autoimmune myocarditis might develop into dilated cardiomyopathy. Experimental autoimmune myocarditis was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, we investigated the effects of torasemide on metabolic and neurohumoral parameters, cardiac fibrosis and remodeling in experimental autoimmune myocarditis rats. Diuresis was increased dose-dependently by torasemide; the urinary potassium and sodium excretion was significantly decreased and increased, respectively. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by torasemide treatment in a dose-dependent manner. The area of fibrosis, myocyte size and the myocardial protein levels of transforming growth factor-beta1, collagen III, and aldosterone synthase were significantly decreased, and the sarcoplasmic reticulum Ca2+ ATPase2 protein level was significantly increased by torasemide treatment. Moreover, the plasma levels of angiotensin II and aldosterone were increased and atrial natriuretic peptide was decreased in a dose-dependent manner. Our results indicate that torasemide treatment significantly improved left ventricular function and ameliorated the progression of cardiac remodeling beyond its renal effects in rats with chronic heart failure after experimental autoimmune myocarditis.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomyopathy, Dilated; Collagen Type III; Disease Progression; Diuretics; Heart Failure; Male; Matrix Metalloproteinase 9; Myocarditis; Myocardium; Rats; Rats, Inbred Lew; RNA, Messenger; Sulfonamides; Torsemide; Transforming Growth Factor beta1; Ventricular Function, Left

Diminished constriction of arteries and veins following exposure to microgravity or bed rest is associated with a reduced ability to augment peripheral vascular resistance (PVR) and stroke volume during orthostasis. We tested the hypothesis that small mesenteric arteries and veins, which are not exposed to large pressure shifts during simulated microgravity via head-down tail suspension (HDT), will exhibit decrements in adrenergic constriction after HDT in rats. Small mesenteric arteries and veins from control (Con; n = 41) and HDT (n = 35) male Sprague-Dawley rats were studied in vitro. Vasoactive responsiveness to norepinephrine (NE) in arteries (10(-9) to 10(-4) M) and veins (pressure-diameter responses from 2 to 12 cmH(2)O after incubation in 10(-6) or 10(-4) M NE) were evaluated. Plasma concentrations of atrial (ANP) and NH(2)-terminal prohormone brain (NT-proBNP) natriuretic peptides were also measured. In mesenteric arteries, sensitivity and maximal responsiveness to NE were reduced with HDT. In mesenteric veins there was a diminished venoconstriction to NE at any given pressure in HDT. Plasma concentrations of both ANP and NT-proBNP were increased with HDT, and maximal arterial and venous constrictor responses to NE after incubation with 10(-7) M ANP or brain natriuretic peptide (BNP) were diminished. These data demonstrate that, in a vascular bed not subjected to large hydrodynamic differences with HDT, both small arteries and veins have a reduced responsiveness to adrenergic stimulation. Elevated levels of circulating ANP or NT-proBNP could adversely affect the ability of these vascular beds to constrict in vivo and conceivably could alter the intrinsic constrictor properties of these vessels with long-term exposure.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Capillaries; Head-Down Tilt; Male; Mesenteric Arteries; Mesenteric Veins; Muscle, Smooth, Vascular; Natriuretic Peptide, Brain; Norepinephrine; Organ Size; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Stimulation, Chemical; Sympathetic Nervous System; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Weightlessness Simulation

Atrial natriuretic peptide (ANP) exerts beneficial effects on the cardiovascular system in part by exerting antioxidant activity. Given that oxidant stress is a key cause of endothelial dysfunction in diabetes, we investigated whether ANP improves endothelial function in rats with diabetes. Rats were injected with streptozotocin (55 mg/kg iv) to induce type 1 diabetes or the citrate vehicle as controls (n=12). After 4 weeks the diabetic rats were treated with ANP (10 pmol/kg/min sc, n=12) or the antioxidant tempol (1.5 mmol/kg/day sc, n=11), both by osmotic minipump, ramipril (1 mg/kg per day in the drinking water) or remained untreated (n=11). After a further 4 weeks, anaesthetised rats were killed by exsanguination and the thoracic aortae collected for examination of vascular activity and measurement of superoxide generation. Diabetic rats showed elevated plasma glucose concentration (45+/-3 mM) compared to controls (10+/-1 mM) and this was not affected by ANP (43+/-3 mM), ramipril (41+/-2 mM) or tempol (43+/-2 mM). Endothelium-dependent relaxation ex vivo in response to acetylcholine was impaired in diabetic rats (Rmax=66+/-4%) compared to control rats (Rmax=94+/-1%) but treatment with ANP (Rmax=80+/-4%), ramipril (Rmax=88+/-2%) or tempol (Rmax=81+/-5%) significantly improved those responses. Relaxant responses to the endothelium-independent vasodilator sodium nitroprusside were enhanced by treatment of diabetic rats with ANP or ramipril and their combination; but not by tempol. Superoxide generation was significantly elevated in aorta from untreated diabetic rats (649+/-146% of control). In diabetic rats, superoxide generation was significantly attenuated by ANP (to 229+/-78%) or tempol (to 186+/-64%). This study demonstrates that ANP improves vascular oxidant stress in concert with endothelial function, independent of any effect on plasma glucose levels. These studies may lead to new therapies, based on natriuretic peptide and/or antioxidant approaches, for ameliorating the vascular complications of diabetes.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cyclic N-Oxides; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelium, Vascular; Male; Muscle Relaxation; NADPH Oxidases; Nitric Oxide Synthase Type III; Nitroprusside; Ramipril; Rats; Rats, Sprague-Dawley; Spin Labels; Superoxides; Vasodilator Agents

Downregulation of the renal glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) during liver cirrhosis may allow activation of the mineralocorticoid receptor (MR) by glucocorticoids and contribute to sodium retention. We tested this hypothesis in male Wistar rats with decompensated liver cirrhosis and ascites 7 wk after bile duct ligation (BDL). Renal 11beta-HSD-2 mRNA, protein, and activity were significantly decreased in decompensated rats. The urinary Na(+)/K(+) ratio was reduced by 40%. Renal epithelial sodium channel (ENaC) mRNA and immunostaining were only slightly affected. Complete metabolic studies, including fecal excretion, showed that the BDL rats had avid renal sodium retention. Treatment of the BDL rats with dexamethasone suppressed endogenous glucocorticoid production, normalized total sodium balance and renal sodium excretion, and reduced ascites formation to the same degree as direct inhibition of MR with K-canrenoate. Total potassium balance was negative in the BDL rats, whereas renal potassium excretion was unchanged. In the distal colon, expression of ENaC was increased in BDL rats. Fecal potassium excretion was increased in cirrhotic rats, and this was corrected by treatment with K-canrenoate but not dexamethasone. We conclude that development of sodium retention and decompensation in cirrhotic rats is associated with downregulation of renal 11beta-HSD-2 activity and inappropriate activation of renal sodium reabsorption by endogenous glucocorticoids. In addition, the overall potassium loss in the BDL model is due to increased fecal potassium excretion, which is associated with upregulation of ENaC in distal colon.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Atrial Natriuretic Factor; Bile Ducts; Blotting, Western; Body Weight; Canrenoic Acid; Dexamethasone; Epithelial Sodium Channels; Feces; Glucocorticoids; Kidney; Liver Cirrhosis; Male; Mineralocorticoid Receptor Antagonists; Nephrons; Nuclease Protection Assays; Organ Size; Potassium; Rats; Rats, Wistar; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Renin; Renin-Angiotensin System; Sodium

Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure.. Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy.. Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.

Topics: Administration, Oral; Animals; Atrial Natriuretic Factor; Body Weight; Cytokines; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Gene Expression; Heart Failure; Heart Rate; Myocardium; Organ Size; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; PPAR gamma; Protein Kinases; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; RNA, Messenger; Stroke Volume; TOR Serine-Threonine Kinases; Ventricular Function, Left; Ventricular Remodeling

Relationships among five markers of volume status - cardio-thoracic ratio (CTR), atrial natriuretic peptide (ANP), inferior vena cava diameter at quiet expiration (IVCe), blood volume change (Delta BV/TUF) during ultrafiltration and filtration coefficients of microvasculature (Lpst) - were investigated. Fifty stable hemodialysis patients were enrolled. The CTR was measured before hemodialysis (HD), and ultrasonic measurement of IVCe and sample collection for ANP were performed shortly after HD. Lpst and Delta BV/TUF were calculated using a CRIT-LINE monitor. Overhydrated patients determined by each marker (OVERctr, OVERivc, OVERanp, OVERlp and OVERbv) were compared. The agreement of volume status determined by each marker was assessed by kappa value, and the sensitivity and specificity of each marker to distinguish overhydrated patients were analyzed by a receiver-operating characteristic (ROC) curve. IVCe, ANP, Delta BV/TUF and Lpst, significantly correlated with each other. The correlation coefficients of Lpst with IVCe, ANP and Delta BV/TUF were higher than the others. The kappa value between ANP and Lpst was the highest. OVERanp was the highest, then OVERlp, OVERivc and OVERbv, in this order. The OVERlp and OVERivc patients were completely included in OVERanp. All patients, except one OVERbv patient, were included in OVERlp. The relatively high distinguishing ability of Lpst was demonstrated by ROC analysis. These results suggest that the determination of overhydration solely by ANP was an overestimation and by Delta BV/TUF was an underestimation. The relatively high correlation coefficients of Lpst with other markers, as well as its distinguishing ability, suggest that Lpst fluctuates in close relation to other markers.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Volume; Body Weight; Echocardiography; Extracellular Fluid; Female; Filtration; Heart; Humans; Male; Middle Aged; Radiography; Renal Dialysis; ROC Curve; Sensitivity and Specificity; Thorax; Vena Cava, Inferior

To test the effect of dehydration on brain atrial natriuretic peptide (ANP) concentrations in areas important to salt appetite, water balance and cardiovascular regulation, we subjected rats to dehydration and rehydration and measured ANP concentration in 18 brain areas, as well as all relevant peripheral parameters. Water deprivation decreased body weight, blood pressure, urine volume, and plasma ANP, while it increased urine and plasma osmolality, angiotensin II, and vasopressin. ANP greatly increased in 17 and 18 brain areas (all cut cerebral cortex) by 24 h. Rehydration for 12 h corrected all changes evoked by dehydration, including elevated ANP levels in brain. We conclude that chronic dehydration results in increased ANP in brain areas important to salt appetite and water balance. These results support a role for ANP as a neuroregulatory substance that participates in salt and water balance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Brain; Cerebral Cortex; Dehydration; Male; Osmolar Concentration; Rats; Rats, Wistar; Thirst; Time Factors; Urine; Vasopressins; Water-Electrolyte Balance

The sympatholytic properties of atrial natriuretic peptide (ANP) contribute to its vasodilatory and natriuretic effects. High circulating catecholamine levels, along with renal dysfunction, present in proANP gene-disrupted (-/-) mice are thought to contribute to the hypertension characteristic of this model. To further understand the mechanism by which the absence of ANP leads to stimulation of sympathetic activity we measured tyrosine hydroxylase expression in mice with and without ANP. The adrenal and prevertebral ganglionic expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine production, was significantly increased in ANP -/- mice. ANP's sympatholytic properties include the depression of ganglionic and adrenal TH expression and catecholamine production. Thus, these results suggest that the absence of ANP's sympatholytic effects is not completely compensated for in ANP -/- mice. In addition, mice devoid of ANP display an increase in renal sympathetic nerve activity from birth through to adulthood which may lead to structural and/or functional changes in the early postnatal kidney that contribute to the hypertensive phenotype of ANP -/- mice. The over-activation of the sympathetic nervous system in mice lacking ANP confirms the important role of this peptide in the modulation of sympathetic nerve activity and its contribution to blood pressure homeostasis.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Body Weight; Catecholamines; Enzyme-Linked Immunosorbent Assay; Ganglia, Sympathetic; Gene Expression; Kidney; Male; Mice; Mice, Knockout; Mutation; Norepinephrine; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tyrosine 3-Monooxygenase

To investigate cardiomyocyte hypertrophy and hormonal profile in cardiac hypertrophy resulting from sequentially applied overloads.. We studied Sprague-Dawley rats with renovascular hypertension (RV), where pressure overload predominates, or deoxycorticosterone acetate (DOCA)-salt (DS), where volume overload predominates, at 2 and 4 weeks of treatment, and the combination of both models in inverse sequence: RV 2 weeks/DS 2 weeks (RV2/DS2) and DS 2 weeks/RV 2 weeks (DS2/RV2), and their sham controls (Sh).. Blood pressure and cardiomyocyte diameter increased to a similar extent in RV and DS at 2 and 4 weeks and in combined models. Cardiomyocyte length increased remarkably in the DS4 group. Circulating atrial natriuretic peptide (ANP) was elevated in all hypertensive groups after 2 and 4 weeks. The RV2/DS2 group showed similar plasma ANP levels to RV4, but DS2/RV2 exhibited a three-fold increase in ANP levels (P<0.001 versus Sh4, DS2 and DS4). Atrial ANP mRNA remained unchanged in all groups. DS treatment alone or in combination with RV increased left ventricular ANP mRNA, meanwhile only RV treatment increased left ventricular B-type natriuretic peptide (BNP) mRNA. Ventricular ANP expression levels, but not circulating ANP, correlated with both cardiomyocyte diameter (r=0.859, P<0.01) and length (r=0.848, P<0.01). Renal expression of natriuretic peptide receptor C (NPR-C) was unchanged in RV4 but decreased to a similar extent in the DS4 group and both combined treatments.. Morphometric patterns seem to be more related to the paracrine function of the heart than to the secretion of ANP and the endocrine function. Plasma ANP in the DS2/RV2 group could indicate a different evolution of the remodelling process. ANP expression seems to be a more sensitive marker for volume than for pressure overload.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Body Weight; Cardiomegaly; DNA Primers; Male; Myocardium; Organ Size; Polymerase Chain Reaction; Pressure; Radioimmunoassay; Rats; Rats, Sprague-Dawley

Although studies have shown that endothelial nitric oxide synthase (eNOS) homozygous knockout mice (eNOS-/-) develop left ventricular (LV) hypertrophy, well compensated at least to 24 wks, uncertainty still exists as to the cardiac functional and molecular mechanistic consequences of eNOS deficiency at later time-points. To bridge the gap in existent data, we examined whole hearts from eNOS-/- and age-matched wild-type (WT) control mice ranging in age from 18 to 52 wks for macroscopic and microscopic histopathology, LV mRNA and protein expression using RNA Dot blots and Western blots, respectively, and LV function using isolated perfused work-performing heart preparations. Heart weight to body weight (HW/BW in mg/g) ratio increased significantly as eNOS-/- mice aged (82.2%, P < 0.001). Multi-focal replacement fibrosis and myocyte degeneration/death were first apparent in eNOS-/- mouse hearts at 40 wks. Progressive increases in LV atrial natriuretic factor (ANF) and alpha-skeletal actin mRNA levels both correlated significantly with increasing HW/BW ratio in aged eNOS-/- mice (r = 0.722 and r = 0.648, respectively; P < 0.001). At 52 wks eNOS-/- mouse hearts exhibited basal LV hypercontractility yet blunted beta adrenergic receptor (betaAR) responsiveness that coincided with a significant reduction in the LV ratio of phospholamban to sarcoplasmic reticulum Ca2+-ATPase-2a protein levels and was preceded by a significant upregulation in LV steady-state mRNA and protein levels of the 28 kDa membrane-bound form of tumor necrosis factor-alpha. We conclude that absence of eNOS in eNOS-/- mice results in a progressive concentric hypertrophic cardiac phenotype that is functionally compensated with decreased betaAR responsiveness, and is associated with a potential cytokine-mediated alteration of calcium handling protein expression.

Topics: Actins; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Gene Expression Regulation, Enzymologic; Gene Silencing; Heart Rate; Heart Ventricles; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Size; Perfusion; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Urodilatin (URO) is a member of the natriuretic family, cleaved by the kidney, which acts as a paracrine hormone in the regulation of natriuresis and diuresis. In newborn infants the excretion of urodilatin and its biological effects have not been explored.. We measured urinary URO excretion, by direct RIA (radioimmunoassay), as well as its correlation to neonatal body weight loss, and sodium homeostasis in 30 full-term newborn infants on the 4th day of life.. The URO excretion, estimated as URO:creatinine ratio, was significantly correlated to sodium excretion.. These data show that in full-term newborn infants the mechanisms that control synthesis, excretion and signal transduction of URO are developed and that URO contributes to natriuresis regulation.

Topics: Apgar Score; Atrial Natriuretic Factor; Body Weight; Creatinine; Homeostasis; Humans; Infant, Newborn; Natriuresis; Peptide Fragments; Sodium; Weight Loss

Preferential and specific down-regulation of genes involved in fatty acid (FA) uptake and metabolism is considered a hallmark of severe hypertrophic remodeling and progression to cardiac failure. Therefore, we investigated the time course of changes in cardiac metabolic gene expression (1) in mice subjected to regional myocardial infarction (MI) for 4 days, 1 month, or 3 months and (2) in mice overexpressing calcineurin (Cn) which initially develop concentric hypertrophy progressing after the age of 4 weeks to dilated cardiomyopathy and failure. In both models, hypertrophy was characterized by increased expression of beta-myosin heavy chain protein and atrial natriuretic factor mRNA, indicative of marked structural remodeling. Fractional shortening progressively decreased from 31% to 15.1% and 3.7% 1 and 3 months after MI, respectively. One month post-MI, the expression of several metabolic genes, i.e., acyl-CoA synthetase (-50%), muscle-type carnitine palmitoyl transferase 1 (-37%) and citrate synthase (-28%), was significantly reduced in the surviving myocardium. Despite overt signs of cardiac failure 3 months post-MI, the expression of these genes had returned to normal levels. In hearts of both 4- and 6-week-old Cn mice, genes involved in both FA and glucose metabolism and mitochondrial citrate synthase were down-regulated, reflecting an overall decline in metabolic gene expression, rather than a specific and preferential down-regulation of genes involved in FA uptake and metabolism. These findings challenge the concept that specific and sustained down-regulation of genes involved in FA uptake and metabolism represents a hallmark of the development of cardiac hypertrophy and progression to failure.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Calcineurin; Cardiomegaly; Collagen Type I; Disease Progression; Down-Regulation; Echocardiography; Fatty Acids; Gene Expression; Heart; Heart Failure; Lipid Metabolism; Male; Mice; Myocardial Infarction; Myosin Heavy Chains; Organ Size; Oxidation-Reduction; Phenotype; RNA, Messenger

The treatment of deranged water homeostasis of hemodialysis (HD) patients needs focusing on an accurate assessment of dry weight (DW). However, the correct estimation of post-dialysis DW is still a problem. Echocardiography of inferior caval vein diameter (ICVD) was recently considered as a reliable technique to estimate DWs of HD patients, whereas conductivity measurements and biochemical parameters remain controversial. In this study, we aimed to compare the noninvasive methods estimating DW in HD patients.. We enrolled 60 patients: 30 hypervolemic (HV) (12 M, 18 F, with a mean age of 41.9 +/- 13.6 years, mean HD duration of 38 +/- 45 months) and 30 normovolemic (NV) patients (19 M, 11 F, with a mean age of 42.2 +/- 14 years, mean HD duration of 62 +/- 51.5 months) according to clinical sign and symptoms as well as the findings on chest x-ray. Furthermore, the DWs of patients were evaluated in post-HD period in terms of echocardiography parameters [ICVD and collapse index (CI) determined by Cheriex], plasma ANP (pANP) levels (RIA), and total body water (TBW) by bioelectrical impedance (BEI).. Forty-one of 60 patients had hypervolemic findings (68%) and 19 patients had normovolemia (32%) according to echocardiography parameters. Determination of "hypervolemia" by clinical acumen and pANP levels were not reliable, especially negative predictive values were lower as follows: sensitivity, specificity, positive predictive value, negative predictive values of clinical acumen and pANP levels: 63%, 69%, 87%, 50%, and 67%, 59%, 79%, 43%, respectively. TBW established by BEI did not correlate with ICVD and CI after HD (p > 0.05). The TBW of HV group according to echocardiography parameters was greater than NV group, but the difference was not statistically significant (27.4 +/- 6.6 kg versus 26.4 +/- 5.8 kg, respectively, p > 0.05). However, there was not any difference in the divided BSA values (1.58 +/- 0.2 kg/m2 versus 1.60 +/- 0.2 kg/m2, respectively, p > 0.05). Hypertension was seen in 37 (90%) of the echocardiographically hypervolemic patients, and the blood pressure was kept under control by previously given medication in only 7 (19%) patients. After the dry weight of the patients was corrected echocardiographically to normal limits, the blood pressure of 31 patients (86%) was normalized without antihypertensive treatment, but only in 6 patients remained the necessity of antihypertensive treatment. In addition, in 8 of 11 normotensive patients using antihypertensive drugs, assessment of their clinical and radiological findings showed normovolemia but ICVD > 11.5 mm/m2; however, the need for antihypertensive drugs disappeared when the ICVD reduced to 8-11.5/m2.. Clinical and radiological assessment, pANP levels, and TBW established by BEI appeared to be less valuable in interpreting DW's of HD patients. In accordance with the literature, echocardiography findings have proven to be reliable, and they are important noninvasive tools that can establish an effective and rational antihypertensive treatment.

Topics: Adult; Atrial Natriuretic Factor; Body Water; Body Weight; Diagnostic Techniques and Procedures; Electric Impedance; Female; Humans; Male; Renal Dialysis; Ultrasonography; Vena Cava, Inferior

Isoproterenol (ISO) infusion increases ANF-mRNA levels and control of ANF expression lies at the level of transcription. In neonatal cardiomyocytes, previous investigations determined that the -125 to -100 region of the rat ANF 5' flanking region contained cis-elements critical for control of ISO induced ANF transcription. However, it is unclear if these same cis-elements regulate ANF transcription in vivo. To examine this question, reporter plasmids containing the ANF 5' flanking/promoter region were injected directly into the left ventricle. Following a recovery period, osmotic pumps were implanted to infuse vehicle or ISO (0.2 or 2.0 mg/kg/d). ISO significantly (p < .05) increased the LV/BW ratio in a dose dependent, but not a time dependent manner. ISO significantly (p < .05) increased ANF reporter expression in both a dose-dependent and time dependent manner. Injections into the midwall of the LV or into the apex did not lead to significant differences in ISO-induced ANF reporter expression. Using site-specific mutations of ANF reporter constructs, comparisons were made of ISO induced ANF transcription in vitro in neonatal cardiomyocytes and in vivo in the adult heart. Cis-elements critical for ISO activation in cultured cardiomyocytes were not essential for the increased expression of the ANF reporters in vivo. The results indicate that distinct differences in ANF transcriptional regulation exist in vivo in the adult heart as compared with neonatal cardiomyocytes, and suggest the recruitment of other signaling pathways beyond adrenergic-receptor mediated pathways.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Consensus Sequence; Gene Expression Regulation; Genes, Reporter; Heart Ventricles; Isoproterenol; Male; Myocytes, Cardiac; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; RNA, Messenger

Hepatitis C virus (HCV) has been reported to be associated with cardiomyopathy. However, the mechanism of cardiomyopathy in chronic HCV infection is still unclear. Therefore, we investigate the development of cardiomyopathy in mice transgenic for the HCV-core gene. After the age of 12 months, mice developed cardiomyopathy that appeared as left ventricular dilatation, and systolic and diastolic dysfunction assessed by Doppler echocardiography. Histologically, hypertrophy of cardiomyocytes, cardiac fibrosis, disarray and scarcity of myofibrils, vacuolization and deformity of nuclei, myofibrillar lysis, streaming of Z-bands, and an increased number of bizarre-shaped mitochondria were found in HCV-core transgenic mice. These histological changes are just consistent with cardiomyopathy. In conclusion, the HCV-core protein directly plays an important role in the development of cardiomyopathy.

Topics: Actin Cytoskeleton; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography, Doppler; Fibrosis; Gene Expression Regulation, Viral; Hepacivirus; Hepatitis C; Hypertrophy, Left Ventricular; Male; Mice; Mice, Transgenic; Mitochondria, Heart; Myocarditis; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; NF-kappa B; Organ Size; RNA, Messenger; RNA, Viral; Transcription Factor AP-1; Ventricular Dysfunction, Left; Viral Core Proteins

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.

Topics: Acetylcholine; Actins; Animals; Atrial Natriuretic Factor; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Guanylate Cyclase; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molsidomine; Muscle, Smooth; Oxadiazoles; Piperazines; Pulmonary Artery; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Systole; Vasodilation; Vasodilator Agents

The aim of this research was to investigate the structural, functional, and molecular features of the remodeling heart in prior swim-trained infarcted rats.. Physical exercise training is a known protective factor against cardiovascular morbidity and mortality. The structural and molecular aspects underlying this protection in the remodeling heart have not been investigated.. After seven weeks of swimming exercise training, rats underwent surgical ligation of the left coronary artery followed by a four-week sedentary period. Untrained control rats underwent the same surgical protocol. Left ventricular function was assessed by echocardiography four weeks after infarction, and hearts were sampled for histological and molecular analysis. Ribonucleic acid from the surviving left ventricle was analyzed by complementary deoxyribonucleic acid arrays followed by Northern blotting or quantitative reverse transcription polymerase chain reaction of selected messenger ribonucleic acids (mRNAs).. Scar area was 1.6-fold smaller (p = 0.0002), arteriolar density was 1.7-fold higher (p = 0.0002), and left ventricular shortening fraction was 1.9-fold higher (p = 0.003) in the exercise-trained compared with sedentary hearts. Eleven genes whose expression level varied by at least +/-1.5-fold distinguished the prior exercised rats from their sedentary counterparts. Compared with sedentary, the exercised hearts displayed 9- and 2.4-times lower levels of atrial natriuretic peptide and aldolase mRNA (p = 0.03 and 0.04, respectively), and a 2.7- and 1.9-fold higher abundance of cytochrome c-oxidase and fatty acid binding protein, respectively (p < 0.03, each).. Swimming exercise training before acute myocardial infarction reduces scar size, increases arteriole density, and manifests adaptation of stress- and energy-metabolism-related genes that may contribute to the improved heart function observed during remodeling.

Topics: Adenosine Triphosphatases; Animals; Atrial Natriuretic Factor; Body Weight; Disease Models, Animal; Electron Transport Complex IV; Exercise Therapy; Gene Expression Profiling; Gene Expression Regulation; Heart Ventricles; Male; Models, Cardiovascular; Myocardial Contraction; Myocardial Infarction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stroke Volume; Ventricular Function, Left

Lower mortality rates among women with chronic heart failure than among men may depend in part on the action of female sex hormones, especially estrogens. The biological effects of estrogens are mediated by 2 distinct estrogen receptor (ER) subtypes (ERalpha and ERbeta). The present study was undertaken to determine the role of ERbeta in the development of chronic heart failure after experimental myocardial infarction (MI).. Female ERbeta null mice (BERKO(Chapel Hill)) and wild-type littermates (WT) were ovariectomized, given 17beta-estradiol, and subjected to chronic anterior MI (MI; BERKO n=31, WT n=30) or sham operation (sham; BERKO n=14, WT n=14). At 8 weeks after MI, both genotypes revealed left ventricular remodeling and impaired contractile function at similar average infarct size (BERKO-MI 32.9+/-5% versus WT-MI 33.0+/-4%); however, BERKO mice showed increased mortality (BERKO-MI 42% versus WT-MI 23%), increased body weight and fluid retention (P<0.01), higher ventricular pro-ANP expression (BERKO-MI 27.9-fold versus sham, WT-MI 5.2-fold versus sham; BERKO-MI versus WT-MI P<0.001), higher atrial natriuretic peptide serum levels, and increased phospholamban expression (P<0.05) compared with WT mice.. Systemic deletion of ERbeta in female mice increases mortality, aggravates clinical and biochemical markers of heart failure, and contributes to impaired expression of Ca(2+)-handling proteins in chronic heart failure after MI. Further studies are required to delineate the relative importance of cardiac and vascular effects of ERbeta and the role of ERalpha in the development of heart failure.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Disease Models, Animal; Disease Progression; Estrogen Receptor beta; Female; Genotype; Heart Failure; Mice; Mice, Knockout; Myocardial Contraction; Myocardial Infarction; Myocardium; Proteins; Survival Rate; Ventricular Remodeling

Atrial natriuretic peptide (ANP) is a known vascular antipermeability and antiangiogenic factor, but its possible alteration during the early stages of diabetic retinopathy has not yet been explored. The present study sought to investigate the expression of ANP and its receptors using a model of streptozotocin (STZ) induced diabetes in the rat.. Diabetes was induced in male Wistar rats by an intraperitoneal injection of STZ. Age matched animals served as control. One and 3 months after the onset of diabetes, the expression of ANP mRNA and that of its receptors (NPRA, NPRB, NPRC) and the immunoreactive ANP was quantified in retinal tissue by quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) and radioimmunoassay, respectively. The locations of ANP and glial fibrillary acidic protein (GFAP) in normal and diabetic retinas were also established by immunohistochemistry.. No alteration in the gene expression of the retinal natriuretic peptide system was noted after 1 month of diabetes. However, 3 months after the onset of diabetes, significantly diminished ANP and NPRC mRNA levels were detected in the retina of diabetic rats compared to controls, while NPRA, NPRB mRNA levels remained unchanged. At this time point, retinal ANP concentrations were significantly diminished in the diabetic rats compared to control rats. However, at 1 month retinal ANP concentrations in diabetic retina were similar to control rats. Diabetes caused the downregulation of ANP protein expression in the layers of the retina at 3 months after the induction of diabetes. ANP immunoreactivity was detected in the cell bodies of the astrocytes and in their processes enveloping vessels.. The downregulation of ANP and NPRC in retinas of diabetic rats suggests a role for this peptide in experimental diabetic retinopathy. Further studies should address the possible involvement of the ANP/NPRC system in the pathophysiology of diabetic retinopathy.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Down-Regulation; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Guanylate Cyclase; Immunoenzyme Techniques; Male; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Retina; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

A reduction of coronary flow reserve has been reported in patients with hypertensive heart disease (HHD), which suggests that myocardial ischemia may contribute to the progression to cardiac failure in HHD. Therefore, we evaluated whether fibroblast growth factor (FGF)-2 and/or heparin, which induce angiogenesis, may affect cardiac function in the setting of HHD. We used Dahl salt sensitive (DS) rats as an HHD model. Direct intramyocardial injection of 100 microg of FGF-2 plus 1.28 microg of heparin (n = 6), 100 microg of FGF-2 (n = 6), 1.28 microg of heparin (n = 6) or saline (n = 6) were performed in 9-week-old rats. Echocardiography was performed to evaluate cardiac function at 9, 11, and 13 weeks of age. Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations were measured at 8 and 13 weeks of age. DS rats were killed 4 weeks after myocardial injection (at 13 weeks of age), and myocardial capillary density was assessed by von Willebrand factor staining. Injection of FGF-2 plus heparin significantly decreased left ventricular end-diastolic diameter (P < 0.0001) and left ventricular end-systolic diameter (P < 0.0001), significantly improved the reduction of left ventricular fractional shortening (P = 0.0005), significantly decreased plasma ANP (P < 0.0001) and BNP (P = 0.016) concentrations, and significantly increased myocardial capillary density (P = 0.0002) compared with injection of saline. These findings indicate that intramyocardial injection of FGF-2 plus heparin suppresses the progression of cardiac failure in DS rats. FGF-2 plus heparin administration may be a new therapeutic strategy for the treatment of HHD.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography; Fibroblast Growth Factor 2; Heart Failure; Heart Rate; Heparin; Hypertension; Hypertrophy, Left Ventricular; Injections; Male; Myocardium; Natriuretic Peptide, Brain; Neovascularization, Pathologic; Rats; Rats, Inbred Dahl; Ventricular Function

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Fibrosis; Heart; Insulin; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Organ Size; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; Thiazepines

Neurohormonal activation has been shown to be a major factor in congestive heart failure progression and mortality. The beneficial effects obtained in clinical trials with angiotensin converting enzyme (ACE) inhibitors, beta-blockers and aldosterone antagonists have confirmed this hypothesis. 5,6-Diisobutirroyloxy-2-methyl-aminotetraline hydrochloride (nolomirole) is a selective agonist of prejunctional D(2)-dopaminergic and alpha(2)-adrenergic receptors. The stimulation of these receptors inhibits catecholamine release from sympathetic nerve endings. To confirm that this mechanism can be useful in congestive heart failure, we studied the effects of nolomirole on monocrotaline-induced congestive heart failure. The ACE inhibitor trandolapril was used as reference compound. Rats were given single intraperitoneal injection of either saline (control group; n=20) or monocrotaline (50 mg kg(-1)). Three days later, the monocrotaline-treated animals were randomly allocated (n=50 per group) to oral treatment with distilled water (vehicle group), nolomirole (0.25 mg kg(-1)) twice a day, or trandolapril (0.3 mg kg(-1)) once a day up to sacrifice. On the fourth week after monocrotaline injection, animals with signs of congestive heart failure were sacrificed for evaluation of heart hypertrophy and neuroendocrine alterations. Atrial natriuretic peptide (ANP) and alderosterone were determined by radioimmunoassay in plasma. Tissue norepinephrine concentration was quantified by high-pressure liquid chromatography. Nolomirole and trandolapril significantly reduced (a) hypertrophy of right atria and ventricles, (b) plasma levels of ANP and presence of pleural/peritoneal effusions and (c) norepinephrine depletion of right ventricle. These findings confirmed that nolomirole, like trandolapril, is able to attenuate the heart failure signs in the monocrotaline-induced congestive heart failure model.

Topics: Administration, Oral; Adrenergic alpha-Agonists; Aldosterone; Animals; Ascitic Fluid; Atrial Natriuretic Factor; Body Weight; Disease Models, Animal; Dopamine Agonists; Drug Evaluation, Preclinical; Esters; Female; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Right Ventricular; Indoles; Monocrotaline; Norepinephrine; Pleural Effusion; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes

Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Body Weight; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Fosinopril; Hypertension; Kidney; Male; Models, Cardiovascular; Neprilysin; Pyridines; Rats; Renin; Statistics as Topic; Survival Analysis; Systole; Thiazepines; Time Factors; Treatment Outcome

Vessel dilator and kaliuretic hormone, two cardiovascular peptide hormones, enhance urine flow 2- to 13-fold and 4-fold, respectively, in persons with class III New York Heart Association congestive heart failure (CHF). The natriuresis and diuresis secondary to vessel dilator and kaliuretic hormone are not blunted as are atrial natriuretic peptide and brain natriuretic peptide effects in persons with CHF compared with healthy individuals. The present investigation determined if the two peptide hormones that do not have blunted effects in persons with CHF may have added beneficial effects when given simultaneously to individuals with class III CHF. Together with each at 100 ng/kg of body weight per minute, vessel dilator and kaliuretic hormone increased urine flow rate 3.5-fold (P < 0.05) compared with their 60-min baseline and control CHF subjects' urine flow rates. Combined, they enhanced the excretion rate of sodium a maximum of 3.6-fold (P < 0.05) with 2.5- and 2-fold enhancement 2 and 3 hrs after infusion. These data indicate that vessel dilator and kaliuretic hormone have diuretic and natriuretic effects when used in combination, but these effects are not additive over their individual effects in persons with CHF.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Case-Control Studies; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments; Potassium; Protein Precursors; Sodium; Sodium-Potassium-Exchanging ATPase; Urodynamics

Angiotensin converting enzyme (ACE) inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin (BK). They prevent not only hypertension but also cardiac hypertrophy and fibrosis. An increase in BK level stimulates the expression of nitric oxide (NO) synthase (NOS) and induces prostaglandins, both of which are powerful vasodilator factors. The direct effect of BK against cardiac hypertrophy is still unclear. This study was performed to examine the cardioprotective effects of BK in hypertrophic models. Renovascular hypertensive (RHT) rats were treated with BK (1,000 ng/kg/day), BK+D-arginyl-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin (HOE140) (a BK B(2) receptor antagonist), and BK+N(omega)-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor) for 3 weeks. Blood pressure was measured and echocardiographic analysis performed during the treatment. Histological data were analyzed to confirm the hypotrophic effect of BK. Treatment with BK improved cardiac remodeling, reducing both the heart weight/body weight ratio and the left ventricular wall thickness. However, co-treatment with HOE140 or L-NAME reversed the anti-hypertrophic action of BK. In particular, cardiac fibrosis or perivascular fibrosis, along with collagen accumulation, were inhibited by treatment with BK, while HOE140 and L-NAME counteracted these changes. In addition, expressions of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP), which are markers of cardiac abnormalities, were down-regulated by treatment with BK. These effects were reversed by co-treatment with HOE140 and L-NAME. Together, these results indicate that BK directly inhibits the progression of cardiac hypertrophy and cardiac fibrosis due to NO release via the BK B(2) receptor. The BK-NO pathway may play an important role in the progression of cardiac remodeling.

Topics: Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Bradykinin; Coronary Circulation; Echocardiography; Enzyme Inhibitors; Fibrosis; Hypertension, Renal; Hypertrophy, Left Ventricular; Male; Myocardium; Natriuretic Peptide, Brain; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Organ Size; Rats; Rats, Wistar; RNA, Messenger; Ventricular Remodeling

To study the effects of increased levels of myocardial angiotensin II type 1 (AT(1)) receptor on microvascular growth following myocardial infarction (MI).. MI was created in transgenic rats (TGR) with a cardioselective overexpression of the AT(1) receptor. We used Sprague-Dawley (SD) rats as controls. Some of the rats were treated with the selective AT(1) receptor blocker losartan (Los). Rats were sacrificed after 3 weeks.. MI caused left ventricular (LV) hypertrophy and LV dysfunction in both SD and TGR, which was prevented by AT(1) receptor blockade. Furthermore, MI decreased microvessel density in the non-infarcted myocardium (SD MI: 1653+/-37/mm(2), P<0.01 vs. sham-operated controls), however, microvessel density decreased significantly more in TGR with MI (1298+/-33/mm(2), P<0.01 vs. SD MI). AT(1) receptor blockade restored microvessel density (SD MI Los: 2046+/-195/mm(2); TGR MI Los: 1742+/-47/mm(2); P<0.01 vs. untreated). The differences in microvessel density were still present after correction for LV hypertrophy. The increase in microvessel density after AT(1) receptor blockade was not accompanied by increased myocardial vascular endothelial growth factor (VEGF) levels. Microvessel density correlated with parameters of myocardial stretch, such as LV end-diastolic pressure (-0.681, P<0.001) and N-ANP (-0.424, P=0.01).. Microvessel density after MI is decreased when the AT(1) receptor is overexpressed, and this is amenable to AT(1) receptor blockade. This suggests that efficacy of AT(1) receptor blockers post-MI may not only be due to attenuation of LV remodeling, but also to a stimulatory effect on angiogenesis.

Topics: Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Body Weight; Coronary Circulation; Endothelial Growth Factors; Heart Ventricles; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Microcirculation; Myocardial Infarction; Neovascularization, Pathologic; Organ Size; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Ventricular Dysfunction, Left; Ventricular Remodeling

The purpose of this study was to clarify whether the secretions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are pulsatile in patients with chronic heart failure (CHF), and whether the rhythmic oscillations for ANP and BNP are abnormal in patients with CHF. Several reports have shown that ANP and especially BNP are valuable indicators of the prognosis in CHF. Previously, a pulsatile secretion has been described for ANP and BNP in healthy humans and for ANP in CHF patients. More information about the secretion pattern of BNP in heart failure is necessary to increase the clinical usefulness of BNP in patients with CHF. Patients with left ventricular systolic dysfunction and CHF ( n =12) and controls ( n =12) were investigated. Plasma ANP and BNP levels were determined every 2 min during a 2-h period by radioimmunoassay and analysed for pulsatile behaviour by Fourier transformation. All patients and controls had significant rhythmic oscillations in plasma ANP levels, and 11 patients with CHF and 10 controls had significant rhythmic oscillations in plasma BNP levels. The amplitude of the main frequency was considerably higher in patients with CHF than in controls (ANP: CHF, 4.76 pmol/l; controls, 0.75 pmol/l; P <0.01. BNP: CHF, 3.24 pmol/l; controls, 0.23 pmol/l; P <0.001; all values are medians), but the main frequency did not differ significantly between the group with CHF and the control group for either ANP or BNP. Patients with CHF demonstrate pulsatile secretion of ANP and BNP with a much higher absolute amplitude, but with the same main frequency as healthy subjects.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Specimen Collection; Body Weight; Female; Fourier Analysis; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Periodicity; Ventricular Dysfunction, Left

Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Atrial natriuretic peptide (ANP) has been postulated to exert local antihypertrophic effects in the heart. Thus, a loss of function of the ANP receptor guanylyl cyclase-A (GC-A) might contribute to the increased propensity to cardiac hypertrophy, although a causative role in vivo has not been definitively demonstrated. To test whether local ANP modulates cardiomyocyte growth, we inactivated the GC-A gene selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination. Thereby we have circumvented the systemic, hypertensive phenotype associated with germline inactivation of GC-A. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy, markedly increased mRNA expression of cardiac hypertrophy markers such as ANP (fivefold), alpha-skeletal actin (1.7-fold), and beta-myosin heavy chain (twofold), and increased systemic circulating ANP levels. Their blood pressure was 7-10 mmHg below normal, probably because of the elevated systemic levels and endocrine actions of ANP. Furthermore, cardiac hypertrophic responses to aortic constriction were enhanced and accompanied by marked deterioration of cardiac function. This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy.

Topics: Actins; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Gene Deletion; Guanylate Cyclase; Hemodynamics; Humans; Mice; Mice, Knockout; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Organ Size; Phenotype; Receptors, Atrial Natriuretic Factor; RNA, Messenger

We sought to examine both the short-term and residual effects of perinatal hypoxia on ventricular mass and function of mice. We postulated that the magnitude of the ventricular hypertrophy would be determined by the timing of the exposure, be linked to augmented atrial natriuretic peptide (ANP) expression, and would persist to young adulthood. Furthermore, mice deficient in the ANP receptor type A (ANPRA) would have even greater hypertrophy. Newborns were placed in a 12% oxygen (O(2)) chamber either shortly after birth or at 8 days of age. Controls were raised in room air. After 8 or 16 days, pups were terminated and the right ventricle (RV) and left ventricle including the septum (LVS) were excised and weighed and total RNA was extracted. Hypoxia caused a reduction in body weight (BW) with an increase in right ventricle (RV) weight, rendering an increased RV to BW ratio and increased LVS/BW, albeit less. Hypertrophy was most pronounced in pups exposed to hypoxia in the first days of extrauterine life. A rapid postnatal decline in both RV and LVS ANP mRNA levels was observed in control animals, while the hypoxia elevated ANP mRNA. In mice missing the ANPRA, both ventricles were more massive than in wild type and hypoxia further augmented RV/BW and LVS/BW. In normal adult animals returned to room air after 16 days of hypoxia, RV but not LVS hypertrophy persisted in both sexes; there was an interaction between gender and the perinatal hypoxic stress on LVS dimension and perhaps on contractility. Thus perinatal hypoxia may "program" the adult mouse heart and vasculature.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Female; Gene Expression; Genotype; Guanylate Cyclase; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice; Organ Size; Pregnancy; Receptors, Atrial Natriuretic Factor; Reference Values; RNA, Messenger; Sex Factors; Ultrasonography

Atrial natriuretic peptide (ANP) plays an important role in the regulation of water and sodium in the body via cyclic GMP (cGMP) pathway. Although ANP has been shown to be protective in cerebral ischemia or intracerebral hemorrhage, its role in traumatic brain injury (TBI) has yet to be elucidated. We herein assessed ANP effects on brain water and sodium in TBI. Controlled cortical impact (3 mm depth, 6 m/sec) was used to induce an experimental cortical contusion in rats. Continuous administration of ANP 0.2 (n = 6) or 0.7 microg/kg/24 h (n = 6), cGMP analogue (8-Bromo-cGMP) 0.1 (n = 5) or 0.3 mg/kg/24 h (n = 5), or vehicle (n = 6) was begun 15 minutes after injury, using a mini-osmotic pump implanted into the peritoneal cavity. At 24 hours after injury, ANP significantly exacerbated brain edema in the injured hemisphere in a dose-dependent manner while it reduced brain sodium concentrations in both hemispheres. These ANP effects could be mimicked by a cGMP analogue. In the second series (n = 20), BBB integrity was assessed by evaluating the extravasation of Evans blue dye. ANP or cGMP analogue significantly worsened BBB disruption in the injured hemisphere at 24 hours after injury. These findings suggest that ANP administration exacerbates brain edema after the experimental cortical contusion in rats, possibly because of an increase in the BBB permeability via cGMP pathway, whereas it reduces brain sodium levels.

Topics: Animals; Atrial Natriuretic Factor; Blood-Brain Barrier; Body Weight; Brain Injuries; Coloring Agents; Cyclic GMP; Electrolytes; Evans Blue; Injections, Intraperitoneal; Male; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Water; Water-Electrolyte Balance

Cardiac hypertrophy is an early landmark during the clinical course of heart failure, and is an important risk factor for subsequent morbidity and mortality. The hypertrophy response to different types of cardiac overload is distinguished both at the molecular and cellular levels. These changes have been extensively characterized for pressure load hypertrophy; however, similar information for volume load hypertrophy is still needed. This study was undertaken to improve the existing method of producing experimental cardiac volume load. Previous investigators have employed surgical aorto-caval shunt (ACS) as a model for volume load hypertrophy (VO) in rats. The procedure is relatively simple and involves glue to seal the aortic hole after ACS. However, it has several limitations mostly related to the use of glue e.g. poor visualization due to hardening of tissues, imperfect sealing of the puncture site and glue seeping through the aortic hole resulting in shunt occlusion. We have modified the procedure using aortic adventitial suture instead of glue and 18G angiocatheter instead of 16G needle, which eliminated the technical difficulties from the former method. The ACS was visually confirmed at sacrifice, and the VO demonstrated by time-related changes in the heart weight/body weight ratio which increased from 78% at 4 weeks to 87% at 10 weeks and increased liver/body weight ratio by 22% at 10 weeks of post aorto-caval shunt. Cardiac expression of atrial natriuretic peptide (ANF) also demonstrated time-related increase in ANF mRNA (+275% increase at 4 weeks, p < 0.05, and +370% increase at 10 weeks, p < 0.001). This modified technique of aorto-caval shunt offers simpler, reproducible and consistent model for VO hypertrophy in rats.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Body Weight; Cardiac Volume; Cardiomegaly; Catheters, Indwelling; Gene Expression; Male; Models, Cardiovascular; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sutures; Time Factors; Vascular Surgical Procedures; Venae Cavae

The aim of this study was to evaluate the effectiveness of an angiotensin-converting enzyne inhibitor (ACEI, quinapril) or angiotensin II receptor blocker (ARB, candesartan) on atrial natriuretic peptide (ANP) activity in rats with hypertension induced by nitric oxide (NO) inhibition. ACEI and ARB have a number of pharmacologic effects, including blood pressure reduction, myocardial preservation, and an unknown effect in the circulation. The changes in ANP in NO inhibitor-induced hypertensive rats were evaluated in order to elucidate the interaction between ANP and NO in the regulation of blood pressure. Thirty-six rats were divided into 4 groups and administered the experimental agents for 8 weeks: group CONTROL was given regular food (n=9), group N(G)-nitro-L-arginine (L-NNA) was administered L-NNA (25 mg. kg(-1). day(-1), n=9), group ACEI was administered L-NNA and quinapril (10 mg. kg(-1). day(-1), n=9), and group ARB was administered L-NNA and candesartan (10 mg. kg(-1). day(-1), n=9). Blood pressure, plasma ANP, atrial ANP, ANP mRNA, and ANP granules were measured. A significant elevation in blood pressure was observed in group L-NNA. However, there were no increases in plasma ANP (L-NNA: 138.8+/-64.4, CONTROL: 86.7+/-36.4), ANP mRNA (L-NNA: 2.2+/-1.0, CONTROL: 1.7+/-0.5) or ANP granules (L-NNA: 61.1+/-10.2, CONTROL: 64.5+/-8.5). No increase in blood pressure was seen in groups ACEI and ARB. However, plasma ANP (ACEI: 1,392.3+/-1,034.4, ARB: 1,142.8+/-667.3), ANP mRNA (ACEI: 52.8+/-29.1, ARB: 42.9+/-21.2), and ANP granules (ACEI: 122.5+/-23.4, ARB: 136.3+/-33.2) increased significantly. NO inhibitor-induced hypertension caused no changes in ANP concentrations. However, the ACEI and ARB had a direct effect on the induction of ANP secretion. The findings suggest that ANP secretion is directly effected by ACEI and ARB, which seems to play a key role in lowering blood pressure, relieving heart failure symptoms, and preserving the myocardium.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Heart; Male; Nitroarginine; Organ Size; Quinapril; Rats; Rats, Wistar; RNA, Messenger; Systole; Tetrahydroisoquinolines; Tetrazoles; Transcription, Genetic

This study examined the effects of growth hormone (GH) on infarct size, survival, and cardiac gene expression in rats with acute myocardial infarction.. Animals randomly received sc injection of either saline vehicle (n = 98) or GH (2mg/kg/day, n = 105) for 14 days commencing the day of left coronary artery ligation. Infarct size was determined by morphometric analysis at the time of death or at 52 weeks post-surgery. Gene expression was analyzed by real-time RT-PCR after 2-week treatment.. GH decreased infarct size by 18% (P < 0.01) and increased survival by 36% at 52 weeks. GH also significantly reduced cardiac expression of atrial natriuretic factor, beta-myosin heavy chain, alpha-smooth muscle actin, collagen I, collagen III, fibronectin, and pro-inflammatory cytokines.. Treatment with GH for 2 weeks beginning on the day of myocardial infarction produced beneficial effects that were associated with reductions in cardiac gene expression symptomatic of pathological remodeling.

Topics: Actins; Animals; Atrial Natriuretic Factor; Body Weight; Collagen Type I; Collagen Type III; Cytokines; Fibronectins; Gene Expression Regulation; Growth Hormone; Heart; Heart Ventricles; Male; Myocardial Infarction; Myosin Heavy Chains; Organ Size; Rats; Rats, Sprague-Dawley; Survival Rate

Acute intravenous administration of moxonidine, an imidazoline I1-receptor agonist, reduces blood pressure (BP) in normotensive and hypertensive rats, induces diuresis and natriuresis, and stimulates plasma atrial natriuretic peptide (ANP). In these studies we investigated the involvement of natriuretic peptides (ANP and brain natriuretic peptide) in the effects of chronic activation of imidazoline receptors.. Spontaneously hypertensive rats (SHR; 12 to 14 weeks old) received 7-day moxonidine treatment at various doses (10, 20, 60, and 120 microg/kg/h) via subcutaneously implanted osmotic minipumps.. Hemodynamic parameters (continuously monitored by telemetry) revealed that, compared with saline-treated rats, moxonidine dose-dependently decreased blood pressures (BPs). Maximal blood pressure lowering effect was achieved by day 4 of treatment, at which point 60 microg/kg/h reduced mean arterial pressure (MAP) by 14.5 +/- 6.8 mm Hg as compared with basal levels. The decrease in MAP was influenced by a drop in both diastolic and systolic pressures. Moxonidine treatment did not alter daily urinary sodium and potassium excretions, but 120 microg/kg/h moxonidine decreased urine volume after 2 days and increased cyclic guanosine 3'5'monophosphate excretion on days 4 to 7 of treatment. Chronic moxonidine treatment dose-dependently increased plasma ANP to reach, at 120 microg/kg/h, a 40% increase (P < .01) above that of corresponding saline-treated SHR, with a concomitant increase in left and right atrial ANP mRNA (more than twofold). Plasma BNP increased by 120 microg/kg/h moxonidine (11.0 +/- 1.1 v 16.5 +/- 1.9 pg/mL, P < .002) without significant increases in atrial and ventricular BNP mRNA.. ANP and BNP may be involved in the antihypertensive effect of chronic moxonidine treatment. Accordingly, natriuretic peptides may contribute to the sympatholytic and cardioprotective effects of chronic activation of imidazoline I1-receptors.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Gene Expression; Imidazoles; Imidazoline Receptors; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Receptors, Drug

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.. We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.. These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Fibrosis; Gene Targeting; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Imidazoles; Mice; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Organ Size; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Ventricular Remodeling

Large myocardial infarction (MI) causes substantial cardiac remodeling and often leads to heart failure. The genetically engineered mouse is believed to provide a powerful tool for investigating the underlying pathophysiological mechanisms and for developing new therapeutic strategies. The present study investigates the functional parameters and expression levels of transforming growth factor (TGF) beta isoforms, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha, which may be involved in the remodeling mechanisms, in a mouse model of MI; comparisons with data from rats were also made. Female Sprague-Dawley rats ( n=10-12 at each time point) and female Balb/c mice ( n=6-8 at each time point) were used. In both mice and rats MI induced a time-dependent reduction in heart function with subsequent development of heart failure. The hemodynamic consequences after 4 weeks are characterized by reduced left ventricular (LV) developed pressure and increased right ventricular (RV) developed pressure. The pattern of increased expression of most, but not all, of the analyzed cytokines and growth factors is comparable. This emphasizes the important role of these factors in the remodeling processes. However, TNFalpha was more strongly expressed in both the infarct and the non-infarcted area of mice. Since functional and molecular biological parameters can readily be measured in mice with advanced technologies, this qualifies this species as a powerful experimental model, particularly in view of the various transgenic and knock-out mice that are available.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Body Weight; Cardiomegaly; Cytokines; Female; Heart; Hemodynamics; Mice; Mice, Inbred BALB C; Myocardial Infarction; Protein Isoforms; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ventricular Function, Left

The first aim of this work was to investigate, under basal conditions in adult male rats, the long-term consequences of perinatal maternal food restriction on the plasma concentrations of vasopressin (VP), aldosterone and atrial natriuretic peptide (ANP) and on plasma renin activity (PRA). Furthermore, under these same conditions, the hypothalamic VP gene expression as well as the density (B(max)), affinity (K(d)) and gene expression of ANP receptors were determined in kidneys and adrenals. The second aim of this work was to examine the responsiveness to dehydration in perinatally malnourished rats. Thus, the latter parameters were studied in these rats after 72 h water deprivation.. This study was conducted on 4-Month-old male rats from mothers exposed to 50% food restriction (FR50) during the last week of gestation and lactation and on age-matched control animals (C). At this stage, both C and FR50 rats were killed by decapitation between 0900 h and 1000 h in order to determine parameters under basal conditions or after 72 h water deprivation. Plasma VP, ANP and aldosterone levels and PRA were determined by radioimmunoassay. Hypothalamic VP gene expression was determined in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) by in situ hybridization. The B(max) and K(d) values of ANP receptors were evaluated from Scatchard plots. ANP receptor gene expression was determined by Northern blot analysis.. Under basal conditions, perinatal malnutrition reduced body weight, absolute weight of kidneys and adrenals, and haematocrit. Compared with control rats, FR50 rats had significantly greater plasma VP and aldosterone levels but PRA, plasma ANP levels, plasma osmolality and hypothalamic VP gene expression were not significantly different. Perinatal malnutrition did not significantly affect glomerular ANP receptor density, but in adrenals it decreased both B(max) and K(d) values of ANP-B receptors (biological receptors) and increased B(max) of ANP-C receptors (clearance receptors). ANP-B(A) (receptor subtype A of ANP-B receptors) receptor gene expression was not significantly affected, whereas ANP-C receptor gene expression was enhanced in both adrenals and kidneys in FR50 rats. After 72 h dehydration, control rats showed a significant rise in haematocrit, plasma osmolality, PRA, circulating levels of VP and aldosterone and VP gene expression in both PVN and SON but showed a decrease in plasma ANP levels. B(max) of ANP-B receptors was decreased whereas B(max) of ANP-C receptors was enhanced in both adrenals and kidneys. ANP-B(A) receptor gene expression was not significantly affected in either kidneys or adrenals in dehydrated control rats. Similarly, ANP-C receptor gene expression was unaffected in kidneys whereas it was significantly enhanced in adrenals. In FR50 rats, the effects of water deprivation were qualitatively similar to those reported in controls concerning plasma parameters except for plasma VP levels which tended to rise (not significant) but this increase was only very slight compared with controls. Moreover, unlike controls, VP gene expression in both PVN and SON was not enhanced after dehydration in FR50 rats. In kidneys, dehydrated FR50 rats, like controls, upregulated ANP-C receptors, but they were unable to downregulate ANP-B receptors. In adrenals, unlike controls, FR50 rats enhanced ANP-B receptor density whereas they decreased both ANP-C receptor density and expression after 72 h dehydration. Similar to controls, the expression of ANP-B(A) receptors in both kidneys and adrenals as well as the expression of ANP-C receptors in kidneys, were unaffected in dehydrated FR50 rats.. Perinatal malnutrition had long-lasting effects on regulation of the fluid and electrolyte balance under basal conditions. The main effects were a significant rise in circulating levels of VP and aldosterone, and changes in density of adrenal ANP-binding sites and ANP-C receptor gene expression in both adrenals and kidneys. Perinatal malnutrition also affects the responsiveness to water deprivation with alterations in both hypothalamic VP gene expression and regulation of ANP-binding sites.

Topics: Adrenal Glands; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Atrial Natriuretic Factor; Binding Sites; Body Weight; Dehydration; Embryo, Mammalian; Endocrine Glands; Hormones; Hypothalamus; Kidney; Male; Nutrition Disorders; Organ Size; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Tissue Distribution; Vasopressins; Water-Electrolyte Balance

Calcium-dependent mechanisms and the renin angiotensin system (RAS) are critically involved in the hypertrophic growth of the myocardium. The calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator in calcium signaling and modulates calcium handling and growth mechanisms in cardiomyocytes. Here we present data on expression of cardiac isoforms of CaMKIIdelta, the dominant form in the myocardium, in compensatory hypertrophy of stroke-prone spontaneously hypertensive rats (SHRSP) compared to the normotensive Wistar-Kyoto (WKY) control strain. Cardiac hypertrophy in SHRSP was documented by an increased heart weight/body weight ratio (HW/BW) of 31% (p < 0.05) and a more than six-fold elevated atrial natriuretic factor (ANF) transcript level (p < 0.05). Compensatory hypertrophic growth in SHRSP produced a specific phenotype of CaMKIIdelta isoforms characterized by increased transcript levels of the embryonic/neonatal isoform delta4 (48%, p < 0.05) and the isoform delta9 (31%, p < 0.05) with no changes in delta2 and delta3. Inhibition of angiotensin converting enzyme (ACE) by cilazapril completely regressed myocardial hypertrophy, normalized ANF transcript levels, and restored the normal phenotype of CaMKIIdelta by reducing transcripts for delta4 and delta9 to levels present in WKY controls. Our data suggest the importance of specific changes in the CaMKII isoform composition for growth processes in the myocardium.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomegaly; Cilazapril; Genetic Predisposition to Disease; In Vitro Techniques; Isoenzymes; Male; Myocardium; Organ Size; Phenotype; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Transcription, Genetic

A fructose-enriched diet induces an increase in blood pressure associated with metabolic alterations in rats. Our hypothesis was that an increase in protein kinase C (PKC) activation, reported in the acute period of fructose overload, and an impaired vessel's response to vasoactive substances contribute to maintain elevated blood pressure levels in the chronic period. The aims of this study were to investigate in this animal model of hypertension: (1) if the increase in PKC activation was also found in the chronic stage; (2) the involvement of nitric oxide and insulin in the vessel's response; and plasma atrial natriuretic factor and nitrites/nitrates (nitric oxide metabolites) behavior. We evaluated the effects of: PKC-stimulator 12,13-phorbol dibutyrate, phenylephrine, insulin, nitric oxide synthase-inhibitor NG-nitro-L-arginine methyl esther (L-NAME) and PKC-inhibitor Calphostin C on aortic rings responses of Sprague-Dawley rats: fructose-fed and control. The fructose-fed group showed higher contractility to 12,13-phorbol dibutyrate than the control group in aortic rings pre-incubated with insulin, and this difference disappeared with L-NAME. The response to phenylephrine in rings pre-incubated with Calphostin C was decreased in the fructose-fed group and increased with Calphostin C plus L-NAME. Fructose-fed rats showed higher levels of plasma atrial natriuretic factor and nitrites/nitrates than controls. In conclusion, chronic fructose feeding seems to develop an impaired response to insulin, dependent on nitric oxide, suggesting a PKC alteration. Vasorelaxant agents, such as atrial natriuretic factor and nitric oxide, would behave as compensatory mechanisms in response to high blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Enzyme Activators; Enzyme Inhibitors; Fructose; Hypertension; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Muscle Contraction; Muscle, Smooth, Vascular; Naphthalenes; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phorbol 12,13-Dibutyrate; Protein Kinase C; Rats; Rats, Sprague-Dawley

The aryl hydrocarbon receptor (AhR) is a member of the basic helix loop helix PAS (Per-ARNT-SIM) transcription family, which also includes hypoxiainducible factor-1alpha (HIF-1alpha) and its common dimerization partner AhR nuclear translocator (ARNT). Following ligand activation or hypoxia, AhR or HIF-1alpha, respectively, translocate into the nucleus, dimerize with ARNT, and regulate gene expression. Mice lacking the AhR have been shown previously to develop cardiac enlargement. In cardiac hypertrophy, it has been suggested that the myocardium becomes hypoxic, increasing HIF-1alpha stabilization and inducing coronary neovascularization, however, this mechanism has not been demonstrated in vivo. The purpose of this study was to investigate the cardiac enlargement reported in AhR(-/-) mice and to determine if it was associated with myocardial hypoxia and subsequent activation of the HIF-1alpha pathway. We found that AhR(-/-) mice develop significant cardiac hypertrophy at 5 mo. However, this cardiac hypertrophy was not associated with myocardial hypoxia. Despite this finding, cardiac hypertrophy in AhR(-/-) mice was associated with increased cardiac HIF-1alpha protein expression and increased mRNA expression of the neovascularization factor vascular endothelial growth factor (VEGF). These data demonstrate that the development of cardiac hypertrophy in AhR(-/-) mice not associated with myocardial hypoxia, but is correlated with increased cardiac HIF-1alpha protein and VEGF mRNA expression.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Biomarkers; Body Weight; Cardiac Myosins; Cardiomegaly; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, Mutant Strains; Models, Cardiovascular; Myocardium; Myosin Heavy Chains; Myosin Light Chains; Nonmuscle Myosin Type IIB; Organ Size; Phenotype; Rats; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics as Topic; Time Factors; Transcription Factors; Vascular Endothelial Growth Factor A

In order to explore the feasibility of gene therapy strategy based on the human atrial natriuretic peptide (hANP) gene delivery for the treatment of nephropathy and compare the diuretic activities of the hANP gene injected intramuscularly(i.m.) and intravenously(i.v.), the naked retroviral vector DNA harboring the hANP cDNA under the control of retroviral 5' long terminal repeat at a dose of 5 mg/kg body weight was injected i.m. or i.v. into the nephrotic model rats induced with adriamycin(ADR) injected i.v. at a dose of 7.5 mg/kg body weight. A single injection of the hANP gene resulted in a marked elevation in plasma level of hANP 5 days after gene delivery and a significant increase in the ratio of urine volume to body weight and the diuretic effect continued for more than 15 days. In addition, there was a significant rise in the body weight of treatment groups as compared with that of negative control group and no difference in the concentrations of electrolytes in urine between groups. There was no significant differences in total effects resulted from the two routes of gene delivery and the way of gene delivery through the skeletal muscle is simpler and easier. These results suggest that somatic gene delivery of the hANP gene could enhance the renal functions in nephrotic rats significantly and would be a potential strategy for the treatment of renal disorders.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Disease Models, Animal; Diuresis; Doxorubicin; Genetic Therapy; Humans; Injections, Intramuscular; Injections, Intravenous; Kidney Diseases; Proteinuria; Rats; Rats, Wistar

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.

Topics: Animals; Atmosphere Exposure Chambers; Atrial Natriuretic Factor; Body Weight; Carbon Monoxide; Cardiomegaly; Endothelin Receptor Antagonists; Endothelin-1; Female; Nicotine; Nicotinic Agonists; Organ Size; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger

Atrial natriuretic peptide (ANP) has negative modulatory effects on a variety of pathophysiological mechanisms; i.e., it inhibits hypoxia-induced pulmonary vasoconstriction and vascular remodeling and facilitates natriuresis and vasorelaxation in NaCl-supplemented subjects. We have previously demonstrated organ-selective potentiation of ANP in the pulmonary circulation of hypoxia-adapted animals by local downregulation of its clearance receptor (NPR-C; Li H, Oparil S, Meng QC, Elton T, and Chen Y-F. Am J Physiol Lung Cell Mol Physiol 268: L328-L335, 1995). The present study tested the hypothesis that NPR-C expression is attenuated selectively in kidneys of NaCl-supplemented subjects. Adult male wild-type (ANP+/+) and homozygous mutant (ANP-/-) mice were studied after 5 wk of normal or high-salt diets. Mean arterial pressure (MAP) and left (LV) and right ventricular (RV) mass were greater in ANP-/- mice than in ANP+/+ mice fed the normal-salt diet; salt supplementation induced increases in plasma ANP in ANP+/+ mice and in MAP and LV, RV, and renal mass in ANP-/- mice but not in ANP+/+ mice. NPR-C mRNA levels were selectively and significantly reduced (>60%) in kidney, but not in lung, brain, LV, or RV, by dietary salt supplementation in both genotypes. NPR-A mRNA levels did not differ among diet-genotype groups in any organ studied. cGMP content was significantly increased in kidney, but not in lung or brain, by dietary salt supplementation in both genotypes. These findings suggest that selective downregulation of NPR-C in the kidney in response to dietary salt supplementation may contribute to local elevation in ANP levels and may be functionally significant in attenuating the development of salt-sensitive hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Down-Regulation; Female; Gene Expression; Genotype; Guanylate Cyclase; Hypertension; Kidney; Male; Mice; Mice, Knockout; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Sodium Chloride, Dietary

Growth hormone (GH) application is a new strategy in the treatment of heart failure. However, clinical and experimental investigations have shown contradictory effects of GH on cardiac performance. We tested the hypothesis that GH could improve cardiac and renal function in volume overload-induced heart failure. The effect of 4 weeks of GH treatment (2 mg/kg daily) was investigated in Wistar rats with aortocaval shunt. GH application did not influence left ventricular contractility and end-diastolic pressure in rats with aortocaval shunt. In contrast, GH treatment normalized impaired diuresis (vehicle 10.8+/-0.6 mL/d, GH 15.8+/-0.7 mL/d; P<0.05) and sodium excretion (vehicle 1.5+/-0.1 mmol/d, GH 2.2+/-0.1 mmol/d; P<0.001) in shunt-operated rats, with a similar increase of fractional sodium excretion. The urinary excretion of cGMP, the second messenger of atrial natriuretic peptide and NO, was higher in animals with shunts than in sham-operated animals and was further increased by GH (vehicle 293+/-38 nmol/d, GH 463+/-57 nmol/d; P<0.01). Although the atrial natriuretic peptide plasma levels were unchanged after GH, the excretion of NO metabolites (nitrate/nitrite) was elevated (vehicle 2020+/-264 nmol/d, GH 2993+/-375 nmol/d; P<0.05) in parallel with increased renal mRNA levels of inducible NO synthase 2. The changes of renal function after GH and the increased excretion of NO metabolites and cGMP were abolished by simultaneous treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. GH treatment did not influence cardiac function in rats with aortocaval shunts. However, GH improved renal function by increasing diuresis and sodium excretion. The responsible mechanism might be the enhanced activity of the renal NO system.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Enzyme Inhibitors; Growth Hormone; Heart; Heart Failure; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Wistar; Recombinant Proteins; RNA, Messenger; Ventricular Dysfunction, Left

The upregulation of left ventricular atrial natriuretic peptide (ANP) serves as a molecular marker of cardiac hypertrophy. The precise mechanisms underlying this gene induction are unclear, since the presently cloned 3.6 kilo base (kb) rat ANP promoter failed to substantially induce coupled reporter genes in chronically hypertrophied hearts. The aim of this study was to clone and to functionally analyse the upstream ANP promoter.. Upstream of the known ANP promoter, a 1.5 kb segment was cloned by the promoter walker method and found to harbour a putative CCAAT-binding site as well as multiple putative transcription factor binding sites. This newly cloned segment was ligated with a reporter gene, in vivo transfected into rat myocardium, and analysed under basal conditions or after stimulation with both acute (isovolumetric contractions in the Langendorff apparatus) and chronic wall stress (aortic banding).. Reporter gene constructs carrying the newly cloned segment conferred only little promoter activity. In hearts exposed to acute wall stress, the previously cloned 3.6 kb ANP promoter as well as a constitutive promoter (pGL3 promoter vector) were active but markedly suppressed after extension with the newly cloned upstream promoter (-88.1 and -85.5%; P < 0.05 respectively). Site directed mutagenesis of two AP-2 transcription factor binding sites (base pairs -3946 to -3954 or -4192 to -4200) eliminated this silencing effect. In hearts with chronic pressure overload hypertrophy as well as in normal, unstimulated hearts the activity of the 3.6 kb ANP promoter was weak and also abolished after ligation with the 1.5 kb upstream segment. Moreover, both putative AP-2 binding sites within the upstream rat ANP promoter bound specifically to nuclear proteins of unstimulated, acute and chronic pressure overloaded hearts as demonstrated by electrophoresis mobility shift assays.. Novel silencer elements were cloned, localized to two AP-2 binding sites in the upstream ANP promoter, and functionally characterized. Given that the putative upregulation of left ventricular ANP by the extensively studied 3.6 kb proximal promoter region is substantially diminished by the newly cloned segment, the functional significance of regulatory elements within the proximal promoter region should be re-evaluated. The molecular mechanism causing ANP mRNA induction in left ventricular hypertrophy remains obscure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cloning, Molecular; DNA; Gene Expression Regulation; Hypertrophy, Left Ventricular; Promoter Regions, Genetic; Protein Binding; Rats; RNA, Messenger; Transcription, Genetic; Transcriptional Activation; Ventricular Function

It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis.. Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 microg x h(-1)) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg x kg(-1) x d(-1)) or cyclosporine A (10 mg x kg(-1) x d(-1)). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg x kg(-1) x d(-1))on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity and its mRNA expression were also increased in aldosterone-induced hypertrophic heart. Treatment with losartan, FK506, or cyclosporine partially prevented aldosterone-induced cardiac hypertrophy and fibrosis.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy and fibrosis induced by mineralocorticoid excess. Inhibition of calcineurin may therefore prevent cardiac hypertrophy and fibrosis in mineralocorticoid hypertension.

Topics: Aldosterone; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Collagen Type III; Cyclosporine; Enzyme Inhibitors; Fibrosis; Heart; Immunosuppressive Agents; Losartan; Male; Mineralocorticoids; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Inbred WKY; RNA, Messenger; Sodium Chloride, Dietary; Tacrolimus

Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the nuclear receptor superfamily. It has been reported that the thiazolidinediones, which are antidiabetic agents and high-affinity ligands for PPARgamma, regulate growth of vascular cells. In the present study, we examined the role of PPARgamma in angiotensin II (Ang II)-induced hypertrophy of neonatal rat cardiac myocytes and in pressure overload-induced cardiac hypertrophy of mice.. Treatment of cultured cardiac myocytes with PPARgamma ligands such as troglitazone, pioglitazone, and rosiglitazone inhibited Ang II-induced upregulation of skeletal alpha-actin and atrial natriuretic peptide genes and an increase in cell surface area. Treatment of mice with a PPARgamma ligand, pioglitazone, inhibited pressure overload-induced increases in the heart weight-to-body weight ratio, wall thickness, and myocyte diameter in wild-type mice and an increase in the heart weight-to-body weight ratio in heterozygous PPARgamma-deficient mice. In contrast, pressure overload-induced increases in the heart weight-to-body weight ratio and wall thickness were more prominent in heterozygous PPARgamma-deficient mice than in wild-type mice.. These results suggest that the PPARgamma-dependent pathway is critically involved in the inhibition of cardiac hypertrophy.

Topics: Actins; Angiotensin II; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Cell Size; Cells, Cultured; Chromans; Disease Models, Animal; Gene Expression; Heart; Heterozygote; Hypoglycemic Agents; Ligands; Mice; Mice, Knockout; Myocardium; Organ Size; Pioglitazone; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone

B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II-induced hypertension by injecting DNA constructs containing the BNP promoter (-2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (P<0.001) at 2 hours and peaked at 12 hours (5.2-fold, P<0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, P<0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (P<0.05) at 2 hours and remained upregulated up to 2 weeks (2.8-fold, P<0.05) during Ang II infusion, except at 12 hours. These results indicate that posttranscriptional control plays a major role in the regulation of ventricular BNP gene expression in Ang II-induced hypertension.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography; Gene Expression Regulation; Heart Rate; Heart Ventricles; Hypertension; Male; Natriuretic Peptide, Brain; Organ Size; Promoter Regions, Genetic; Protein Binding; Rats; Rats, Sprague-Dawley; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcription Factor AP-1

The present study was aimed to investigate whether hyperglycemia may alter the regulation of vascular natriuretic peptide receptors (NPR). The hyperglycemia was induced in rats by the treatment with streptozotocin (50 mg/kg, i.v.). The expression of different subtypes of NPR was determined in the thoracic aorta by reverse transcriptase-polymerase chain reaction and quantitative in vitro receptor autoradiography. The isometric tension and the guanylyl cyclase activity of the isolated thoracic aorta in response to natriuretic peptides were also determined. Following the treatment with streptozotocin, the plasma concentration of atrial natriuretic peptide (ANP) was significantly increased. The expression of NPR-A was increased, while that of NPR-C was reduced. The receptor binding study demonstrated an increased maximal binding capacity of NPR, with its affinity not significantly altered. The magnitude of vasodilation and guanylyl cyclase activity in response to ANP was significantly increased. On the other hand, the vasodilator response as well as the tissue formation of cGMP in response to acetylcholine or sodium nitroprusside was significantly reduced. These results indicate that the hyperglycemia may cause an altered regulation of vascular NPR.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Carrier Proteins; Gene Expression; Guanylate Cyclase; Hyperglycemia; Intracellular Signaling Peptides and Proteins; Iodine Radioisotopes; Isometric Contraction; Male; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Streptozocin; Time Factors; Vasodilation

Epidemiological studies have produced evidence that unfavorable intrauterine environments during fetal life may lead to adverse outcomes in adulthood. We have previously shown that a low-sodium diet, given to pregnant rats over the last week of gestation, results in intrauterine growth restriction (IUGR). We hypothesize that pups born with IUGR are more susceptible to the development of hypertension in adulthood. IUGR fetuses and rats aged 1 wk were characterized for organ growth and renal morphogenesis. The adults (12 wk) were evaluated for weight, systolic blood pressure, activity of the renin-angiotensin-aldosterone system (RAAS), and renal function; hearts and kidneys underwent a histological examination. Brain and cardiac ventricle-to-body ratios were increased in IUGR fetuses compared with age-matched controls, whereas the kidney-to-body ratio was unchanged. Systolic blood pressure was elevated in both IUGR male and female adults. Plasma aldosterone levels were not correlated with increased plasma renin activity. Moreover, urinary sodium was decreased, whereas plasma urea was elevated in both males and females, and creatinine levels were augmented only in females, suggesting a glomerular filtration impairment in IUGR. In our model of IUGR induced by a low-sodium diet given to pregnant rats, high blood pressure, alteration of the RAAS, and renal dysfunction are observed in adult life. Differences observed between male and female adults suggest the importance of gender in outcomes in adulthood after IUGR.

Topics: Aging; Angiotensins; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Corticosterone; Female; Fetal Growth Retardation; Heart Ventricles; Hypertension; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Male; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) regulate cardiac hypertrophy. We investigated ventricular alterations of ANP and BNP in interleukin-6 (IL-6) transgenic mice (TG) and wild type (WT) mice with or without viral infection. The ANP and BNP mRNA/GAPDH mRNA ratios in the ventricles of IL-6 TG mice were twice that of WT mice, but were not increased significantly by viral inoculation. In WT mice, both ANP and BNP responses were significantly increased in the ventricles of mice 10 days after encephalomyocarditis (EMC) viral inoculation. Cardiac weight in IL-6 TG mice was significantly greater than in WT 10 days after viral inoculation. Left ventricular wall thickness and the diameter of ventricular myocytes also were greater in IL-6 TG than WT after viral infection. Primary cultures of neonatal rat cardiac myocyte showed that IL-6 increased ANP and BNP mRNA expression in a dose-responsive fashion. In summary, overexpression of ANP and BNP occurs in the ventricles of IL-6 TG mice, along with increased cardiac weight after infection with EMC virus, and impaired responses in the expression of ANP and BNP.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; DNA Probes; Encephalomyocarditis virus; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Transgenic; Natriuretic Peptide, Brain; Organ Size; Rats

Topics: Aldosterone; Atrial Natriuretic Factor; Body Fluids; Body Weight; Humans; Plasma Volume; Potassium; Renin; Sodium, Dietary; Water-Electrolyte Balance

Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Arteriosclerosis; Atrial Natriuretic Factor; Body Weight; Bradykinin; Cholesterol; Cholesterol, HDL; Drug Evaluation, Preclinical; Indans; Male; Mice; Mice, Knockout; Neprilysin; Propionates; Protease Inhibitors; Pyridines; Substance P; Thiazepines; Triglycerides

Endogenous as well as exogenous atrial natriuretic peptide (ANP) attenuates the development of chronic hypoxic pulmonary hypertension (CHPH) in rats. We built a recombinant adenovirus type 5 containing ANP cDNA under the control of the Rous sarcoma virus long terminal repeat (Ad.ANP). The efficiency of this vector in delivering the ANP gene was first examined in rat primary cultures of pulmonary vessel smooth muscle cells (SMCs) in comparison with Ad.beta GAL. Conditioned medium collected from Ad.ANP-infected cells (1000 TCID(50)/cell) contained 5 x 10(9) M immunoreactive ANP and elicited relaxation of isolated rat pulmonary arteries preconstricted with phenylepinephrine. To examine the effects of adenovirus-mediated ANP expression in the CHPH rat lung, Ad.ANP or Ad.beta GAL was administered via the tracheal route. Immunoreactive ANP was detected in bronchoalveolar fluid as early as 4 days and until 10-17 days after Ad.ANP administration (5 x 10(8) TCID(50)). Lung ANP immunostaining was mainly localized in bronchial and alveolar epithelial cells. As compared with Ad.beta GAL-treated controls, rats given Ad.ANP (5 x 10(8) TCID(50)) on the day before a 2-week exposure to hypoxia (10% O(2)) had lower values for pulmonary artery pressure (32.1 +/- 1.93 vs. 35.5 +/- 2 mmHg, p < 0.01) and Fulton's index (0.52 +/- 0.089 vs. 0.67 +/- 0.12, p < 0.001) and less severe right ventricular hypertrophy and distal vessel muscularization. These results suggest that induction of ANP expression in the lung may hold promise in the treatment of pulmonary hypertension.

Topics: Adenoviridae; Animals; Atrial Natriuretic Factor; Avian Sarcoma Viruses; Body Weight; Bronchoalveolar Lavage Fluid; Cells, Cultured; Culture Media, Conditioned; Cyclic GMP; DNA, Complementary; Dose-Response Relationship, Drug; Epinephrine; Gene Transfer Techniques; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Lung; Muscle, Smooth; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Tissue Distribution; Trachea; Transfection; Transgenes

Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).. SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups.. Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05).. These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Topics: Acrylates; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Heart Rate; Hypertension; Imidazoles; Kidney; Magnetic Resonance Imaging; Male; Myocardium; Natriuresis; Organ Size; Peptide Fragments; Protein Precursors; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Survival Rate; Thiophenes; Ventricular Remodeling

The circulating immunoreactive atrial natriuretic peptide (C-terminal; alpha-ANP) increases during exercise to become suppressed in the first hours of the recovery. The response of the N-terminal ANP fragments to acute exercise is not known while proANP (31-67) appears to be elevated with chronic exercise. We evaluated the plasma concentrations of the N-terminal ANP fragments (1-30) and (31-67) in oarsmen (n=10) before and after two acute exercise bouts separated by 5 h. As control, measurements were made on a day with no exercise (n=12). At rest, the concentrations of proANP(1-30) and proANP(31-67) were 344+/-42 and 810+/-172 pmol x l(-1), respectively. Half an hour after the first exercise bout, proANP(1-30) was elevated (to 404+/-48 pmol x l(-1); P<0.05) and decreased below the pre-exercise level (to 316+/-41 pmol x l(-1); P<0.05) 4 h into the recovery period. Also, 30 min after the second exercise session, the concentration of proANP(1-30) was elevated to 408+/-45 pmol x l(-1) (P<0.05) and the pre-exercise level was re-established on the following morning. Thus, proANP(1-30), rather than proANP(31-67), responded to acute exercise. These results suggest that atrial distension and, therefore, the central blood volume changes markedly in athletes during a day with repeated exercise bouts.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Height; Body Weight; Electric Impedance; Exercise; Heart Rate; Humans; Male; Peptide Fragments; Protein Precursors; Thorax

Activation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) is considered a hallmark of myocardial remodeling. To determine magnitude and relative proportion of activation during the progression to heart failure, we assessed ANP and BNP gene expression in atrial and left ventricular (LV) tissue in a newly developed model of progressive rapid ventricular pacing-induced heart failure in rabbits.. Six animals underwent progressive pacing with incremental rates (330 beats per min (bpm) to 380 bpm over 30 days), resulting in congestive heart failure (CHF). Five animals underwent pacing at 330 bpm for 10 days only (early LV dysfunction, ELVD) and five additional animals served as control group (CTRL).. ELVD was characterized by decreased mean arterial pressure (P=0.05 vs. CTRL) as well as significantly impaired LV function (LV fractional shortening (FS) P<0.01 vs. CTRL) and dilatation (P<0.01 vs. CTRL). CHF was characterized by further decreased mean arterial pressure (P<0.01 vs. ELVD), further impaired LV function (FS P<0.03 vs. ELVD) and dilatation (P<0.01 vs. CTRL). In control animals, significant ANP expression was observed only in atrial tissue (P<0.02 vs. BNP) while BNP expression was ubiquitous but marginal (LV P<0.05 vs. ANP). In ELVD, activation of ANP (atria and LV P<0.05 vs. CTRL) and BNP (atria P<0.05 vs. CTRL, LV n.s.) was observed. In CHF, LV-BNP increased further markedly (P<0.01 vs. CTRL, P<0.05 vs. ELVD) while atrial ANP and BNP expression as well as LV ANP expression remained unchanged (all P=n.s. vs. ELVD).. The current studies demonstrate differential activation of atrial and LV ANP and BNP under normal conditions and during the progression to heart failure and provide a molecular basis for the superiority of BNP as marker of LV dysfunction and CHF.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Disease Models, Animal; Disease Progression; Gene Expression; Heart Failure; Male; Myocardium; Natriuretic Peptide, Brain; Organ Size; Rabbits; RNA, Messenger; Ventricular Dysfunction, Left

Atrial natriuretic peptide (ANP) is an important regulator of sodium metabolism and indirectly of blood pressure. Evidence has accumulated that ANP regulates sodium metabolism through a cascade of steps involving an increase in the level of cGMP, activation of cGMP-dependent protein kinase (PKG), and inhibition of renal tubular Na+, K+-ATPase activity. One of the major substrates for PKG is DARPP-32. In the present study we observed that ANP does not induce natriuresis in mice that lack DARPP-32. In contrast, there was a 4-fold increase in urinary sodium excretion following ANP administration to wild type mice. ANP as well as Zaprinast, a selective inhibitor of cGMP phosophodiesterase, inhibited renal Na+, K+-ATPase activity in wild type mice but had no such effect in mice lacking DARPP-32. Mean arterial blood pressure, measured in conscious animals, was significantly increased in DARPP-32 deficient mice as compared to wild type mice. The results confirm that DARPP-32 acts as a third messenger in the ANP signaling pathway in renal tissue and suggest an important role of DARPP-32 in the maintenance of normal blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Male; Mice; Mice, Knockout; Natriuresis; Nerve Tissue Proteins; Organ Size; Phenotype; Phosphoproteins; Sodium

Enhanced atrial natriuretic factor (ANF) production by the heart is related to hemodynamic overload, cardiac growth, and hypertrophy. The heart is one of the most affected organs during Trypanosoma cruzi infection. We tested the hypothesis that myocarditis produced by parasite infection alters the natriuretic peptide system by investigating the behavior of plasma ANF during the acute and chronic stages of T. cruzi infection in rats. Sprague-Dawley rats were infected with T. cruzi clone Sylvio-X10/7. Cardiac morphology showed damage to myocardial cells and lymphocyte infiltration in the acute phase; and fibrosis and cell atrophy in the chronic period. Plasma ANF levels (radioimmunoassay) were significantly higher in acute (348 +/- 40 vs. 195 +/- 36 pg/ml, P < 0.05, n = 17) and chronic T. cruzi myocarditis (545 +/- 81 vs. 229 +/- 38 pg/ml, P < 0.001, n = 11) than in their respective controls (n = 10 and 14). Rats in the chronic phase also showed higher levels than rats in the acute phase (P < 0.01). The damage of myocardial cells produced by the parasite and the subsequent inflammatory response could be responsible for the elevation of plasma ANF during the acute period of T. cruzi infection. The highest plasma ANF levels found in chronically infected rats could be derived from the progressive failure of cardiac function.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Body Weight; Chagas Cardiomyopathy; Chronic Disease; Disease Models, Animal; Heart; Male; Myocardium; Rats; Rats, Sprague-Dawley

Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17beta-estradiol (E(2)) on the development of pressure-overload hypertrophy.. Ovariectomized mice receiving E(2) or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E(2) treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E(2) blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E(2) had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E(2) treatment led to an increased expression of ANP in animals with pressure overload.. Here, we show that E(2) attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E(2) has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Disease Models, Animal; Estradiol; Estrogen Replacement Therapy; Female; Immunoblotting; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Organ Size; Ovariectomy; p38 Mitogen-Activated Protein Kinases; Peptidyl-Dipeptidase A; Phosphorylation; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction

In this study, semiquantitative reverse transcription-PCR analysis showed that estrogen receptor alpha (ERalpha) and beta (ERbeta) mRNAs are developmentally regulated in the rat heart. We found that ERalpha mRNA was low in all heart chambers of 4-day-old rats, but was elevated in the atria (6- to 18-fold) and ventricles (3- to 4-fold) of adult rats. Western blotting analysis confirmed that these differences were efficiently translated into 67-kDa ERalpha protein. ERbeta mRNA was expressed at its highest level in the left atrium and was 3- to 4-fold lower in other heart chambers of 4-day-old animals. In adult rats ERbeta was decreased dramatically in the left atrium (20-fold) and, to a lesser extent in the other heart chambers (2- to 4-fold). Significant ER changes occurred already in the first week after birth. Accordingly, estrogen regulation in cells from neonatal hearts, as reported in several studies, may not correspond to that occurring in fully differentiated adult hearts, because of an altered degree of ER expression. In adult rats, ovariectomy decreases atrial ERalpha, the atria/body weight ratio, and atrial natriuretic peptide (ANP) transcription. Treatment of ovariectomized rats with 17-beta-estradiol (25 microg, 10 days, s.c.) reversed these changes. In addition, there was no effect of ovariectomy and 17-beta-estradiol supplementation on systolic blood pressure, but in ovariectomized rats a decreased heart rate followed 17-beta-estradiol administration. Similar to the effects on ERalpha in the atria, ovariectomy lowered plasma ANP levels, and 17-beta-estradiol administration restored ANP in the plasma of ovariectomized rats. Changes in plasma ANP correlated with changes in ANP content in the right atrium, as demonstrated by RIA. Increased ANP expression and secretion in response to ERalpha activation may be a protective mechanism in the heart.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Blood Pressure; Body Weight; DNA Primers; Embryo Implantation; Estradiol; Estrogen Receptor beta; Female; Heart; Heart Rate; Male; Myocardium; Organ Size; Ovariectomy; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Ribosomal, 16S; Weight Gain

To evaluate the effect of age and body weight on several neurohumoral variables that are commonly altered in heart failure in Cavalier King Charles Spaniels.. 17 healthy privately owned Cavalier King Charles Spaniels, 10 males and 7 females, ranging in age from 0.4 to 9.7 years, and ranging in body weight from 6.6 to 12.2 kg.. The clinical condition of the dogs was evaluated by physical examination, thoracic radiography, and echocardiography. Plasma nitrate and nitrite (P-NN), N-terminal atrial natriuretic and brain natriuretic peptides (NT-ANP and BNP, respectively), endothelin (ET-1), urine cyclic guanosine monophosphate (U-cGMP), and urine nitrate and nitrite (U-NN) concentrations were analyzed.. Plasma concentrations of NT-ANP and P-NN increased significantly with age, but plasma NT-ANP and P-NN also correlated significantly, irrespective of age. A modest increase of left atrial size did not explain the increase of NT-ANP and P-NN with age. Concentration of ET-1 correlated positively with heart rate; heart rate did not change with age. Weight had a negative impact on NT-ANP, P-NN, and U-cGMP concentrations and left atrial relative size.. Age-matched controls are essential for evaluation of NT-ANP and P-NN concentrations and left atrial size. Weight may alter reference values of plasma NT-ANP, P-NN, and urine cGMP concentrations. Natriuretic peptides can be used as further evidence that heart failure exists. The increased plasma concentrations of NT-ANP (but not BNP) and P-NN with aging reflect neurohumoral physiologic changes that must be distinguished from pathologic changes in patients with heart failure.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Body Weight; Cardiac Output; Creatinine; Cyclic GMP; Dogs; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Failure; Heart Rate; Male; Natriuretic Peptide, Brain; Neurotransmitter Agents; Nitrites; Radiography, Thoracic; Regression Analysis

The regulatory neuropeptide calcitonin-gene related peptide (CGRP) has been shown to evoke a hypertrophic response in isolated cardiomyocytes in vitro, an effect which was attributed to PKC activation. Activation of PKC has previously been implicated in the development of cardiac hypertrophy. We therefore investigated the role of CGRP in pressure overload-induced hypertrophy in vivo, which has not previously been reported. Constriction of the ascending aorta of rats resulted in an increase in the heart weight to body weight ratio, increased myocyte diameter, re-expression of the fetal genes ANF, MHCbeta and skeletal alpha-actin, and decreased expression of the adult genes GLUT4 and SERCA2a. Treatment of neonatal rat pups (1-2 days old) with capsaicin (50 mg/kg), resulted in the permanent de-afferentation of small-diameter unmyelinated CGRP-containing sensory C-fibres. Such treatment caused a 68% decrease in the CGRP-like immunoreactivity of hearts isolated from 10 week old rats (p < 0.001). Contrary to expectations, aortic constriction of capsaicin treated rats had no effect on the development of hypertrophy at the trophic, morphometric or gene expression levels. The results suggest that the development of pressure overload-induced hypertrophy in vivo does not require the regulatory neuropeptide CGRP.

Topics: Actins; Animals; Animals, Newborn; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcitonin Gene-Related Peptide; Calcium-Transporting ATPases; Capsaicin; Cardiomegaly; Cells, Cultured; Constriction, Pathologic; Glucose Transporter Type 4; Histocompatibility Antigens Class I; Monosaccharide Transport Proteins; Muscle Proteins; Myocardium; Organ Size; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Uroguanylin, originally isolated from urine, is a new natriuretic peptide. Its plasma level is increased in association with renal impairment and fluid retention in patients with renal diseases.. Uroguanylin concentrations were measured in patients on hemodialysis (HD, n = 76) and those on continuous ambulatory peritoneal dialysis (CAPD, n = 10) using a sensitive ra- dioimmunoassay for human uroguanylin.. Plasma concentrations of immunoreactive (ir)-uroguanylin in the patients on HD and CAPD (212.0 +/- 17.4 and 245.3 +/- 39.5 fmol/ml) were significantly higher than the value for the normal controls (5.0 +/- 0.3 fmol/ml). Plasma ir-uroguanylin levels before the start of regular HD were correlated with predialysis excess weight based on their dry weights (r = 0.33, p < 0.01) and with dialysis duration (r = 0.26, p < 0.05). The plasma levels in patients with HD, for whom high-flux membranes were used, were decreased at the end of regular HD as compared with the prior levels (p < 0.05), but not in those who underwent HD with conventional membranes.. These findings suggest that the plasma ir-uroguanylin level is related to the patient's volume status as well as renal impairment. Whether the accumulation of uroguanylin has a pathological effect has yet to be determined.

Topics: Adult; Atrial Natriuretic Factor; Body Weight; Female; Humans; Immunoassay; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Natriuretic Peptides; Peptides; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis

The present study was conducted to determine whether preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and whether the increase of plasma atrial natriuretic peptides improves the ability of the kidneys to excrete the fluid load after the operation.. We evaluated 42 patients who underwent the maze procedure. The right atrial appendage was preserved in 22 patients but not in 20. Blood samples were obtained before and after the operation for measurement of atrial natriuretic peptides. To evaluate the influence of atrial natriuretic peptides on the ability of the kidneys, we also measured body weight, fluid balance, and the doses of furosemide and dopamine administered after the operation.. The restoration to sinus rhythm at 1 month after was comparable in the two groups. Plasma atrial natriuretic peptide levels significantly increased after the operation in patients in whom the right atrial appendage was preserved (1 day after: 23.4 +/- 17.8 vs 3 days after: 42.7 +/- 23.6 and 7 days after: 36.3 +/- 23.7 pg/mL, P <.05) but not in patients in whom the right atrial appendage was not preserved (1 day after: 20.0 +/- 19.6, 3 days after: 28.5 +/- 19.3, and 7 days after: 23.0 +/- 16.1 pg/mL). Furthermore, plasma atrial natriuretic peptide levels were significantly lower in patients in whom the right atrial appendage was not preserved than in patients in whom the right atrial appendage was preserved at 3 and 7 days after the operation. The fluid balance during the first 7 days of the postoperative period was comparable in the two groups, although the total dose of dopamine used in the same period was significantly smaller in patients in whom the right atrial appendage was preserved than in patients in whom the right atrial appendage was not preserved (155.3 +/- 119.0 vs 244.9 +/- 129.0 microg/kg, P <.05).. The present study showed that preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and that increased plasma atrial natriuretic peptides may improve the ability of the kidneys to excrete the fluid load after the operation.

Topics: Atrial Appendage; Atrial Fibrillation; Atrial Natriuretic Factor; Body Weight; Cardiac Surgical Procedures; Cardiotonic Agents; Diuretics; Dopamine; Female; Furosemide; Humans; Kidney; Male; Middle Aged; Urine; Water-Electrolyte Balance

To determine the role of endothelin-1 (ET-1) in the upregulation of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) observed in deoxycorticosterone acetate (DOCA)-salt hypertension, the selective ET-1 type-A receptor (ET(A)) antagonist ABT-627 was chronically administered to normal controls and hypertensive rats. Chronic ET(A) blockade in DOCA-salt-treated rats prevented the increase in blood pressure and circulating natriuretic protein (NP) levels and partially prevented left ventricular hypertrophy. The changes observed in NP gene expression in the atria were not affected by ABT-627. In the ventricles, ABT-627 reduced NP gene expression. Rats receiving the ET(A) antagonist alone showed reduced left ventricular NP gene expression. ABT-627 did not affect ventricular collagen III gene expression but enhanced left ventricular alpha-myosin heavy chain expression. These findings suggest that in vivo, ventricular but not atrial NP production is regulated by ET-1. This difference in response between atrial and ventricular NP gene expression to ET(A) receptor blockade is similar to that observed by us after applying angiotensin-converting enzyme inhibitors in other hypertensive models. In general therefore, atrial NP gene expression may not be as sensitive to the endocrine environment as is ventricular NP gene expression.

Topics: Animals; Atrasentan; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Endothelin Receptor Antagonists; Gene Expression Regulation; Heart; Heart Ventricles; Hypertension; Male; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; Organ Size; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium, Dietary; Transcription, Genetic

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Body Weight; Cardiotonic Agents; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardial Contraction; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Serine Proteinase Inhibitors; Vasodilator Agents

Although myocarditis has been implicated in the pathogenesis of heart failure, a definitive relationship between myocardial inflammation, cardiac dysfunction, and changes in myocyte gene expression has not been established. In this study, we examined the hypothesis that myocardial inflammation and replacement fibrosis following an autoimmune response can progress to cardiac dysfunction and may result in progression to the heart failure phenotype. SWXJ mice were immunized with cardiac myosin on day 0 and day 7, in order to induce an autoimmune response to the myosin protein. Cardiac catheterization via the right carotid artery was performed on days 14, 21, 28, 35, and 42, using a 1.4F Millar transducer-tipped catheter. Hearts were weighed, and cross-sections were cut and stained with either haematoxylin and eosin or Masson's trichrome, in order to identify areas of inflammation and/or fibrosis. Myocardial gene expression was determined by Northern blot analysis. In mice with histological evidence of myocarditis, the heart weight/body weight ratio increased beginning on day 14, and cardiac function decreased beginning on day 21. Myocardial inflammation was accompanied by significant fibrosis beginning on day 21. Quantitation of mRNA showed expression of ventricular atrial naturietic factor, as well as a decrease in myosin heavy chain alpha, beginning on day 21. These data demonstrate that autoimmune inflammation of the heart results in significant cardiac dysfunction, leading to phenotypic alterations similar to those demonstrated in human heart failure and animal models of heart failure.

Topics: Animals; Atrial Natriuretic Factor; Autoantigens; Autoimmune Diseases; Body Weight; Endomyocardial Fibrosis; Gene Expression Regulation; Heart; Heart Failure; Male; Mice; Mice, Inbred Strains; Models, Animal; Molecular Motor Proteins; Muscle Proteins; Myocarditis; Myocardium; Myosin Heavy Chains; Myosins; Organ Size; RNA, Messenger; T-Lymphocytes, Cytotoxic; Ventricular Dysfunction, Left

The electrical instability of hypertrophied and failing hearts is caused by delayed repolarisation, which is thought to be due in part to altered levels and/or patterns of expression of ion channel genes. The aim of this study was to investigate changes in the levels and pattern of cystic fibrosis transmembrane conductance regulator (cftr) mRNA expression in a combined pressure and volume overload model of heart failure in the rabbit, using in situ mRNA hybridisation. There was a decrease in cftr mRNA expression, primarily due to a decrease in epicardial expression and, hence, loss of the normal epicardial to endocardial gradient of cftr mRNA expression in the rabbit left ventricle. In contrast there was an increase in atrial natriuretic factor (anf) mRNA expression in the hypertrophied hearts with preferential reexpression in subendocardial regions. The patterns of both cftr and anf mRNA expression in the hypertrophied hearts were similar to those seen in embryonic hearts. This suggests that the reversion to an embryonic pattern of gene expression in cardiac hypertrophy applies to ion channel genes. The loss of the normal transmural gradient of repolarising ion channels is likely to contribute to instability of repolarisation in the hypertrophied heart and hence increased risk of cardiac arrhythmias in patients with heart failure.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cystic Fibrosis Transmembrane Conductance Regulator; Endocardium; Gene Expression; Hypertrophy, Left Ventricular; In Situ Hybridization; Ion Channels; Oligonucleotides, Antisense; Organ Size; Pericardium; Rabbits; RNA, Messenger

To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Body Weight; Calcium-Binding Proteins; Calcium-Transporting ATPases; Cardiomegaly; Diastole; Gene Expression; Heart Ventricles; Hemodynamics; Hypertrophy; Irbesartan; Male; Myocardial Infarction; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; RNA, Messenger; Tetrazoles

Angiotensin-converting enzyme (ACE) inhibitors have proven an effective means to control hypertension and manage cardiac hypertrophy. It is presently unknown if newer specific angiotensin II subtype 1 receptor (AT1R) antagonists are as effective or more effective in treating these conditions compared with ACE inhibitors. There is evidence that these classes of drugs may affect cardiac hypertrophy by different mechanisms. This study compared the effect of irbesartan, an AT1R antagonist, with that of captopril, an ACE inhibitor, on expression of early genetic markers of cardiac hypertrophy in lean male SHHF/Mcc-fa(cp) rats. SHHF/Mcc-fa(cp) rats (n = 10/group) were given captopril (100 mg/kg/day), irbesartan (50 mg/kg/day), or placebo for 16 weeks. Irbesartan and captopril significantly reduced systolic pressure and produced similar rightward shifts in the angiotensin I dose-response curve. Renal renin gene expression was increased 8.6-fold by irbesartan and 17.7-fold by captopril. The only effect on echocardiographic findings was a similar decrease in aortic peak velocity, an index of systolic function, by both treatments. Early markers of cardiac hypertrophy were significantly attenuated by both drugs. Both drugs produced marked and equivalent reductions in left ventricular atrial natriuretic peptide (ANP) messenger RNA (mRNA) levels compared with controls. This decrease in ANP gene expression was accompanied by a decrease in plasma ANP concentration in the treatment groups. The shift from V1 to V3 myosin isozymes was similarly decreased in both treatment groups, compared with controls. These data suggest that captopril and irbesartan are similarly effective in controlling expression of genes associated with ventricular hypertrophy in heart failure-prone SHHF/Mcc-fa(cp) rat.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Body Weight; Captopril; Cardiomegaly; Dose-Response Relationship, Drug; Echocardiography; Gene Expression; Heart Failure; Irbesartan; Isoenzymes; Male; Myosin Heavy Chains; Organ Size; Rats; Rats, Inbred Strains; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; RNA, Messenger; Systole; Tetrazoles

The effect of volume reduction on vasoactive substances and their role in estimating dry weight in haemodialysis patients was studied. Plasma atrial natriuretic peptide (ANP), catecholamines, antidiuretic hormone, renin activity and serum aldosterone were measured in 12 patients before and after bicarbonate haemodialysis. Haemodynamical changes were registered and cardiac function and diameter of the inferior vena cava were measured by echocardiography before and after dialysis. Plasma concentration of ANP was significantly reduced by haemodialysis from 209 +/- 51 to 69 +/- 13 pg mL(-1) (n = 12, P < 0.05), whereas concentrations of the other hormones were unchanged. The change in the concentration of ANP did not have significant correlation with weight reduction. The concentration of ANP correlated positively with the diameter of the inferior vena cava (r = 0.70, P < 0.05) after dialysis, but not before dialysis. The concentration of ANP before or after haemodialysis or its change during dialysis did not correlate with any other biochemical parameter. The results show that plasma ANP level is decreased after volume reduction in patients with chronic renal failure, whereas other hormonal systems are unresponsive. However, plasma concentration of ANP seems to have no role in estimating dry weight in chronic haemodialysis patients.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Body Weight; Catecholamines; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neurotransmitter Agents; Renal Dialysis; Renin; Ultrasonography; Vasopressins

Topics: Adult; Atrial Natriuretic Factor; Body Weight; Edema; Female; Humans; Renin

To clarify the mechanism of cardiac hypertrophy in carnitine-deficient JVS mice, we studied the possible role of catecholamine metabolism. Cardiac hypertrophy occurs 2 weeks after birth. The turnover of norepinephrine in the ventricles of JVS mice at 2 weeks was 3 times that of control, but it was not different from control at 5 days when the heart weight was not changed. To evaluate the accelerated norepinephrine turnover, we examined the effects of catecholamine metabolism inhibitors (alpha-methyltyrosine and 6-hydroxydopamine) and catecholamine receptor blockades (propranolol, prazosin and yohimbine) on the ratio of heart weight to body weight (HW/BW) and on the augmented expression of atrial natriuretic peptide (ANP) and the down-regulated carnitine deficiency-associated gene expressed in ventricle (CDV-1). The HW/BW ratio in JVS mice treated with catecholamine metabolism inhibitors and receptor blockades was significantly lower than in JVS mice without treatment, but still higher than in controls treated with each drug and in JVS mice treated with carnitine. The HW/BW ratio of JVS mice with propranolol was not significantly different from that of JVS mice treated with catecholamine metabolism inhibitors and was significantly lower than that of JVS mice treated with prazosin and yohimbine. Northern blot analysis showed that the altered expression of ANP and CDV-1 was not corrected in the ventricles of JVS mice treated with any of the drugs except carnitine. These results suggest that the catecholamine metabolism accelerated in JVS mice ventricles at 2 weeks is not the major cause of cardiac hypertrophy, but probably promotes cardiac hypertrophy mainly through the beta-adrenergic signaling pathway. The aberrant gene expression of ANP and CDV-1 found in JVS mice seems to be independent of catecholamine metabolism, and mediated primarily by the systemic carnitine deficiency.

Topics: Adrenergic Antagonists; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Carnitine; Cyclosporine; Disease Models, Animal; Mice; Microtubule-Associated Proteins; Muscle Proteins; Norepinephrine; RNA, Messenger

We have previously established the existence of atrial natriuretic factor (ANF) gene expression within the renal parenchyma. Neither the role nor the regulation of this extracardiac source of ANF is clearly defined. To determine whether renal ANF gene expression, similar to cardiac expression, is linked to the activity of the renin-angiotensin system (RAS), we compared renal ANF gene expression in rats after suprarenal aortic banding, a hypertension model associated with activation of RAS, and in the deoxycorticosterone acetate (DOCA)-salt model, which is characterized by depression of RAS. Renal ANF mRNA was measured with a quantitative competitive reverse transcription polymerase chain reaction method. DOCA-salt hypertension significantly reduced the expression of renal ANF. In contrast, aortic banding significantly increased renal ANF expression. In both cases, ANF gene expression in the heart increased. Ramipril treatment at 10 micrograms/kg of aortic-banded rats, a treatment that specifically affects local RAS but maintains hypertension, normalized renal ANF mRNA levels. Altogether, these results suggest that renal ANF gene expression is modulated by local RAS and is independent of circulating RAS and hypertension per se. The marked decrease of renal ANF mRNA in DOCA-salt hypertension suggests a pathogenic role for renal ANF gene downregulation by decreasing the sodium excretory mechanism mediated by the local expression of ANF acting on receptors found in the inner medullary collecting ducts. In aortic banding, renal ANF gene expression upregulation suggests a local compensatory function consistent with the consensus role of natriuretic peptides in the modulation of RAS, thus ameliorating the sodium-retaining effects of renal underperfusion.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression Regulation; Hypertension; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium, Dietary; Transcription, Genetic

We investigated the effects of long-term treatment with a selective phosphodiesterase 5 inhibitor E4010, 4-(3-chloro-4methoxybenzyl)amino-1-(4-hydroxypiperidino)-6-phth alazin ecarbonitrile monohydrochloride, on the survival rate of rats with pulmonary hypertension induced by monocrotaline (MCT). After an s.c. injection of 40 mg/kg MCT (day 0), male Wistar rats of 4 weeks of age were divided into four groups. Vehicle-treated rats (control, n = 8) and MCT-treated rats (n = 32) were fed a commercial diet. E4010-treated rats were given a commercial diet containing 0.01% (E4010 0.01%, n = 32) and 0.1% (E4010 0.1%, n = 32) of E4010, respectively. At day 23, all rats in the control group and 28.1% of those in the MCT group (P <.01 versus control) were alive. Although the survival rate of E4010 0.01%-treated rats was not improved (50%) compared with MCT, those at 0.1% showed a significant difference (84. 4%, P <.01 versus MCT). For MCT rats (n = 9), right ventricle weight and the levels of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, and cyclic AMP were higher compared with control (n = 8). In E4010 0.1%-treated rats (n = 27), the right ventricular hypertrophy was suppressed, and the increase in plasma cGMP level was amplified compared with MCT without any effects on plasma ANP, BNP, and cyclic AMP levels. Accordingly, we consider that the mechanism of action of E4010 may be related to the decreased pulmonary arterial pressure caused by the augmentation of pulmonary arterial relaxation through an ANP and/or BNP-cGMP system. These results suggest that E4010 will be useful for the treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Body Weight; Calcium Signaling; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Hypertension, Pulmonary; Ligands; Male; Monocrotaline; Nitric Oxide; Nitriles; Organ Size; Phosphodiesterase Inhibitors; Piperidines; Rats; Rats, Wistar; Survival Rate

The effects of water deprivation for 3 days were studied in pregnant rats and their fetuses on day 21 of gestation. Maternal water deprivation induced a significant decrease of the body weight in both maternal and fetal rats. This weight loss was accompanied by significant increases in plasma osmolality and haematocrit in both maternal and fetal rats. Similarly, dehydration significantly decreased plasma atrial natriuretic peptide (ANP) concentrations and increased plasma aldosterone concentrations in maternal and fetal rats. Water-deprived maternal rats presented a significant increase in total ANP receptor density in isolated renal glomeruli and adrenal zona glomerulosa membranes. This increase was due to a significant increase in ANPc receptor density in both renal glomeruli and adrenal zona glomerulosa. The densities of total ANP, ANPb and ANPc receptors in fetal kidneys and adrenal glands were not affected by maternal dehydration. These results suggest that the dehydrated maternal rat is able to up-regulate the number of its ANP receptors in its kidneys and adrenal glands, in response to a decrease in plasma ANP concentrations. In contrast, the fetal rat does not seem to be able to regulate its own ANP receptors in response to maternal dehydration, in spite of a decrease in plasma ANP concentrations.

Topics: Adrenal Glands; Animals; Atrial Natriuretic Factor; Body Weight; Dehydration; Female; Fetus; Gestational Age; Kidney; Male; Pregnancy; Pregnancy, Animal; Rats; Receptors, Atrial Natriuretic Factor; Water Deprivation

This study was undertaken to improve the measurement of glomerular filtration rate (GFR) during the acute diuretic phase induced by atrial natriuretic peptide (ANP), which may indeed alter the renal clearance of inulin (GFRCL) due to dead space error. A technique to measure GFR without urine collections was therefore developed in anaesthetized rats prepared as for micropuncture. To do so, arterial blood was periodically collected and renal venous blood was withdrawn simultaneously from a catheter inserted into the left suprarenal vein to determine the renal extraction coefficient of inulin (CEIN). In addition, renal blood flow (RBF) was continuously measured with an electromagnetic flow transducer fitted around the left renal artery to estimate renal plasma flow (RPF). GFR (GFRCE) was then calculated as the product of RPF and CEIN. To study the effects of ANP on GFR, rats were injected i.v. with 10 microliters of saline without (n = 6; vehicle) or with 1 microgram ANP (n = 6; ANP) and GFRCE and GFRCL were compared before and after each treatment. They did not differ significantly during baseline measurements in each experimental group and were not modified after vehicle. Similarly, RBF remained constant. In contrast, RBF and GFRCE increased rapidly and simultaneously 90 s after ANP, from 9.07 +/- 0.25 to 10.07 +/- 0.35 (12%) and from 1.209 +/- 0.188 to 1.715 +/- 0.190 ml min-1 (42%), respectively (P < 0.05). GFRCL increased to an even greater extent (88%). Moreover, the peak enhancement of GFRCL was delayed and occurred 180 s after ANP. The renal clearance of inulin was thus unduly elevated due to sudden changes in the dead space induced by the diuretic effect of ANP. In conclusion, determination of glomerular filtration rate by the method of renal extraction of inulin provided more reliable results than those achieved using the classical method of renal clearance of inulin. Moreover, it was sufficiently sensitive to detect small and transient changes in GFR induced by the injection of 1 microgram ANP.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Glomerular Filtration Rate; Hematocrit; Injections, Intravenous; Inulin; Kidney; Male; Organ Size; Rats; Rats, Wistar; Renal Circulation; Urination

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) upregulation are genetic markers for the chronic hypertrophic phenotype but also have important acute physiologic effects on salt and water balance and blood pressure control. The presence of a dual NP-system led us to hypothesize a differential expression of ANP and BNP in response to an acute hemodynamic stress of volume overload in the left ventricle (LV) and right ventricle (RV). Accordingly, we examined the temporal relationship between the RV and LV expression of ANP and BNP mRNA and NP receptor mRNA levels on days 1, 2, 3, and 7 after induction of aortocaval fistula in the rat. LV end-diastolic pressure was increased 1.5-fold by day 3 and 2.0-fold by day 7 compared to control (P<0.05). LV weight increased by day 7 compared to control (2.34+/-0.04 vs 3.07+/-0.10 mg/g, P<0.05) while RV weight did not change over the 7 days. There was a 7-fold increase of ANP mRNA in LV at day 1, which was sustained through day 7, while LV BNP mRNA levels did not differ from controls over the 7 days. In contrast, RV mRNA transcript levels for ANP and BNP were increased >2-fold by day 2 and this increase was sustained throughout 7 days. NP clearance receptor was decreased by 75% by day 7 in the LV but did not change in the RV. Thus, LV ANP mRNA levels increased before the onset of LV hypertrophy and RV BNP mRNA levels increased in the absence of RV hypertrophy. The disparate response of BNP and the NP clearance receptor transcript levels in the LV and RV may be related to differences in load and/or differential expression of the NP system in the LV and RV in response to acute haemodynamic stress.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Gene Expression Regulation; Hemodynamics; Male; Myocardium; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Transcription, Genetic

Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.. Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment.. The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Volume; Body Weight; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Echocardiography; Fibrosis; Gene Expression; Genes, Immediate-Early; Heart Rate; Immunosuppressive Agents; Male; Myocardium; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Signal Transduction; Tacrolimus

The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg.kg-1.day-1 s.c.) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2-3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs (P < 0.01, +2.0 +/- 0.5 vs. +0.3 +/- 1.1 kg; 1,043 +/- 218 vs. 241 +/- 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant tau) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated (P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.

Topics: Adrenergic beta-Agonists; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Pacing, Artificial; Dobutamine; Dogs; Growth Hormone; Heart Failure; Insulin-Like Growth Factor I; Isoproterenol; Kidney; Microscopy, Electron; Myocardial Contraction; Myocardium; Vascular Resistance; Ventricular Function, Left

We examined the effect of a calcium antagonist, manidipine hydrochloride, on cardiac hypertrophy and the expression of the atrial natriuretic peptide (ANP), transforming growth factor beta 1 (TGF-beta 1), and extracellular matrix protein genes in rats with isoproterenol-induced cardiac hypertrophy. Rats were continuously infused with saline or isoproterenol (0.5 mg/kg per day) for 7 days using an osmotic minipump. Treatment with manidipine hydrochloride (once a day at 3 mg/kg) began 1 day before minipump implantation and continued until the end of the experiments (each group; n = 6). After treatment, left ventricular weight was measured and mRNA was extracted and analyzed by Northern blot hybridization. Isoproterenol increased left ventricular weight (2.40 +/- 0.04 g/kg; p < 0.01) without increasing blood pressure. ANP, collagen type I and type III, and fibronectin mRNAs were increased 1.5-(p < 0.01), 1.9- (p < 0.01), 2.7- (p < 0.01), and 3.2-fold (p < 0.01), respectively, by isoproterenol infusion. However, TGF-beta 1, collagen type IV, and laminin B1 and B2 mRNA levels were unchanged by isoproterenol. Manidipine hydrochloride prevented isoproterenol-induced left ventricular hypertrophy (2.26 +/- 0.02 g/kg; p < 0.01) and expression of mRNA of ANP (0.9-fold of the control value; p < 0.01), collagen types I (1.1-fold; p < 0.01) and type III (1.6-fold; p < 0.01), and fibronectin (1.1-fold; p < 0.01). Thus, manidipine hydrochloride prevented cardiac hypertrophy and changes in the expression of genes for ANP and interstitial components of extracellular matrix induced by isoproterenol.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Body Weight; Calcium Channel Blockers; Collagen; Dihydropyridines; Fibronectins; Heart Ventricles; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardium; Nitrobenzenes; Organ Size; Piperazines; Pulse; Rats; Rats, Wistar; RNA, Messenger

Brain natriuretic peptide (BNP) is a pulmonary vasodilator that is elevated in the right heart and plasma of hypoxia-adapted rats. To test the hypothesis that BNP protects against hypoxic pulmonary hypertension, we measured right ventricular systolic pressure (RVSP), right ventricle (RV) weight-to-body weight (BW) ratio (RV/BW), and percent muscularization of peripheral pulmonary vessels (%MPPV) in rats given an intravenous infusion of BNP, atrial natriuretic peptide (ANP), or saline alone after 2 wk of normoxia or hypobaric hypoxia (0.5 atm). Hypoxia-adapted rats had higher hematocrits, RVSP, RV/BW, and %MPPV than did normoxic controls. Under normoxic conditions, BNP infusion (0.2 and 1.4 micro g/h) increased plasma BNP but had no effect on RVSP, RV/BW, or %MPPV. Under hypoxic conditions, low-rate BNP infusion (0.2 micro g/h) had no effect on plasma BNP or on severity of pulmonary hypertension. However, high-rate BNP infusion (1.4 micro g/h) increased plasma BNP (69 +/- 8 vs. 35 +/- 4 pg/ml, P < 0.05), lowered RV/BW (0.87 +/- 0.05 vs. 1.02 +/- 0.04, P < 0.05), and decreased %MPPV (60 vs. 74%, P < 0.05). There was also a trend toward lower RVSP (55 +/- 3 vs. 64 +/- 2, P = not significant). Infusion of ANP at 1.4 micro g/h increased plasma ANP in hypoxic rats (759 +/- 153 vs. 393 +/- 54 pg/ml, P < 0.05) but had no effect on RVSP, RV/BW, or %MPPV. We conclude that BNP may regulate pulmonary vascular responses to hypoxia and, at the doses used in this study, is more effective than ANP at blunting pulmonary hypertension during the first 2 wk of hypoxia.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart Ventricles; Hemodynamics; Histocytochemistry; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Vasodilator Agents

The effect of blood volume repletion after frusemide administration on the right atrial and pulmonary artery pressure responses of horses to exercise has not been reported. We examined right atrial and pulmonary artery pressure and plasma atrial natriuretic peptide concentration (ANP) responses to an incremental exercise test in 6 Standardbred mares. Horses were treated, in a 3 way cross over design, with isotonic saline, frusemide (1 mg/kg bwt, i.v.), and frusemide followed 3 h later by lactated Ringer's solution (12 ml/kg bwt, i.v.). Three and a half hours after saline or frusemide administration the horses completed a standard exercise test. Frusemide significantly affected the right atrial and pulmonary artery pressure and ANP responses to exercise. Fluid administration decreased plasma total protein concentrations at rest and during running and abolished the effects of frusemide on the haemodynamic and ANP responses to exercise. These results suggest that the haemodynamic effect of frusemide in running horses is mediated, in large part, by a reduction in plasma and blood volume.

Topics: Animals; Atrial Function, Right; Atrial Natriuretic Factor; Blood Proteins; Blood Volume; Body Weight; Cross-Over Studies; Diuretics; Female; Fluid Therapy; Furosemide; Heart Rate; Hematocrit; Hemodynamics; Horse Diseases; Horses; Hypotension; Isotonic Solutions; Physical Conditioning, Animal; Pulmonary Wedge Pressure; Ringer's Solution; Sodium Chloride

1. Calcium and potassium intakes inversely correlate with blood pressure in experimental hypertension. Therefore, we examined the effects of calcium and potassium supplements alone and in combination on arterial tone in spontaneously hypertensive rats (SHR). Wistar-Kyoto (WKY) rats served as normotensive controls. Calcium and potassium contents in the control diet were both 1%, while those in supplemented chows were 3% and 3.5%, respectively. The sodium content of all diets was moderately elevated to 1.1%. 2. After 12 weeks of the study systolic blood pressures in SHR on high calcium and on high potassium diets were markedly lower (about 53 and 58 mmHg, respectively) than in hypertensive controls, while combined supplementation of these cations reduced blood pressure even further (about 69 mmHg). 3. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Both high calcium and high potassium diets improved the impaired relaxation to acetylcholine (ACh) in SHR, while the combination of these supplements completely normalized this response. Cyclo-oxygenase inhibition by diclofenac augmented the relaxation to ACh in hypertensive controls but not in the other groups. Nevertheless, enhanced endothelium-mediated dilatation was still observed in the presence of diclofenac and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in all supplemented groups. Interestingly, additional blockade of Ca2+-activated K+ channels by tetraethylammonium abolished the improved relaxation to ACh in SHR on high calcium and on high potassium, but distinct responses were still observed in WKY rats and SHR on the combined supplement. 4. When hyperpolarization of smooth muscle was prevented by precontraction of the preparations with 50 mM KCl, only marginal differences were observed in the diclofenac and L-NAME-resistant relaxations to ACh between the study groups. Finally, endothelium-independent vasorelaxations of noradrenaline-precontracted rings to nitroprusside, isoprenaline and cromakalim were comparably augmented by all supplements. 5. In conclusion, the vascular mechanisms underlying the antihypertensive effect of high calcium and high potassium diets during moderately elevated sodium intake in SHR may involve enhanced arterial hyperpolarization, increased smooth muscle sensitivity to nitric oxide and decreased production of vasoconstrictor prostanoids. The administration of these cations in combination was more effec

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium; Male; Mesenteric Arteries; Muscle Tonus; Myocardium; Organ Size; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Neutral endopeptidase inhibition (NEPI) provides a potential avenue to modulate the actions of atrial natriuretic peptide (ANP). We tested the hypothesis that acute and chronic NEPI increased the renal responses at baseline and after acute volume expansion in rats. ANP plasma levels and cGMP excretion were significantly increased with acute NEPI by SQ 28.603, whereas chronic inhibition with SCH 34826 did not lead to any changes. The ratio of cGMP excretion per plasma ANP, however, was significantly increased (6.2 +/- 0.9) by chronic treatment with SCH 34826 compared to chronic vehicle treatment (4.2 +/- 0.7) indicating an activated renal ANP receptor system. Baseline diuresis and natriuresis were enhanced with acute but not with chronic treatment. After acute volume expansion, ANP increased five-fold with acute NEPI, whereas it only increased about 70% in chronically inhibited rats. The natriuretic (497 +/- 62 vs. 329 +/- 42 micromol/60 min with vehicle, P < 0.05) and diuretic responses were significantly enhanced with chronic treatment. Together with an increased cGMP/ANP ratio, these data suggest that chronic activation of the renal ANP system after long-term NEPI facilitated the excretion of an acute volume load. These findings may have therapeutic implications in patients with chronic sodium retention.

Topics: Alanine; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Diuresis; Enzyme Inhibitors; Heart Rate; Hemodynamics; Kidney; Male; Natriuresis; Neprilysin; Rats; Rats, Wistar

In rats with streptozotocin (STZ)-diabetes for 2 or 4 weeks, the atrial natriuretic peptide (ANP) concentrations in the atria decreased whilst that of ANP in the plasma and ventricles increased. ANP concentrations in the hypothalamus and in the brainstem did not change in either 2- or 4-week diabetic rats. Atrial ANP content was partly restored by insulin replacement in 4-week diabetic rats. Plasma ANP concentrations and ventricular ANP contents were reversed to normal by insulin treatment in both 2- and 4-week diabetic rats. Solution-hybridization-RNase protection assay showed a significant increase in the preproANP mRNA expression in the ventricles but not in the atria. These results indicated that the STZ-diabetes increased the synthesis of ANP in the ventricles and consequently its release from the ventricles. The synthesis of ANP in the atria did not change as judged from the preproANP mRNA expression but the release of ANP from the atria might also be increased for ANP content decreased in the atria. The reason for the difference in the response of atrial and ventricular preproANP concentrations to STZ-diabetes is not known.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Brain Stem; Diabetes Mellitus, Experimental; Gene Expression; Heart Atria; Heart Ventricles; Hypothalamus; Male; Myocardium; Nucleic Acid Hybridization; Rats; Rats, Sprague-Dawley; Ribonucleases; RNA, Messenger

The increase in natriuretic peptides (NP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP) production and release by cardiocytes that occurs in hypertension has been considered to be a compensatory mechanism against ventricular overload. Studies on NP production in the spontaneously hypertensive rat (SHR), an experimental model of human hypertension, have produced controversial results and were carried out when hypertension was already established (> 17 weeks). At this time, age-related physiologic and molecular changes in cardiac muscle are difficult to separate from those related to hypertension, ie, increased ANF production and plasma levels. In addition, most of the studies used male rats because the rate of increase in arterial blood pressure--as well as the level to which it rises--is greater in males than in females. Studies of a similar nature using female SHR are not available. The aim of this work was to determine 1) whether ANF and BNP production and secretion increase with the development of hypertension in genetically hypertensive rats; 2) whether a sexual dimorphism in ANF and BNP production and secretion is present in the genetically hypertensive rat during the development of hypertension; and 3) whether the demand for ANF and BNP is the same from each chamber of the heart under these experimental conditions. Age-matched male and female SHR, Wistar-Kyoto (WKY), and Sprague Dawley (SD) rats at 2, 4, and 8 weeks of age were used. The normotensive SD were included to provide a wider basis for baseline findings, as WKY rats are not always a suitable control for SHR due to genetic variations. Natriuretic peptide plasma levels and tissue content were measured by radioimmunoassay. ANF, BNP, as well as alpha- and beta-myosin heavy chain (MHC) mRNA were estimated by Northern blot analysis. Blood pressure (BP) of more than 150 mm Hg was found only in 8-week-old male SHR. Plasma immunoreactive (ir)ANF and irBNP increased significantly at puberty (8 weeks) in both male and female SHR. The earliest molecular change encountered during the development of hypertension was a significant increase in BNP mRNA in the right and left atria from both male and female 8-week-old SHR. In the ventricles from both male and female SHR, there was no increase in the ratio of left ventricular wet weight/body weight, no increase in ventricular ANF mRNA transcripts, and no myosin heavy chain isoform switch (a protein marker of hypertrophy). irBNP ventri

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Gene Expression; Heart Ventricles; Hypertension; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Sex Factors

The present study was carried out to determine whether the increased salt intake induce by increased specific sodium appetite in pregnant rats modifies water-salt homeostasis throughout pregnancy. Two groups of pregnant rats were used, one fed ad libitum with a normal sodium (NS) diet consisting of standard rat chow and distilled water, and the other fed with a high-sodium (HS) diet with free access to chow, distilled water plus saline solution (1.5% NaCl). Virgin rats in dioestrus were also studied as non-pregnant controls. Pregnant animals were studied on days 4, 9, 14, 20 and 21 of gestation at which time body weight, water and saline intake, sodium excretion, plasma atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) concentrations, as well as plasma osmolality were determined. Data showed that water intake was higher in the NS group, but total fluid intake (water plus saline) was higher in the HS group throughout pregnancy. Dietary sodium intake was the same for both groups but total sodium intake (chow plus saline) was 60-98% higher in the HS rats. Pregnant HS rats excreted more fluid (35-50%) and sodium (up to 100%) compared with NS rats, indicating that the animals could change their renal excretion in response to a 2.5-fold higher dietary sodium intake compared with the control level. Salt satiety during pregnancy did not modify plasma ANP concentration. In both groups of pregnant rats ANP levels increased 3-fold on day 14 without significant alteration in sodium excretion, suggesting that the natriuretic action of ANP is attenuated at least after the second week of pregnancy. High sodium intake did not change plasma AVP concentration or osmolality and both groups showed the same gradual decrease in plasma osmolality (approximately 8 mosmol kg-1) at the end of pregnancy that was not accompanied by decreased plasma AVP concentration. The present data show that rats maintain the special homeostatic equilibrium that occurs in normal pregnancy even when they are allowed to increase sodium intake to satisfy their salt appetite during this period of the reproductive cycle.

Topics: Animals; Appetite; Arginine Vasopressin; Atrial Natriuretic Factor; Body Weight; Diet; Female; Gestational Age; Homeostasis; Osmolar Concentration; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar; Sodium, Dietary; Water; Water-Electrolyte Balance

We evaluated the effects of myocardial infarction (MI) on the hemodynamics and the expression of atrial natriuretic peptide (ANP) mRNA in rats with streptozotocin-induced diabetes. Eight weeks after streptozotocin injection, the diabetic rats and age-matched nondiabetic controls underwent coronary artery ligation. One week later, the left ventricular end-diastolic pressure, systolic blood pressure, infarct size, and serum ANP levels did not differ significantly between the diabetic and nondiabetic rats. Compared with control animals without MI, the atrial ANP/beta-actin mRNA ratio in rats with MI was increased to 195% in diabetic animals and 213% in nondiabetic animals. In the left ventricle, however, the ANP/beta-actin mRNA ratio in diabetic animals with MI was increased to only 131% compared with control animals, whereas the corresponding increase in nondiabetic animals was 240% (p<0.05). Thus, the modulation of ANP mRNA expression after MI was impaired in the left ventricle, but not in the atria, of diabetic rats. A reduced myocardial expression of ANP could increase the morbidity and mortality associated with cardiovascular disorders in patients with diabetes.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Coronary Disease; Diabetes Mellitus, Experimental; Heart Atria; Heart Ventricles; Hemodynamics; Ligation; Male; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar; RNA, Messenger

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are potent pulmonary vasodilators that are upregulated in hypoxia-adapted rats and may protect against hypoxic pulmonary hypertension. To test the hypothesis that C-type natriuretic peptide (CNP) also modulates pulmonary vascular responses to hypoxia, we compared the vasodilator effect of CNP with that of ANP on pulmonary arterial rings, thoracic aortic rings, and isolated perfused lungs obtained from normoxic and hypoxia-adapted rats. We also measured CNP and ANP levels in heart, lung, brain, and plasma in normoxic and hypoxia-adapted rats. Steady-state CNP mRNA levels were quantified in the same organs by relative RT-PCR. CNP was a less potent vasodilator than ANP in preconstricted thoracic aortic and pulmonary arterial rings and in isolated lungs from normoxic and hypoxia-adapted rats. Chronic hypoxia increased plasma CNP (15 +/- 2 vs. 6 +/- 1 pg/ml; P < 0.05) and decreased CNP in the right atrium (35 +/- 14 vs. 65 +/- 17 pg/mg protein; P < 0.05) and in the lung (3 +/- 1 vs. 14 +/- 3 pg/mg protein; P < 0.05) but had no effect on CNP in brain or right ventricle. Chronic hypoxia increased ANP levels fivefold in the right ventricle (49 +/- 5 vs. 11 +/- 2 pg/mg protein; P < 0.05) but had no effect on ANP in lung or brain. There was a trend toward decreased ANP levels in the right atrium (2,009 +/- 323 vs. 2,934 +/- 397 pg/mg protein; P = not significant). No differences in CNP transcript levels were observed between the two groups of rats except that the right atrial CNP mRNA levels were lower in hypoxia-adapted rats. We conclude that CNP is a less potent pulmonary vasodilator than ANP in normoxic and hypoxia-adapted rats and that hypoxia raises circulating CNP levels without increasing cardiopulmonary CNP expression. These findings suggest that CNP may be less important than ANP or BNP in protecting against hypoxic pulmonary hypertension in rats.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Brain; Hemodynamics; Hypoxia; In Vitro Techniques; Lung; Male; Muscle, Smooth, Vascular; Natriuretic Peptide, C-Type; Organ Size; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasodilation; Ventricular Function, Right

It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatmen

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Captopril; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Hypertension; Male; Methionine; Neprilysin; Propionates; Rats; Rats, Inbred SHR; Renal Circulation; Renin; Sulfhydryl Compounds

Sodium and water retention are common in acromegaly and upon GH administration. The underlying mechanisms, however, have not been clearly characterized as yet. Therefore, the aim of this study was to examine possible alterations of atrial natriuretic peptide (ANP), an endogenous regulator of volume homeostasis, in response to chronic elevated GH. We used GH-transgenic mice (GH-TM) as a model for chronic hypersomatotropinemia and moreover investigated 7 and 27 week old animals, respectively, in order to discriminate between short and long term effects of GH overexpression. Hematocrit values were reduced in GH-TM compared to control animals and it is known that plasma volume is increased in these animals. Structural lesions of the kidney were found in the GH-TM, however, in the animals studied there were no signs of renal insufficiency as evidenced by serum creatinine and urea levels. The serum concentration of immunoreactive ANP (IR-ANP) determined by RIA was significantly (P < 0.005) elevated in the young GH-TM as compared to control littermates (81.7+/-13.3 vs. 50.9+/-10.8 fmol/ml). The increase in serum IR-ANP of 27 week old GH-TM, however did not reach the level of significance (57.13+/-16.3 vs. 50.25+/-16.4 fmol/ml). Serum samples of control mice as well as of the 7 week old animals mainly contained ANP 99-126, known to be the circulating form of ANP. In contrast, serum of 27 week old GH-TM predominantly showed the cardiac storage form of ANP, ANP 1-126. Cardiac expression of ANP was quantified by Northern blot analysis. mRNA coding for ANP was found 1.2- and 2-fold increased in the atria of 7 and 27 week old GH-TM, respectively. In parallel, a 2.2-fold (7 week) and 2-fold (27 week) increase of IR-ANP was observed in transgenic atria compared to tissue of control animals. In contrast, no significant difference of ANP mRNA expression or of content of IR-ANP was observed in the ventricles of both groups of animals. In conclusion, GH-TM show various alterations in their ANP status suggesting an influence of the peptide on the effect of GH in fluid retention.

Topics: Aging; Animals; Atrial Natriuretic Factor; Blotting, Northern; Body Weight; Chromatography, High Pressure Liquid; Growth Hormone; Hematocrit; Hypertrophy; Kidney; Liver; Mice; Mice, Transgenic; Myocardium; Organ Size; Peptide Fragments; Plasma Volume; Protein Precursors; Radioimmunoassay

We investigated the relation between atrial natriuretic factor (ANF) gene expression and the status of the renin-angiotensin system (RAS) in aortic tissue in rats made hypertensive by either aortic banding or by deoxycorticosterone acetate (DOCA)-salt administration. These experimental models of hypertension are known to have differences in terms of the status of RAS. ANF messenger RNA (mRNA) levels were measured in aortic tissue by using a newly developed quantitative competitive reverse transcription polymerase chain reaction (QC-RT-PCR) technique. Changes in the proportions of alpha1 and alpha2 isoforms of Na+K+-adenosine triphosphatase (ATPase) mRNA levels were used as indicators of aortic hypertrophy. Treatment with DOCA alone, salt alone, or DOCA-salt for 5 weeks increased aortic-weight/body-weight ratio and aortic angiotensinogen mRNA levels, but did not change alpha1 or alpha2 Na+K+-ATPase mRNA levels. Aortic ANF mRNA levels had a tendency to increase after treatment with DOCA, salt, or DOCA-salt, but this change did not reach statistical significance. Suprarenal aortic banding for 6 weeks or 12 weeks increased aortic-weight/body-weight ratio (12 weeks), decreased alpha2 Na+K+-ATPase and angiotensinogen mRNA levels, but did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Treatment with ramipril, an angiotensin-converting enzyme (ACE) inhibitor was carried out for 6 weeks just after aortic banding (prevention experiment) or after 6 weeks in rats that were banded for the previous 6 weeks (regression experiment). High-dose ramipril (1 mg/kg)--a treatment known to inhibit both tissue and circulating RAS--normalized aortic-weight/body-weight ratio, and also normalized alpha2 Na+K+-ATPase mRNA levels. Aortic angiotensinogen mRNA levels of banded rats treated with high-dose ramipril was higher than those of the normal control, sham operated, and banded rats. Treatment with high-dose ramipril did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Low-dose ramipril (10 microg/kg)--a treatment that selectively inhibits tissue RAS--normalized aortic-weight/body-weight ratio but did not normalize alpha2 Na+K+-ATPase mRNA levels (regression experiment) or angiotensinogen mRNA levels (prevention experiment) and did not change either alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. The results suggest that, in contrast to previous findings in heart and kidney, the regulation of ANF mRNA levels in aortic tissue is largely independent

Topics: Angiotensinogen; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression; Gene Expression Regulation; Hypertension; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium-Potassium-Exchanging ATPase

During the EXEMSI experiment, an international crew of 4 subjects (1 woman and 3 men) was confined for 60 days in a normobaric diving chamber (with 1060 mbar atmospheric pressure) to simulate life in a space station and to assess the effects of confinement on psychological and physiological factors. Blood pressure and blood volume regulating hormones (atrial natriuretic peptide, renin, aldosterone) and urine data (24-h urine outputs, ionogram) were measured before (BDC: baseline data collection), during (D: day) and after (R: recovery) confinement. We also measured energy expenditure and total body water, 14 days before, and after 27 days of confinement, by the double-labeled water method. We found a marked increase in 24-h urine output during most of the confinement in the men and the woman. Body weight (-1.8 +/- 0.9 kg) and energy expenditure (-1064 +/- 143 kcal/d, p<0.01) decreased in the 3 men. The total body water (TBW) decreased by 1.5 +/- 1.2 l in the men. Stress was not indicated by plasma and urine catecholamines but plasma growth hormone was elevated on D2 (p<0.01 vs. BDC) in the men. This study shows that confinement conditions can modify body fluid (increases in 24-h urine outputs and TBW changes) and energetic metabolisms.

Topics: Adaptation, Physiological; Adult; Aldosterone; Atmosphere Exposure Chambers; Atrial Natriuretic Factor; Blood Pressure; Body Water; Body Weight; Confined Spaces; Energy Intake; Energy Metabolism; Female; Hormones; Humans; Male; Osmolar Concentration; Plasma Volume; Renin; Social Isolation; Space Simulation; Spacecraft; Urinalysis; Water-Electrolyte Balance; Weightlessness Simulation

Contralateral uninephrectomy attenuates unilateral ischemic injury. The present work was performed to elucidate whether the beneficial effect of uninephrectomy was associated with the modification of ischemia-induced changes in plasma or renal renin activity. A 60-min left renal artery occlusion was conducted in right nephrectomized (Nx) and sham-nephrectomized (Sham-Nx) rats. The decline in inulin clearance 48 h after ischemia was significantly less in Nx rats than in Sham-Nx animals (0.50 +/- 0.10 vs. 0.052 +/- 0.029 ml/min/kidney, p < 0.05). Following ischemia, plasma renin activity (PRA) significantly increased in Sham-Nx (from 5.4 +/- 0.9 to 15.5 +/- 1.4 ng AI/ml/min, p < 0.01) but not in Nx (from 3.5 +/- 0.5 to 5.0 +/- 1.0 ng AI/ml/ min) animals. PRA and renal cortical renin content (2,200 +/- 225 vs. 1,257 +/- 187 ng AI/h/mg protein, p < 0.05) were significantly less in Nx rats than in Sham-Nx animals 48 h after renal ischemia. The decrease in body weight was greater in Nx rats than in Sham-Nx animals. Plasma atrial natriuretic peptide (ANP) (195 +/- 30 vs. 302 +/- 40 pg/ml, p < 0.05) and renal dopamine (DA) content (3.2 +/- 0.5 vs. 13.7 +/- 1.3 ng/g tissue, p < 0.01) were rather lower in the Nx group when compared with the Sham-Nx group. No significant difference was found in the intrarenal content of norepinephrine (NE) between two ischemic groups. These findings suggested that uninephrectomy prevents the ischemia-induced increase in renin activity. The prevention of the increase in renin activity in Nx rats is not be mediated through the modulation of ischemia-induced changes in sodium balance, plasma ANP level and/or intrarenal contents of NE and DA.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Carbon Radioisotopes; Dopamine; Inulin; Ischemia; Kidney; Male; Nephrectomy; Norepinephrine; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Renal Artery Obstruction; Renin; Reperfusion Injury; Sodium

In 15 patients with end-stage renal failure and proven coronary heart disease, profile haemodialysis with decreasing ultrafiltration rate and hyperionic, decreasing dialysate solute concentration was compared with conventional, extracorporeal bicarbonate haemodialysis (Na+D = 138 mmol/l). Body fluid distribution and the release of vasoactive hormones (plasma renin activity, aldosterone, norepinephrine, epinephrine, and atrial natriuretic peptide) were investigated. Haemodialysis with constant ultrafiltration rate and constant dialysate composition (A) was followed by two dialysis profiles: decreasing ultrafiltration rate (B) and additional hyperionic, decreasing dialysate sodium concentration (C). In all 15 patients, the dialysis procedures (A) - (C) were used for 2 weeks each with six sessions, the last being taken for investigation. Body fluid distribution was calculated. In patients with serum sodium above 136 mmol/l, the conventional dialysis (A) as well as the Uf profile (B) showed a net fluid shift from extracellular volume (ECV) to intracellular volume (ICV). Using the profile with hyperionic, decreasing Na+D (C), the reverse fluid shift with decreasing ICV was achieved not only in those with serum Na+ <136 mmol/l, but also in those with serum Na+ > or = 136 mmol/l. The release of vasoactive hormones decreased already at profile haemodialysis (B) compared with (A) and was further reduced in (C). These results would suggest, profile dialyses B and C to have less impact on the cardiovascular system in elderly patients assuming higher patient comfort compared with the standard dialysis procedure. A higher benefit was obtained in C compared with B, presumably due to the additional prevention of the ICV shift and plasma volume depletion in patients with initial serum sodium > or = 136 mmol/l using transiently hyperionic Na+D. These results show that in elderly patients, hyperionic profile haemodialysis (Na+D > Na+S) had less impact on cardiovascular regulation than conventional bicarbonate dialysis.

Topics: Aged; Aging; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Coronary Disease; Epinephrine; Extracellular Space; Female; Humans; Intracellular Fluid; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Renal Dialysis; Renin; Sodium; Ultrafiltration

To characterize cardiac hypertrophy in juvenile visceral steatosis (JVS) mice with systemic carnitine deficiency, we investigated how the hypertrophy develops and whether it is associated with altered expression of any specific genes, especially atrial natriuretic peptide (ANP) and contractile protein genes, in the hypertrophied ventricle. Cardiac hypertrophy in JVS mice became apparent at 10 days after birth and progressed during development. The hypertrophy was observed in the ventricles but not in the atria. ANP mRNA was more intensively expressed in JVS ventricles than in control even at 5 days. Carnitine administration ameliorated the cardiac hypertrophy and suppressed the augmentation of ANP mRNA in the ventricles. Isoform change of expression of alpha-actin genes from cardiac to skeletal was seen in the ventricles of JVS mice at 2 weeks. There was no difference in the ratio of beta-myosin heavy chain mRNA to alpha-myosin heavy chain mRNA between control and JVS mice at 5 days, but at 2 weeks the ratio was significantly lower in JVS mice than in control. These results suggest that the molecular characteristics of cardiac hypertrophy caused by carnitine deficiency are different from those of cardiac hypertrophy caused by aortic constriction.

Topics: Actins; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Carnitine; Disease Models, Animal; Gene Expression Regulation, Developmental; Heart Ventricles; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Myocardial Contraction; Myosin Heavy Chains; Organ Size; RNA, Messenger; Time Factors

Chronic pressure overload is known to increase cardiac mass and expression levels of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs. Although mechanical stretching of cardiac myocytes could cause these changes, humoral factor(s) secondary to pressure overload may also be involved. To dissociate humoral effects from the effects of mechanical loading on cardiac hypertrophic responses, we examined expression of ANP and BNP at both mRNA and protein levels and proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded under conditions with or without hypertension by aortic coarctation. Seven days after transplantation, cardiac atrophy that usually occurs in transplanted hearts without hypertension by coarctation was prevented in the transplanted hearts with hypertension by coarctation. The levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts with relative to those without hypertension by coarctation. The plasma level of angiotensin II was higher in rats with than without hypertension by coarctation. Plasma endothelin-1 levels were not significantly different between the two groups. In addition, levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts without hypertension relative to those in the in situ hearts. The proportion of the V3 myosin isoform was also increased in the transplanted hearts without hypertension relative to the in situ hearts. These results indicate that humoral factor(s) secondary to the pressure overload produced by aortic coarctation enhanced the cardiac hypertrophic response and elevated the levels of mRNAs encoding these embryonic markers. Moreover, our findings regarding ANP and BNP expression in the transplanted hearts provide additional evidence that the fetal genes are reexpressed during the process of cardiac atrophy as well as in cardiac hypertrophy.

Topics: Angiotensin II; Animals; Aortic Coarctation; Atrial Natriuretic Factor; Atrophy; Blood Pressure; Body Weight; Cardiomegaly; Endothelin-1; Heart Rate; Heart Transplantation; Hypertension; Male; Myosins; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred Lew; RNA, Messenger; Transcription, Genetic; Transplantation, Heterotopic; Transplantation, Isogeneic

Mechanisms that regulate atrial natriuretic peptide (ANP) expression during hypoxia are not well defined. We hypothesized that plasma immunoreactive ANP (irANP) and right heart irANP and ANP mRNA levels would be greater in a strain of Sprague-Dawley rats that develops more severe hypoxic pulmonary hypertension (H rats) than another strain (M rats). After 3 wk of hypoxia (0.5 atm), right ventricular systolic pressure (RVSP) and the right ventricle (RV) weight-to-left ventricle plus septum (LV (+) S) weight ratio [RV/(LV+S)] were greater in H rats than in M rats (70 +/- 4 vs. 40 +/- 2 mmHg and 0.59 +/- 0.02 vs. 0.50 +/- 0.02, respectively; P < 0.05 for both), but plasma ANP increased twofold and RV irANP and ANP mRNA increased fivefold in both rat strains. After 3 days of normoxic recovery from chronic hypoxia, RVSP, RV/(LV+S), and RV irANP and ANP mRNA levels decreased in M rats but not in H rats. Plasma irANP decreased to baseline levels in both rat strains. We conclude that, in addition to changes in RV pressure and hypertrophy, hypoxia acts through other mechanisms to modulate RV ANP synthesis and circulating ANP levels in hypoxia-adapted rats.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Heart; Heart Atria; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Male; Myocardium; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Species Specificity; Systole; Time Factors; Transcription, Genetic; Ventricular Function, Left; Ventricular Function, Right

Adaptation of cardiac muscle to prolonged hypobaric hypoxia (770-740 mbar, 2,250-2,550 m), endurance training, and their combination was studied in rats by investigating the gene expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in atria and ventricles. Rats were assigned into the following groups according to the barometric conditions and physical activity; normobaric sedentary (NS), normobaric training, hypobaric sedentary (HS), and hypobaric training (HT). Experimental periods were 10, 21, and 56 days; the groups at 91 days served as recovery groups from exposure to and training in normobaric and hypobaric conditions for 56 days. The right ventricular hypertrophy in HT rats at 10 days and 56 days was associated with elevated BNP mRNA levels (2.1- and 1.7-fold, P < 0.05, respectively), whereas hypobaric exposure without training was not sufficient to significantly increase ventricular BNP gene expression, although it lead to hypertrophy of the right ventricle. Right and left atrial BNP mRNA levels were also increased (up to 3.9-fold, P < 0.01) in 10-day HS and 10-day HT groups. ANP mRNA levels in right ventricle and left ventricular epicardium were over twofold higher (P < 0.05-0.01) in 10-day HS and 10-day HT groups in comparison to 10-day NS group. Plasma immunoreactive ANP concentration was increased (P < 0.05) in both hypobaric groups up to 21 days. The results show that exposure to hypobaric hypoxia itself and endurance training in hypobaric, hypoxic conditions lead to a marked early increase in ventricular and atrial ANP and BNP mRNA levels. The adaptational response to hypoxia was more pronounced when the oxygen availability was lowered additionally by endurance training carried out in hypobaric hypoxic conditions.

Topics: Acclimatization; Animals; Atmospheric Pressure; Atrial Natriuretic Factor; Body Weight; Heart; Heart Atria; Hypertrophy, Right Ventricular; Hypoxia; Male; Myocardium; Natriuretic Peptide, Brain; Organ Size; Physical Conditioning, Animal; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Transcription, Genetic

The natriuretic peptide system is suggested to be involved in the pathogenesis of salt-sensitive hypertension; a recent report indicated that disruption of the atrial natriuretic peptide precursor gene caused salt-sensitive hypertension. However, natriuretic peptide receptor (NPR)-A knockout mice did not show enhanced salt sensitivity of blood pressure. The aim of the present study was to investigate the role of NPR-C, the other receptor for atrial natriuretic peptide, in increased salt sensitivity of blood pressure. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were placed on a 0.3% or 8% NaCl diet for 4 weeks. Blood pressure was elevated by salt loading only in DS rats. RNase protection assay demonstrated that NPR-C transcript level in the kidney was reduced by chronic salt loading in both DR and DS rats, whereas expression of NPR-A and NPR-B was not altered. The reduction of NPR-C mRNA in response to salt loading was enhanced in DS compared with DR rats. In situ hybridization indicated that the salt-induced NPR-C change was attributed mainly to suppressed expression of NPR-C in the podocytes. NPR-C gene expression was regulated by salt loading in a tissue-specific manner; the marked decrease in NPR-C mRNA by salt loading was seen only in the kidney. These data suggest that the exaggerated salt-induced reduction of NPR-C in the kidney of DS rats may play an important role in the pathogenesis of salt hypertension in this animal, possibly related to impaired renal sodium excretion.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Body Weight; Gene Expression; Hypertension; Isomerism; Kidney; Male; Natriuretic Agents; Rats; Rats, Inbred Strains; Receptors, Cell Surface; RNA, Messenger; Sodium Chloride; Tissue Distribution

We postulated that the cyclin-dependent kinase inhibitors p21 and p27 could regulate the alterations in growth potential of cardiomyocytes during left ventricular hypertrophy (LVH). LVH was induced in adult rat hearts by aortic constriction (AC) and was monitored at days 0, 1, 3, 7, 14, 21, and 42 postoperation. Relative to sham-operated controls (SH), left ventricle (LV) weight-to-body weight ratio in AC increased progressively with time without significant differences in body weight or right ventricle weight-to-body weight ratio. Atrial natriuretic factor mRNA increased significantly in AC to 287% at day 42 compared with SH (P < 0.05), whereas p21 and p27 mRNA expression in AC rats decreased significantly by 58% (P < 0.03) and 40% (P < 0.05) at day 7, respectively. p21 and p27 protein expression decreased significantly from days 3 to 21 in AC versus SH, concomitant with LV adaptive growth. Immunocytochemistry showed p21 and p27 expression in cardiomyocyte nuclei. Thus downregulation of p21 and p27 may modulate the adaptive growth of cardiomyocytes during pressure overload-induced LVH.

Topics: 3T3 Cells; Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Body Weight; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; Enzyme Inhibitors; Heart; Hypertrophy, Left Ventricular; Male; Mice; Microtubule-Associated Proteins; Myocardium; Organ Size; Polymerase Chain Reaction; Rats; Rats, Wistar; Reference Values; RNA, Messenger; Time Factors; Transcription, Genetic; Tumor Suppressor Proteins; Vasoconstriction; Ventricular Function, Left

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Cyclic GMP; Dihydropyridines; Hemodynamics; Hormones; Hypertension; Kidney; Rats; Rats, Inbred SHR; Renin; Tetrazoles

Baroreceptor-heart rate reflex sensitivity is decreased in congestive heart failure. The reflex control of heart rate and sympathetic nerve activity in rats with chronic volume overload, an established model for moderate heart failure, is still unknown. Therefore, we investigated the regulation of humoral and neuronal sympathetic activity and the baroreflex control of heart rate and sympathetic nerve activity in conscious, unrestrained rats with aortocaval shunt. Rats with aortocaval shunts had larger hearts (388 +/- 11 vs. 277 +/- 4 mg/100 g body wt), elevated central venous pressures (14 +/- 4 vs. 4 +/- 3 mmHg), and higher atrial natriuretic peptide plasma levels (87 +/- 16 vs. 25 +/- 3 pmol/l) than controls but had similar systemic blood pressure and heart rate values. Plasma epinephrine (0.63 +/- 0.16 vs. 0.21 +/- 0.08 pmol/l, P < 0.05) and norepinephrine concentrations (0.27 +/- 0.03 vs. 0.16 +/- 0.02 pmol/l, P < 0.05) were elevated in shunted rats compared with controls. Nitroprusside-induced hypotension led to a significantly greater increase in efferent splanchnic sympathetic nerve activity in shunted rats than in controls (0.9 +/- 0.1 vs. 2.6 +/- 0.6 microV, P < 0.05), whereas the heart rate responses were not different between the groups. These results indicate that the regulation of the autonomic nervous system is altered in chronically volume-overloaded rats. The arterial baroreflex control of efferent splanchnic sympathetic nerve activity was dissociated from the control of heart rate. Therefore, analysis of the activation of sympathetic nervous system assessed by direct measurements of efferent sympathetic nerve activity appears to be more sensitive for the detection of altered autonomic nervous system function than the analysis of baroreflex control of heart rate.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Body Weight; Epinephrine; Heart; Heart Rate; Male; Nitroprusside; Norepinephrine; Organ Size; Portasystemic Shunt, Surgical; Rats; Rats, Wistar; Reference Values; Splanchnic Circulation; Sympathetic Nervous System; Vena Cava, Inferior

In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix.. Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.. (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Atrial Natriuretic Factor; Base Sequence; Body Weight; Constriction; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Renin

Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ETA and ETB receptor antagonist.. Seventy male Sprague-Dawley rats (175 to 200 g) were divided into four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600 micrograms.kg-1.h-1 by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan. Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1 day before operation. Norepinephrine caused increases in absolute ventricular weight and ratios of ventricular weight to body weight and ventricular RNA to protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal alpha-actin, and beta-myosin heavy chain, which in adult rat ventricle are indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine did not significantly increase expression of ET-1 mRNA. Bosentan attenuated norepinephrine-induced increases in ventricular weight, ratio of RNA to protein, and expression of skeletal alpha-actin mRNA and beta-myosin heavy chain mRNA at 5 days, but it did not attenuate increased ventricular expression of atrial natriuretic factor mRNA.. These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.

Topics: Actins; Administration, Oral; Animals; Animals, Newborn; Atrial Natriuretic Factor; Biomarkers; Body Weight; Bosentan; Cells, Cultured; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelins; Gene Expression Regulation; Hypertrophy, Left Ventricular; Male; Muscle Proteins; Myocardium; Myosin Heavy Chains; Norepinephrine; Organ Size; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; RNA, Antisense; RNA, Messenger; Sulfonamides

Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.

Topics: Administration, Oral; Animals; Aorta, Thoracic; Arteriosclerosis; Atrial Natriuretic Factor; Body Weight; Cholesterol, Dietary; Diet, Atherogenic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glycopeptides; Hemodynamics; Hypercholesterolemia; Indans; Lipids; Male; Natriuretic Peptide, C-Type; Neprilysin; Nitroprusside; Organ Culture Techniques; Propionates; Proteins; Rabbits; Substance P; Vasodilation

The usefulness of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and cyclic guanosine 3',5'- monophosphate (cGMP) as markers of fluid overload was examined in hemodialysis (HD) patients without diabetes mellitus. Plasma concentrations of ANP, BNP, CNP, and cGMP all decreased significantly during HD. Before HD, there was a strong correlation between plasma concentrations of ANP and those of BNP, and plasma concentrations of cGMP correlated significantly with those of all three natriuretic peptides. The cardiothoracic ratio also correlated significantly with plasma concentrations of ANP and those of BNP before HD. Systolic blood pressure correlated significantly only with plasma concentrations of CNP, both before and after HD. Changes in body weight during HD correlated only with those in plasma ANP; there was thus no correlation between changes in body weight and those in plasma CNP. In conclusion, only plasma ANP is a useful marker of the proper volume and dry weight of HD patients. Furthermore, CNP may participate in cardiovascular regulation in HD patients in a manner different from those of ANP and BNP.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Atrial natriuretic peptide (ANP)-gene knockout mice of three genotypes (+/+, +/-, and -/-) were maintained on a low-salt diet (0.008% NaCl). They were then fed either the same low-salt diet or a high-salt diet (8% NaCl) for 1 wk. No differences were found among genotypes in daily food and water intakes or in urinary volume and electrolyte excretions. Arterial blood pressures measured in anesthetized animals at the end of the dietary regimen were significantly and similarly increased in -/- compared with +/+ mice on each diet. Renal excretion of fluid and electrolytes was measured in anesthetized mice before and after acute blood volume expansion. No genotype differences were observed before volume expansion. After volume expansion the wild-type (+/+) mice had much greater saluretic responses than either the heterozygous (+/-) or the homozygous mutant (-/-) animals on the low-salt diet but not on the high-salt diet. We conclude that ANP lowers blood pressure in the absence of detected changes in renal function; ANP is not essential for normal salt balance, even on high-salt intake; and ANP is essential for the natriuretic response to acute blood volume expansion on a low-salt but not high-salt intake.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Body Fluids; Body Weight; Diet, Sodium-Restricted; Electrolytes; Female; Genotype; Glomerular Filtration Rate; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuresis

The transgenic rat TGR(mRen2)27, carrying the mouse Ren-2 gene, is a new model to elucidate the role of the local renin-angiotensin system in vivo. However, the role of the local renin-angiotensin system in the heart remains to be determined in TGR(mRen2)27.. TGR(mRen2)27 were treated with various antihypertensive drugs for 6 weeks to examine the effects on cardiac hypertrophy and gene expression. Cardiac mRNAs were examined by Northern blot analysis. In TGR(mRen2)27, left ventricular hypertrophy was associated with a decrease in alpha-myosin heavy chain expression of 31% and an increase in skeletal alpha-actin and atrial natriuretic polypeptide expression by 2.6- and 21-fold, respectively (P < .05), thereby showing the shift of myocardium to a fetal phenotype. Furthermore, cardiac collagen and laminin expressions were increased in TGR(mRen2)27 (P < .05), suggesting the occurrence of cardiac remodeling. Although treatment of TGR(mRen2)27 with a high dose of TCV-116 (angiotensin AT1 receptor antagonist) or manidipine (calcium antagonist) combined with atenolol (beta 1-adrenergic receptor blocker) completely normalized blood pressure, TCV-116 regressed cardiac hypertrophy and suppressed the changes in cardiac mRNA levels of TGR(mRen2)27 much more potently than manidipine with atenolol. Furthermore, the inhibitory effects of a low dose of TCV-116 on cardiac hypertrophy and altered gene expressions of TGR(mRen2)27 were greater than those of doxazosin (alpha 1-adrenergic receptor blocker) combined with atenolol, despite their similar hypotensive effects.. Our present observations provide evidence that the cardiac renin-angiotensin system in TGR(mRen2)27 is responsible for cardiac hypertrophy, phenotypic modulation, and remodeling.

Topics: Actins; Analysis of Variance; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Heart; Heart Rate; Laminin; Male; Mice; Muscle, Skeletal; Myocardium; Organ Size; Phenotype; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger; Transcription, Genetic

A correct estimation of volume status and so-called dry weight in dialysis patients remains a difficult clinical problem. Clinical status and chest X-ray are not sensitive enough, while invasively measured central venous pressures are not routinely available. Recently, the sonographic determination of the diameter and collapse of the inferior vena cava (IVC) has been proposed as a noninvasive method for estimating intravascular volume. We tried to evaluate the clinical relevance of this method in dialysis patients by comparing it with central venous pressures (CVP) and atrial natriuretic peptide (ANP). To establish a normal range and to control for confounding variables, we examined a large number of healthy controls. Furthermore, the influence of tricuspid insufficiency was examined echocardiographically. Measurements of the IVC diameters were well reproducible, with a coefficient of variation for interobserver error of 2.2%, and a coefficient of variation of 1.4% for intraobserver error. The collapse index was less well reproducible and therefore not used for further analysis. In 86 normal controls (age 18 to 76 years), IVC diameters showed a wide variation, and they were not correlated to age, height, weight, or body surface area. However, there was a significant correlation of IVCex to heart rate (r = 0.63, P < 0.001). Therefore, we calculated percentiles of the heart rate-IVCex relation in normals, and compared the results in patients to these. In 10 overhydrated haemodialysis patients, CVP was closely correlated to IVCex (r = 0.72, P < 0.001), but there was a wide interindividual variation of the slope of this relation. An IVCex above the 95th percentile of normal was a good predictor of an elevated CVP (i.e. > 12 cmH2O). In another 39 stable, chronic haemodialysis patients, there was a significant correlation of the intradialytic decrease of ANP and IVCex (r = 0.69, P < 0.001). However, this correlation existed only in patients without tricuspid insufficiency. In summary, sonography of the inferior vena cava is a valuable tool for estimating dry weight in dialysis patients, provided that some caveats are kept in mind: (i) there is a wide variation of IVC diameters in normals, and single measurements are not helpful in individual patients; (ii) there is a significant, inverse correlation between IVC diameters and heart rate, and the precision of intravascular volume assessment is enhanced by interpreting heart rate corrected diameters; (iii) the pre

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Body Weight; Humans; Middle Aged; Renal Dialysis; Ultrasonography; Venae Cavae

To determine the effect of hindlimb suspension on body fluid volume, salt and water balance, and relevant hormones, two series of experiments were performed in an experimental protocol including periods of isolation (7 days), horizontal attachment (7 days), and suspension (14 days). 1) During the first experiment, water and electrolyte balance, arginine vasopressin (AVP), and guanosine 3',5'- cyclic monophosphate (cGMP) were determined in urine, atrial natriuretic peptide in plasma and atria, and renin concentration and AVP in plasma in 30 rats. 2) During the second experiment, blood volume and extracellular fluid volume were measured by a dilution technique (Evans blue and sodium thiocyanate) in another 30 rats. We observed a pronounced and early effect of horizontal attachment on the renal variables. After 48 h, diuresis (49%), natriuresis (44%), kaliuresis (36%), osmotic load (39%), creatinine (28%), and AVP excretion (155%) were significantly increased in attached rats (P < 0.05). There was no short-term (24-h) effect of suspension on urine flow and Na+, K+, creatinine, and AVP excretion, but the urine cGMP decreased significantly (45%; P < 0.05). Significant decreases in natriuresis, kaliuresis, urine creatinine, and osmotic load occurred in the suspension group 7 days after suspension. After the 14-day tail suspension, plasma volume and extracellular fluid volume measured in suspended rats were not different from isolated rat values, whereas plasma volume increased by 15% (P < 0.05) in the attached rats. Plasma immunoreactive plasma atrial natriuretic levels of suspended rats were significantly reduced by 35% vs. isolated rats (P < 0.001) and by 18% vs. attached rats (P < 0.05). By using this experimental protocol, the physiological alterations revealed that suspension produced some acute and long-term effects, but the fixation to the suspension device, restraint, and confinement have their own influence on fluid distribution and renal function.

Topics: Animals; Atrial Natriuretic Factor; Body Water; Body Weight; Electrolytes; Hindlimb; Male; Rats; Rats, Wistar; Vasopressins

The clinical criteria to assess hydration status are not always reliable. Hence, the development of techniques to estimate more accurately post-dialysis dry weight (DW) remains a major challenge. The present study evaluates the value of the inferior vena cava (IVC) diameter, plasma concentration of atrial natriuretic peptide (ANP), and plasma renin activity (PRA) in determining the DW in chronic haemodialysis children.. Twelve overhydrated haemodialysis patients (4 girls, 8 boys) with a mean age of 12.8 were admitted to the study. Clinical, electrocardiographic, telecardiographic and echocardiographic findings, IVC and collapsibility indices and plasma concentrations of ANP and PRA were investigated before and after ultrafiltration (UF) therapy. Twelve age-matched normal children were studied as controls. Analysis of variance and Dunnett's test were applied for comparisons between patients and controls.. Following UF therapy the patients' mean IVC collapsibility index was increased from 42.3 to 53.6% and IVC index was decreased from 1.08 to 0.81 cm/m2, both statistically significant. The pre-UF therapy collapsibility and IVC indices of the patient group were significantly different from those of the control group (56.9% and 0.70 cm/m2 respectively). The patients' mean plasma concentrations of ANP were 171 +/- 47.4 pg/ml before UF, 129 +/- 51.3 pg/ml after UF and 102 +/- 38.7 pg/ml in the control group. The ANP levels of the patients showed a significant decrease following the UF therapy. PRA was measured as 0.82 ng/ml/h before UF and 1.08 ng/ml/h after UF, but the increase was not statistically significant.. Our findings revealed increased diameter of the IVC and plasma ANP concentrations and decreased collapsibility due to overhydration. Echography of IVC may be a promising non-invasive tool to estimate the DW in haemodialysis children. Further studies providing normative values for the IVC indices in both haemodialysis and normal children are required.

Topics: Adolescent; Atrial Natriuretic Factor; Body Water; Body Weight; Child; Echocardiography; Female; Humans; Male; Methods; Renal Dialysis; Renin; Time Factors; Vena Cava, Inferior

Factors related to atrial natriuretic peptide (alpha-ANP) regulation and its potential impact on excretory transplant function were examined in a prospective cohort study of 20 patients with end-stage renal disease over 21 days after allogenic kidney transplantation. Depending on posttransplant graft function, patients were separated into those with primary renal function (PF group, n = 10) and posttransplant acute renal failure (ARF group, n = 10). ANP concentrations were markedly elevated in both PF and ARF immediately after renal transplantation, even when compared with the pretransplant dialysis phase (PF group: 939 +/- 467 pg/ml; ARF group: 648 +/- 306 pg/ml, on 3rd postoperative day; "normals': 72 +/- 35 pg/ml). Whilst ANP levels were persistently elevated in patients with acute renal failure, there was a steady decrease in plasma concentrations in patients with primary renal function (PF: 270 +/- 122 pg/ml on 21st day). ANP concentration correlated with endogenous creatinine clearance (rz = 0.56, p < 0.01, PF group). Moreover, there was a greater correlation between ANP levels and postoperative hydration status, measured as central venous pressure or the difference from predialysis dry weight (rz = 0.79 and rz = 0.74, p < 0.01, PF group). Systolic blood pressure was also positively correlated with ANP concentrations. Together, these factors accounted for a total correlation coefficient of r = 0.87 (p < 0.001) in multiple regression analysis. No significant relation was found between plasma ANP levels and total or fractional sodium excretion or free water clearance. With the restoration of renal function most vasoactive hormones (renin-aldosterone system, catecholamines, vasopressin) decreased towards normal values, whilst ANP plasma concentrations remained elevated.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Catecholamines; Central Venous Pressure; Cohort Studies; Creatinine; Cyclic GMP; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Period; Prospective Studies; Renin; Transplantation, Homologous; Vasopressins

The purpose of this study was to characterize the hormonal responses to a restraining system in four adult male rhesus monkeys (Macaca mulatta) in preparation for a spaceflight project. After the monkeys were accustomed to food and water (Phase I), blood-volume-regulating hormones were measured during three phases: 10 days in a metabolic cage (Phase II), 16 days sitting in a restrained position in a specially designed metabolism chair (Phase III) and 10 days in metabolic cage (Phase IV). An increase of active renin (30%) and vasopressin (25%) was observed at the end of Phase III. A decrease of atrial natriuretic peptide (ANP), urodilatin, and sodium excretion occurred during the first days of Phase III. Catecholamines were unchanged. A dramatic increase (tenfold) in urinary excretion of growth hormone occurred during all of Phase III and at the beginning of Phase IV. These findings are similar to those found in man during isolation inactivity and during confinement stress.

Topics: Aldosterone; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Body Weight; Catecholamines; Creatinine; Growth Hormone; Heart Rate; Hormones; Humans; Hydrocortisone; Macaca mulatta; Male; Peptide Fragments; Renin; Restraint, Physical; Social Isolation; Sodium; Stress, Psychological; Time Factors; Urea; Vasopressins

We examined the relationship between cardiac hypertrophy, myosin heavy chain (MHC) isoform expression, and production of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) before and after the development of DOCA-salt hypertension. DOCA-salt rats exhibited significant left ventricular hypertrophy at the prehypertensive stage (1 week of treatment), without MHC isoform switch or change in natriuretic peptide gene expression. In the hypertensive stage (5 weeks of treatment), pronounced left ventricular hypertrophy was observed, and this was characterized by an increase in beta-MHC protein, resulting in a switch from 90% alpha-MHC to 51% alpha-MHC and 49% beta-MHC. ANF and BNP mRNA levels and peptide content were significantly increased at this stage. Unexpectedly, the MHC isoform switch was evident in the non-hypertrophied right ventricle to the same degree as in the left ventricle. Natriuretic peptide production was also increased in the right ventricle at 5 weeks of treatment, but to a lesser degree than in the left ventricle. In contrast, in the hypertrophied left atrium there was no MHC isoform switch, while ANF and BNP mRNA levels were augmented. Plasma ANF was significantly increased in the prehypertensive stage; this was accompanied by a partial depletion of atrial ANF stores. Plasma BNP was increased only in the hypertensive stage, reflecting an increase in ventricular BNP synthesis and secretion. These results suggest that 1) cardiac hypertrophy, MHC isoform expression, and stimulation of natriuretic peptide production are processes that may be dissociated from each other; 2) increases in plasma ANF without a concomitant increase in plasma BNP reflect atrial hemodynamic overload, while increases in both ANF and BNP in plasma are associated with ventricular hypertrophy; and 3) there exist differences in the storage, secretion, and processing patterns of ANF and BNP in the atria.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Body Weight; Cardiomegaly; Centrifugation, Density Gradient; Chromatography, High Pressure Liquid; Desoxycorticosterone; Hypertension; Isomerism; Male; Myocardium; Myosin Subfragments; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA; Sodium Chloride

The effects of two types of anti-aging dietary restrictions restrictions-60% diet restriction (DR) and every-other-day feeding (intermittent feeding, IF)-on age-related changes in atrial natriuretic factor (ANF) metabolism were studied in male Sprague Dawley rats by standard radioimmunological procedures and transmission electron microscopy. Both diet restrictions decreased plasma ANP (atrial natriuretic peptide) levels significantly (12-month-old rats: ad libitum fed controls 96 +/- 17.3 pg/mL, IF 63 +/- 4.8 pg/mL, DR 74 +/- 14.4 pg/mL; 24-month-old rats: AL 109 +/- 6.3 pg/mL, IF 75 +/- 8.9 pg/mL, DR 65 +/- 9.1 pg/mL). Dietary restriction prevented the age-related increase in ANP concentration in both the right atrium (12-month-old rats: AL 0.25 +/- 0.033 microgram/mg, IF 0.22 +/- 0.023 microgram/mg, DR 0.30 +/- 0.044 microgram/mg; 24-month-old rats: AL 0.39 +/- 0.037 microgram/mg, IF 0.10 +/- 0.015 microgram/mg, DR 0.07 +/- 0.011 microgram/mg) and left atrium (12-month-old rats: AL 0.23 +/- 0.033 microgram/mg, IF 0.13 +/- 0.019 microgram/mg, DR 0.17 +/- 0.035 microgram/mg; 24-month-old rats: AL 0.44 +/- 0.037 microgram/mg; IF 0.07 +/- 0.009 microgram/mg, DR 0.07 +/- 0.011 microgram/mg). Endocrine cardiocytes of diet-restricted senescent rats could be readily distinguished ultrastructurally from cells of ad libitum fed controls due to a higher number of beta-atrial specific granules of lower electrondensity. In conclusion, anti-aging diet restriction regimens fully prevented the age-related increase in the hormone store in atrial tissue, and lowered plasma ANP levels.

Topics: Age Distribution; Aging; Animal Nutritional Physiological Phenomena; Animals; Atrial Natriuretic Factor; Body Weight; Cell Size; Diet; Energy Intake; Heart Atria; Immunohistochemistry; Male; Microscopy, Electron; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley

To understand the secretion and synthesis of atrial natriuretic peptide we measured immunoreactive atrial natriuretic peptide from plasma, heart tissues and brain areas, and ANP mRNA was determined from heart auricles and ventricles of vasopressin-deficient Brattleboro rats (DI) and from desmopressin treated Brattleboro rats (DI+DDAVP). Long-Evans rats (LE) served as controls. DI+DDAVP rats were given for 3 days sc. injections of 0.5 micrograms 1-desamino-8-D-arginine vasopressin in 1 mL saline twice a day. The rats were housed in single metabolic cages and urinary output and water intake were measured daily. All the body and organ weight parameters were similar in the three groups when the rats were killed. No change was seen in the plasma ANP level between the groups. The right ventricle of DI+DDAVP rats had significantly (P < 0.05) higher concentration of ANP than LE rats (15.8 +/- 4.4 vs. 3.4 +/- 0.6 ng mg-1 tissue). The left ventricle of DI and DI+DDAVP had significantly (P < 0.05) lower amounts of ANP mRNA than LE rats (0.5 +/- 0.2 vs. 1.3 +/- 0.2 and 0.5 +/- 0.1 vs. 1.3 +/- 0.2 arbitrary units). In the hypothalamus, the ANP concentration was significantly (P < 0.05) lower both in DI and in DI+DDAVP rats than in LE rats (9.3 +/- 1.3 vs. 14.5 +/- 1.6 and 6.1 +/- 0.6 vs. 14.5 +/- 1.6 pg mg-1 tissue). To conclude, although the water intake and urinary output of DI rats were changed towards normal with desmopressin treatment, the heart ventricular and hypothalamic ANP did not parallel the change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Brain; Deamino Arginine Vasopressin; Diabetes Insipidus; Drinking; Heart Atria; Heart Ventricles; Hypoglycemic Agents; Male; Myocardium; Organ Size; Rats; Rats, Brattleboro; RNA, Messenger; Urination; Vasopressins; Water-Electrolyte Balance

The cardiovascular consequences of inhibition of the neutral endopeptidase 24.11 (NEP) with the orally active NEP inhibitor sinorphan were evaluated by determining long-term effects of the drug on hemodynamic, hormonal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Systolic blood pressure increased in young SHR-SP from 194 +/- 2 to 266 +/- 7 mmHg, whereas in sinorphan (30 mg/kg p.o. bid) treated animals systolic blood pressure increased only from 193 +/- 4 to 229 +/- 4 mmHg during the treatment period of 9 weeks. The increase in relative heart weight was also delayed. Plasma ANP was higher in the sinorphan group than in the controls. The results of a second study demonstrate a substantial improvement of cardiac pump function and ventricular hypertrophy in old SHR-SP with compromised cardiac function by long-term inhibition of NEP. Thirteen-month-old SHR-SP were treated with sinorphan (30 mg/kg p.o. bid) for two weeks. At the end of experiment, the increase in ANP plasma levels did not reach statistical significance, whereas plasma cGMP was higher in sinorphan treated animals than in controls. Left ventricular end-diastolic pressure was markedly elevated in controls and significantly lower in sinorphan treated animals. In addition, sinorphan reduced cardiac hypertrophy in these old SHR-SP. In conclusion, the results of the present studies demonstrate that long-term NEP inhibition with sinorphan has inhibitory effects on malignant hypertension and associated cardiac hypertrophy in young SHR-SP on a high-sodium diet. NEP inhibition substantially improves cardiac pump function and reduces ventricular hypertrophy of old SHR-SP with compromised cardiac function.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart Failure; Hemodynamics; Kidney Function Tests; Neprilysin; Rats; Rats, Inbred SHR; Sodium, Dietary; Thiorphan; Time Factors

Although it is known that the atrial natriuretic peptide (ANP) level in right ventricular (RV) blood supplying the caudal part of the fetus is greater than in left ventricular blood perfusing the cephalic part of the fetus, the extent to which any preferential passage of coronary sinus blood into the right ventricle contributes to regional differences between ANP levels in fetal cephalic and caudal arteries is unknown. To address this question, experiments were performed in eight late-gestation fetal lambs, 3-7 days after catheters were inserted into the left atrium, major arteries and veins, and coronary sinus (via the left hemiazygous vein). The plasma ANP level in the abdominal aorta (171 +/- 33 pg/ml) was higher than in the carotid artery (103 +/- 15 pg/ml; P < 0.05), and both were lower than in the coronary sinus (736 +/- 89 pg/ml; P < 0.005). The coronary sinus outflow, measured with radioactive microspheres injected into the hemiazygous vein, was preferentially distributed to the right ventricle (94.7 +/- 1.3%) and thence to the abdominal aorta (89.5 +/- 1.6%). This streaming of the coronary sinus outflow contributed 13.3 +/- 0.9 and 1.4 +/- 0.4 pg/ml to ANP levels in the abdominal aorta and carotid artery, respectively, and thereby accounted for 11.9 +/- 0.9 pg/ml of the abdominal aorta-carotid artery ANP difference of 68 +/- 25 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Circulation; Body Weight; Coronary Circulation; Fetal Blood; Fetus; Gases; Hemodynamics; Sheep

Because the phosphatidylinositol pathway may be part of the signaling system associated with stretch-induced release of atrial natriuretic peptide (ANP), we tested the hypothesis that formation of the intermediate inositol-1,4,5-trisphosphate (IP3) is impaired when ANP release is decreased in response to atrial stretch in hearts from aging genetically hypertensive (GH) rats. Immunoreactive ANP release into the coronary effluent and IP3 levels were studied in cardiac tissues of isolated perfused hearts from normotensive control (WAG) or GH rats aged 4, 11, or 16 months. Left atria were repeatedly distended and released with a latex balloon. ANP was measured in coronary effluent, and IP3 was measured in cardiac tissues. In all age groups, stretch and relief of stretch evoked considerably less ANP release in spontaneously beating hearts from GH than from WAG rats. Hearts from GH rats aged 16 months released no ANP, but electrical pacing restored some stretch-induced ANP secretion. With repeated stretch and release of stretch of the left atrium for 2 min, IP3 levels increased in left atrial tissue in WAG but not in GH hearts of all age groups. IP3 levels in (unstretched) left ventricles were much lower than in left atria and were unaltered by atrial stretch. In aging GH rats, the capacity to release ANP on atrial stretch is largely lost, in association with complete suppression of stimulus-induced increase in IP3 levels. These data support a role for IP3 in stretch-mediated atrial ANP secretion and suggest a progressive uncoupling of this signaling pathway in aging hypertensive rats.

Topics: Aging; Analysis of Variance; Angioplasty, Balloon; Animals; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Pacing, Artificial; Compliance; Disease Models, Animal; Hypertension; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Male; Myocardium; Organ Size; Rats; Rats, Wistar

Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype-related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal alpha-actin, beta-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular alpha-myosin heavy chain and smooth muscle alpha-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-beta 1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II-induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actins; Angiotensin II; Animals; Atrial Natriuretic Factor; Base Sequence; Body Weight; Cardiomegaly; Collagen; Gene Expression; Heart; Male; Molecular Sequence Data; Phenotype; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

To determine whether decreased renal responsiveness to atrial natriuretic peptide (ANP) in diabetes is mediated by alterations in the renal ANP receptor, ANP receptor density and affinity were measured 17-20 d after streptozotocin injection and compared with values in vehicle-treated controls and streptozotocin-treated rats made euglycemic with insulin. Plasma ANP concentration was significantly greater in hyperglycemic diabetic rats than in control or euglycemic diabetic rats. Both in glomeruli and inner medulla, ANP receptor dissociation constant did not differ among the three study groups, whereas the maximum binding capacity was decreased significantly in hyperglycemic diabetics in comparison with controls and euglycemic diabetics. Glomerular clearance receptors were also decreased significantly in hyperglycemic diabetic rats in comparison with control and euglycemic diabetic rats. To determine whether the decreased number of renal ANP receptors in diabetic rats was associated with a decreased biological response, we measured ANP-dependent cyclic GMP (cGMP) accumulation by isolated glomeruli and inner medullary collecting duct cells in vitro. cGMP accumulation was significantly less in hyperglycemic diabetic rats than in controls or euglycemic diabetic rats both in the presence or absence of the phosphodiesterase inhibitor zaprinast. cGMP phosphodiesterase activity in inner medullary collecting duct cells obtained from control and hyperglycemic diabetic rats did not differ. Thus, the decreased number of biologically active ANP receptors in the kidneys of diabetic rats is accompanied by decreased biological responsiveness in vitro and provides a potential explanation for the reduction in renal sensitivity to ANP in this condition.

Topics: Animals; Atrial Natriuretic Factor; Autoradiography; Body Weight; Cell Membrane; Cyclic GMP; Cytosol; Diabetes Mellitus, Experimental; Guanylate Cyclase; Kidney; Kidney Glomerulus; Male; Phosphoric Diester Hydrolases; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Signal Transduction

Hemorrhage induces a rapid redistribution of protein from extravascular spaces into the blood. We studied the effects of acute, nontraumatic hemorrhage on tracer-albumin clearances into individual tissues of rats to determine if reduced protein extravasation could account for intravascular protein gain. Three groups were studied: 1) HEM animals were anesthetized with pentobarbital sodium and bled to a mean arterial pressure of 50 mmHg for 90 min; 2) HEM-RS animals were treated identical to group 1 and then resuscitated with 5% bovine serum albumin (BSA) until baseline arterial pressures were regained; 3) SHAM animals served as time controls. Hemodynamic variables were measured periodically throughout hemorrhage and clearance periods, and plasma samples were collected prior to death for protein and hormone analysis. Plasma clearance of 131I-BSA into individual tissues was measured over the final 30 min of each protocol with a terminal injection of 125I-BSA used to correct for intravascular volume. Reduction of blood volume by 35% in HEM-treated animals resulted in a marked decrease in albumin transport relative to the SHAM group (p < or = .05) in the following tissues: skeletal muscle (-65%), skin (-49%), ileum (-75%), cecum (-66%), colon (-67%), heart (-67%), and lung (-71%). Significant changes were not observed in the remaining tissues sampled: pancreas, kidney, and cerebrum. Albumin clearances in the HEM-RS group were slightly but not significantly lower than SHAM animals except for skeletal muscle, where transport remained depressed following resuscitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Biological Transport; Blood Glucose; Blood Volume; Body Water; Body Weight; Brain; Colon; Coronary Vessels; Disease Models, Animal; Extravascular Lung Water; Hematocrit; Hemodynamics; Hemorrhage; Ileum; Lung; Male; Osmolar Concentration; Plasma Volume; Rats; Rats, Wistar; Resuscitation; Serum Albumin; Skin; Tissue Distribution; Vasopressins

Transgenic mice with intense cardiac expression of a human beta-adrenergic receptor gene were engineered and shown to display marked improvements in baseline myocardial and left ventricular function. Heart/body weight ratios and histologic appearance were not found to be significantly altered, suggesting that receptor gene expression did not induce pathologic changes. Given the substantial reduction in beta-adrenergic receptor density and resultant reduction in inotropic responsiveness observed in chronic heart failure, these findings represent a novel approach for increasing myocardial function with important clinical implications.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Body Weight; Female; Gene Expression; Gene Transfer Techniques; Heart; Heart Failure; Humans; Male; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Myosins; Organ Size; Receptors, Adrenergic, beta-2; Ventricular Function, Left

Plasma atrial natriuretic peptide (ANP) concentrations were determined in basal conditions and after infusion of 1000 ml of 0.9% NaCl in women with anorexia nervosa, in normotensive obese women and in healthy women of the control group. Additionally, in the obese women and in the controls, plasma ANP was measured after iv injection of clonidine. Anorectic patients were investigated in the period of weight loss (mean deficit of body weight was 40%). The mean body mass index (BMI) in the obese women was 36.44 +/- 0.36 kg/m2. Basal plasma ANP concentrations were significantly higher in both anorectic and obese women (p < 0.001 and p < 0.01, respectively). The response of ANP to acute water load was markedly blunted in anorexia nervosa and in obesity (delta % = 232% in control group, 14% in anorexia nervosa and 21% in obesity. A significant increase of ANP was found after iv injection of clonidine in the control group and in obesity (p < 0.001 and p < 0.01, respectively). However, the increase of response (expressed as a percentage change) in obese patients was lower than that in the control group (delta % = 64% and 199%, respectively). The response of ANP to alpha 2-adrenergic stimulation was higher than to hemodynamic stimulus. Our results suggest that the disturbed control of neuropeptides and neurotransmitters as well as changes in peripheral metabolism may explain the impaired responsibility of ANP to hemodynamic stimuli in anorectic and obese patients.

Topics: Adolescent; Adult; Anorexia Nervosa; Atrial Natriuretic Factor; Body Weight; Clonidine; Female; Humans; Injections, Intravenous; Middle Aged; Obesity; Sodium Chloride; Water

Renal interstitial hydrostatic pressure (RIHP) plays a key role in the link between renal hemodynamics and the rate of the tubular reabsorption of sodium and water. Our objective was to determine whether the natriuretic response to a rise in RIHP induced by acute saline infusion would be altered in prehypertensive, Dahl salt-sensitive (DS) rats. We compared the effects of an acute saline load (2.5 ml/100 g BW over 30-min) on RIHP and urinary sodium excretion in Dahl salt-resistant (DR) (n = 11) and DS rats (n = 11) maintained from birth on a low-sodium diet. Baseline mean arterial pressure, glomerular filtration rate rate, and urinary sodium excretion did not differ between DR and prehypertensive DS rats. Urine flow rate and urinary sodium excretion increased significantly in both groups following saline loading. Increases were significantly (p < 0.05) less in the prehypertensive DS rats (0.32 +/- 0.07 to 3.62 +/- 0.79 microEq/min) than in the DR rats (0.71 +/- 0.22 to 6.30 +/- 1.35 microEq/min). RIHP also increased significantly in both groups, but did not differ significantly in DR (7.3 +/- 1.1 to 9.7 +/- 1.7 mmHg) vs. DS rate (7.9 +/- 1.0 to 9.8 +/- 1.3 mmHg). At an equal mean arterial pressure, DS rats showed a reduced natriuretic capacity after an acute saline load, prior to the development of hypertension. Renal tubular sensitivity to the increased RIHP that was induced by an acute saline load was blunted in prehypertensive DS rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Body Weight; Diet, Sodium-Restricted; Glomerular Filtration Rate; Hydrostatic Pressure; Hypertension, Renovascular; Male; Potassium; Rats; Rats, Sprague-Dawley; Salts; Sodium; Sodium, Dietary

The effect of prednisolone, given as a 4-day oral treatment, on 24-h ambulatory blood pressure rhythm, vasoactive hormones and correlation between blood pressure and vasoactive hormones were studied in 11 healthy men. Blood pressure was monitored at intervals of 15 min during the day and of 30 min during the night. Plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and arginine vasopressin and serum concentration of insulin were measured in the morning during basal conditions. The 24-h systolic, diastolic and mean blood pressures were significantly higher after prednisolone treatment. Waking blood pressure was not significantly changed, but sleeping systolic and mean blood pressures were significantly elevated after treatment. The nocturnal systolic blood pressure fall was less pronounced after treatment (before 22%, and after 16%, p<0.01), whereas the nocturnal, mean and diastolic dips were preserved. ANP was significantly increased by prednisolone treatment, from 10.1 to 14.6 pmol l-1, p<0.005. The changes in concentration of ANP were significantly correlated to the changes in 24-h diastolic blood pressure (r = -0.63, p<0.05), 24-h mean blood pressure (r = -0.68, p<0.05), waking diastolic blood pressure (r = 0.83, p<0.01) and waking mean blood pressure (r = -0.67, p<0.01). We found that short-term prednisolone treatment elevated the overall 24-h blood pressure, reduced systolic blood pressure fall during sleep, and increased plasma concentration of ANP, and that the increase in ANP was inversely correlated to the increase in blood pressure. We suggest that the increase in ANP is a secondary and compensatory phenomenon which at least to some extent counteracts the hypertensive and sodium retaining effect of prednisolone.

Topics: Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Circadian Rhythm; Heart Rate; Humans; Insulin; Male; Middle Aged; Potassium; Prednisolone; Sodium; Vasopressins

EXEMSI'92 was a 60-day isolation and confinement experiment with an international crew. During this second experiment of the European Space Agency (the first one was a 28-day confinement with 6 men: ISEMSI'90), blood volume regulating hormones and water balance were studied. During ISEMSI'90, stress level was elevated as shown by specific markers and we observed some interesting results which have been already observed before, during bed-rest experiments. Thus, our conclusion was that some of the physiological effects observed during bed rest could be the consequence of the "confinement effect" and/or stress imposed to the subjects during such experiments. The aim of the present physiological study was: 1/to define the origin of the blood pressure increase seen during ISEMSI'90; 2/ to study the blood volume regulating hormones (ANP, renin, aldosterone) variations; 3/ to determine the dehydration level by measuring the total body water with the doubly labeled water (DLW) method and fluid balance in general.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Water; Body Weight; Catecholamines; Female; Humans; Hydrocortisone; Male; Renin; Renin-Angiotensin System; Social Isolation; Space Flight; Water-Electrolyte Balance

1. Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2. One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3. Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NC10) and all other animals were placed in a normobaric hypoxic chamber (F1 O2 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-1, twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4. Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5. CHC10 rats had significant right ventricular hypertrophy (0.53 +/- 0.08) and pulmonary vascular remodelling (29.0 +/- 0.01%) and had gained significantly less body weight (33.2 +/- 5.5 g) than NC10 rats (0.31 +/- 0.04, 10.9 +/- 0.01%, and 59.2 +/- 11.9 g respectively). CHC10 rats had significantly elevated plasma ANP levels (58.4 +/- 9.9 pM) compared with NC10 rats (23.9 +/- 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 +/- 0.01%) and right ventricular hypertrophy (0.52 +/- 0.09) in CHT20 rats compared with CHV20 controls (33.0 +/- 0.02% and 0.61 +/- 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals.6. Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Chronic Disease; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Methionine; Myocardium; Neprilysin; Pulmonary Circulation; Rats; Rats, Wistar

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Prazosin

Atrial natriuretic peptide (ANP) inhibits the growth of a variety of cell types in vitro including mesangial cells. The effects of ANP on the growth of the kidney in vivo were evaluated. A 2-h infusion of 0.2 microgram/250 g body wt per minute of ANP suppressed the subsequent uptake of [3H]thymidine into the renal DNA of uninephrectomized but not intact rats. This treatment also depressed the ratio of RNA/DNA in kidneys undergoing compensatory growth. Correlative physiologic studies revealed enhanced GFR in rats with two kidneys infused with ANP, but no increase in the GFR of uninephrectomized rats. It was concluded that ANP may oppose the growth factor(s) mediating compensatory renal growth.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; DNA; Glomerular Filtration Rate; Hypertrophy; Kidney; Male; Mitosis; Nephrectomy; Organ Size; Rats; Rats, Sprague-Dawley

Transgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR). These transgenic animals demonstrated cardiac-specific expression of this alpha 1-AR with resultant activation of phospholipase C as shown by increased myocardial diacylglycerol content. A phenotype consistent with cardiac hypertrophy developed in adult transgenic mice with increased heart/body weight ratios, myocyte cross-sectional areas, and ventricular atrial natriuretic factor mRNA levels relative to nontransgenic controls. These transgenic animals may provide insight into the biochemical triggers that induce hypertrophy in cardiac disease and serve as a convenient experimental model for studies of this condition.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Diglycerides; Gene Expression; Heart Ventricles; Humans; Mice; Mice, Transgenic; Mutagenesis, Site-Directed; Myocardium; Myosins; Organ Size; Point Mutation; Promoter Regions, Genetic; Radioligand Assay; Receptors, Adrenergic, alpha-1; Reference Values; RNA, Messenger; Type C Phospholipases

Plasma atrial natriuretic factor (ANF) is normally released into the circulation primarily by volume expansion and atrial distension, but we have shown that plasma ANF is elevated in pregnant sheep before volume expansion. Because alterations in the metabolic clearance of ANF could lead to elevated plasma ANF levels, the present study was designed to determine the pharmacokinetics of plasma ANF in pregnant sheep. Chronically instrumented nonpregnant and pregnant sheep received intravenous injections of monoiodinated human ANF (125I-hANF). Plasma decay curves of 125I-hANF followed a biexponential function in both groups. High-performance liquid chromatography (HPLC) revealed the accumulation of smaller degradation products by 2 min postinjection, and by 30 min no intact ANF was present. Because HPLC identification of ANF and its metabolites was shown to be more efficient than precipitation with 10% trichloroacetic acid (TCA) or extraction by Sep-Pak cartridges, ANF kinetic parameters were calculated from HPLC-corrected plasma decay curves. Injected ANF was rapidly distributed in an initial distribution volume (IDV) that was expanded in pregnant sheep. Metabolic clearance rate (MCR) was greater in pregnant sheep (2.8 +/- 0.3 vs. 6.8 +/- 1.2 l/min, P = 0.002), while plasma half-life (t1/2) was not altered (2.2 +/- 0.5 vs. 2.4 +/- 0.4 min). The data demonstrate that during pregnancy, the t1/2 of ANF is not altered but the MCR of ANF is enhanced. These findings imply that plasma ANF is increased by mechanisms other than reduced clearance in pregnant sheep.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Female; Humans; Iodine Radioisotopes; Metabolic Clearance Rate; Potassium; Pregnancy; Pregnancy, Animal; Radioisotope Dilution Technique; Reference Values; Sheep; Sodium

We studied the effects of physical endurance training on atrial natriuretic peptide (ANP) gene expression in beagle dogs, Wistar rats, and spontaneously hypertensive rats (SHR). The dogs underwent a gradually increased running training up to 40 km/day on a treadmill for 55 wk while the nontrained sibling control dogs were kept in their cages throughout the study. Endurance training caused a significant 13% (P < 0.05) increase in ventricular hypertrophy but did not change plasma immunoreactive (ir)-ANP levels at rest or ventricular ANP mRNA or irANP levels. When normotensive Wistar rats ran up to 2,200 m/day for 8 wk, no significant change was seen in ventricular hypertrophy or in plasma or ventricular irANP levels at rest compared with nontrained controls. However, endurance training caused a 2.2-fold increase in epicardial ANP mRNA levels (P < 0.05). In the SHR strain, running training up to 900 m/day for 31 wk increased ventricular hypertrophy of trained SHR by 7% (P < 0.01) and caused a concomitant 1.6- to 1.7-fold elevation in ventricular irANP and ANP mRNA levels (P < 0.01-0.001) compared with nontrained SHR. In contrast, changes in atrial ANP mRNA or irANP levels in response to training were small in all three protocols. This study shows that in the normal heart induction of ANP synthesis by endurance training is not associated with ventricular hypertrophy. Moreover, the common stimulus for ventricular ANP synthesis induced by both chronic pressure overload and physical training may be mechanical stretching of cardiac myocytes, because endurance training further stimulated ANP synthesis in hypertrophied ventricles in SHR.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Body Weight; Cardiomegaly; Dogs; Eating; Female; Lactates; Lactic Acid; Male; Myocardium; Organ Size; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; RNA, Messenger

The aim of the study was to compare, in a rat model of congestive heart failure, the effect of captopril, a selective angiotensin-converting enzyme (ACE; EC 3.4.15.1) inhibitor, to that of alatriopril, a mixed inhibitor of ACE and atriopeptidase (EC 3.4.24.11), an enzyme implicated in the degradation of atrial natriuretic factor (ANF). Myocardial infarction was induced by ligation of the left coronary artery. Groups of rats received orally twice daily captopril (10 mg/kg), alatriopril (100 mg/kg) or vehicle. Treatments were started 18 to 20 h after ligation and continued for 4 weeks. Hypertrophic and hormonal changes reflecting congestive heart failure were assessed in rats with large infarcts by measuring the relative weight of cardiac tissues as well as by assaying ANF in heart and plasma and by measuring renin activity in plasma. Both treatments significantly reduced cardiac hypertrophy, but alatriopril showed a greater efficacy than captopril--the increase in relative heart weight reaching 38% with captopril and only 22% with alatriopril (P < .05). The hypertrophy of right ventricle was reduced by 47% with alatriopril and by 35% with captopril (N.S.), whereas the corresponding reductions for atria were 47% vs. 21% (P < .05). Both treatments prevented the ligation-induced increase of ANF level in the right ventricle. In contrast, plasma ANF level was significantly reduced after captopril but not after alatriopril treatment, a difference that probably reflects the protection of endogenous ANF in circulation resulting from atriopeptidase inhibition. Plasma renin was increased by 36-fold after captopril but only by 1.6-fold after alatriopril, a difference that presumably reflects the inhibition of renal renin secretion by endogenous ANF after alatriopril. These data suggest that enhancement of ANF levels in circulation via atriopeptidase inhibition magnifies the capacity of ACE inhibitors to prevent cardiac hypertrophy, and they show the potential therapeutic value of mixed ACE-atriopeptidase inhibitors in congestive heart failure.

Topics: Alanine; Amino Acid Sequence; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Bradykinin; Captopril; Cardiomegaly; Dioxoles; Disease Models, Animal; Heart Failure; Hormones; Male; Molecular Sequence Data; Myocardial Infarction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin

We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Bicarbonates; Biomarkers; Body Weight; Cardiac Pacing, Artificial; Cardiomegaly; Dogs; Electric Stimulation; Electrolytes; Heart; Heart Failure; Muscle Denervation; Neuropeptide Y; Neuropeptides; Norepinephrine; Oxygen; Partial Pressure; Propranolol; Reference Values; Respiration; Vagus Nerve; Ventricular Function, Left

Atrial natriuretic peptide (ANP) infusion increases hematocrit and decreases plasma volume by inducing a transfer of plasma fluid from the vascular to the interstitial compartment. Diabetes mellitus is associated with resistance to the renal actions of ANP. We explored the possibility that the extrarenal responses to ANP may also be altered in the diabetic state by measuring changes in arterial pressure and hematocrit during infusion of ANP (1 microgram.kg-1 x min-1 for 45 min) into anesthetized, acutely nephrectomized rats 2-3 wk after induction of diabetes from intravenous streptozotocin (STZ) injection (60 mg/kg). Blood glucose was significantly elevated in diabetic rats when compared with control and insulin-treated diabetic rats. Arterial pressure during ANP infusion decreased similarly in control; diabetic, and insulin-treated diabetic rats (by 7.6 +/- 1.6, 9.6 +/- 1.9, and 8.2 +/- 2% respectively; all P < 0.002). In control rats, hematocrit increased progressively to a maximum value of 9.5 +/- 0.9% as a result of the infusion, corresponding to a decrease in plasma volume of 16.3 +/- 1.3%. In contrast, the ANP-induced increase in hematocrit was markedly blunted in diabetic rats (1.6 +/- 0.8%; P < 0.0001 vs. ANP infusion in control rats). Reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit in response to ANP (8.5 +/- 1.1%; P < 0.0001 vs. ANP infusion in diabetic rats and P = NS vs. control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate (cGMP) was significantly less in diabetic as compared with control and insulin-treated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Blood Proteins; Blood Volume; Body Weight; Cyclic GMP; Diabetes Mellitus, Experimental; Glucose Clamp Technique; Hematocrit; Humans; Infusions, Intravenous; Insulin; Kidney; Kinetics; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reference Values; Time Factors

The effects of hyperhydration, induced by oral loading via a stomach tube (41 of 0.9% NaCl within 2-3 min), intra-peritoneal and intra-jugular infusions (41 of 0.9% NaCl solution at a rate of 21 hr-1) in normally hydrated goats, on fluid retention, plasma expansion, kidney function and drinking response were compared. Higher fluid retention (67 and 65% vs. 40% at 3 hr after the termination of the infusion, P < 0.01), attenuated diuretic (P < 0.01) and natriuretic (P < 0.01) responses and lower expansion of plasma volume (P < 0.05) were recorded in the orally and intra-peritoneally treated goats in comparison with the intra-jugularly treated animals. Portal expansion apparently induces acceleration of saliva secretion which recycles water to the gut. Recycling of water to the gut reduced excessive expansion of plasma fluid and load on the kidney. Retention of water in the rumen satiated the urge to drink in the orally and intra-peritoneally treated goats for at least 24 hr. The intra-jugularly treated goats consumed a significant amount of water (1l), which was approximately half of their normal requirement. Under arid conditions, these responses are appropriate to the animals' regular exposure to severe dehydration and rapid rehydration.

Topics: Administration, Oral; Animals; Atrial Natriuretic Factor; Body Weight; Drinking; Female; Goats; Hematocrit; Injections, Intraperitoneal; Injections, Intravenous; Kidney; Kidney Function Tests; Osmolar Concentration; Sodium; Water

Elevated plasma atrial natriuretic peptide (ANP) levels have been shown to blunt pulmonary hemodynamic responses to chronic hypoxia, but whether elevated circulating ANP levels negatively feedback on cardiac expression of the ANP gene is unknown. Using a recently developed strain of transgenic mouse (TTR-ANF) that expresses a transthyretin promoter-ANP fusion gene in the liver, we studied the effect of chronically elevated plasma ANP levels on cardiac hypertrophic and pulmonary hemodynamic responses and expression of the endogenous cardiac ANP gene during chronic hypoxia. Plasma ANP levels were 10-fold higher in TTR-ANF mice than in their non-transgenic littermates. After 3 wk of hypobaric hypoxia (0.5 atm), right ventricular hypertrophy and pulmonary hypertension had developed in both groups of mice, but TTR-ANF mice had lower right ventricle-to-left ventricle plus septum weight ratios (0.39 +/- 0.01 vs. 0.45 +/- 0.02), right ventricular systolic pressures (25 +/- 2 vs. 29 +/- 2 mmHg), and lung dry weight-to-body weight ratios (0.48 +/- 0.03 vs. 0.57 +/- 0.01 mg/g) and less muscularization of peripheral pulmonary vessels (8.3 +/- 1.4 vs. 17.4 +/- 2.5%) than nontransgenic controls. Right atrial and ventricular steady-state ANP mRNA levels were the same in both groups of mice under normoxic and hypoxic conditions despite much higher plasma ANP levels and less pulmonary hypertension in TTR-ANF mice. We conclude that chronically elevated plasma ANP levels attenuate the development of hypoxic pulmonary hypertension in mice but do not suppress cardiac expression of the endogenous ANP gene under normoxic conditions nor blunt the upregulation of right ventricular ANP expression during chronic hypoxia.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Body Weight; Feedback; Female; Heart; Hematocrit; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pulmonary Circulation; RNA; Up-Regulation

1. The pathophysiologic role of atrial natriuretic factor (ANF) in genetic hypertension was investigated in 5- and 21-week-old genetically hypertensive (LH), normotensive (LN) and low blood pressure (LL) rats of the Lyon strain. 2. Plasma ANF was significantly higher in 5-week-old LH than in age-matched LN and LL animals. It tended to be lower in 21-week-old LH than in LN rats. 3. Left and right atrial ANF content was also significantly lower at 21 weeks in the LH group. 4. Glomerular ANF receptors showed a significant decrease in LH in comparison to LL and LN animals.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Hematocrit; Hypertension; Kidney Glomerulus; Male; Organ Size; Protein Binding; Rats

The state of the vasodilator systems in congestive heart failure is poorly defined. Plasma atrial natriuretic peptide is increased, whereas endothelium derived relaxing factor activity can be decreased. Atrial natriuretic peptide and endothelium derived relaxing factor both cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP), by activating the particulate and the soluble guanylate cyclase, respectively. This study examines the biological effects of atrial natriuretic peptide and endothelium derived relaxing factor in experimental heart failure by assessing the plasma, urinary, and tissue concentrations of their common second messenger cGMP.. Myocardial infarctions (n = 31) were induced and sham operations (n = 25) were performed on Wistar rats, and the rats were monitored for three months. Aortic and pulmonary cGMP contents were measured, as the aorta is mainly matrix and smooth muscle cells, and the lung is particularly rich in capillaries, hence in endothelial cells. The concentrations of the other second messenger cyclic adenosine monophosphate (cAMP) was also determined, as were those of cGMP dependent protein kinase in the arteries.. 17 of the 31 rats with myocardial infarction had oedema. The total heart weight to body weight ratio and the ratio of the myocardium haemodynamically upstream from the infarcted left ventricle to body weight were increased in proportion to the infarct size. Plasma atrial natriuretic peptide and plasma and urinary cGMP concentrations were increased in proportion to the degree of heart failure (p < 0.0001). The pulmonary cGMP concentration was significantly higher in the rats with myocardial infarction than in the control group (p < 0.0001). Pulmonary cGMP concentrations were correlated with the plasma concentrations of atrial natriuretic peptide and cGMP (r2 = 0.59 and 0.66 respectively, p < 0.0001). The cGMP, cAMP, and cGMP, and cGMP dependent kinase concentrations in the aortic wall of rats with myocardial infarctions were the same as in control rats.. The increase in plasma, urinary, and pulmonary cGMP in rats with myocardial infarctions were highly correlated with the increase in circulating atrial natriuretic peptide. By contrast, the aortic cGMP concentration was unchanged in these rats, despite high plasma atrial natriuretic peptide. In congestive heart failure, a discrepancy seems to exist between pulmonary (mainly endothelium) and aortic wall (mainly smooth muscle cells) cGMP.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Heart Failure; Male; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar

The major stimulus for atrial natriuretic peptide (ANP) release is atrial stretch and increased values are observed in volume overload states such as chronic renal failure. Since successful kidney transplantation restores volume homeostasis, we compared the effects of human cadaveric kidney transplantation on time course and changes of plasma ANP in the early postoperative period in 4 patients with successful and 4 patients with failed transplantation. ANP concentrations were elevated before transplantation in both groups (91 +/- 16 and 70 +/- 32 pmol/l) and decreased after successful (50 +/- 27 pmol/l, day 16) but increased after failed transplantation (146 +/- 45 pmol/l, day 16). Moreover, there was a close correlation between changes of body weight and ANP concentrations. Plasma renin activity decreased and plasma noradrenaline increased non-significantly in both groups, the latter more so after failed transplantation (116 +/- 42 to 194 +/- 156 vs 156 +/- 157 to 425 +/- 287 ng/l). No correlation was found between changes of renin activity or plasma catecholamines and ANP concentrations. The results indicate that the mechanisms governing release of atrial natriuretic peptide are operative in patients with chronic end-stage renal failure and after successful kidney transplantation with a return of atrial natriuretic peptide concentrations towards normal in the latter.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Weight; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Norepinephrine; Renin

Eight dromedary camels were studied for 24 days under control conditions (3 days), and during water deprivation (14 days) and rehydration (7 days) in Tadla (Morocco), during the summer. During dehydration, food intake gradually fell and was zero on the last day and animals lost about 30% of their body weight. However, most of this reduction in weight was attributed to water loss, since body weight of the animals returned to control values following rehydration. Dehydration was associated with a decrease in plasma volume (-42 +/- 3%) and a concomitant rise in plasma Na concentration (from 154 +/- 2 to 191 +/- 3 mM). These changes were accompanied by increased plasma arginine-vasopressin (from 0.2 +/- 0.1 to 5.7 +/- 2.2 pg ml-1) and plasma renin activity (from 1.2 +/- 0.2 to 20.0 +/- 5.2 ng Al ml-1 hr-1), without significantly changed plasma concentrations of aldosterone and atrial natriuretic peptide. Dehydration was associated with increased urine osmolality (from 952 +/- 515 to 1963 +/- 498 mosm kg-1 H2O), reduced urine production (from 4565 +/- 2230 to 817 +/- 178 ml day-1), and increased Na excretion. Most of these parameters returned to control values during initial rehydration, except for plasma renin activity, which remained elevated for 7 days, and diuresis, which rose to 12773 +/- 6707 ml day-1 on Day 7 of rehydration.

Topics: Aldosterone; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Body Temperature; Body Water; Body Weight; Camelus; Dehydration; Eating; Female; Hematocrit; Hemoglobins; Hormones; Male; Osmolar Concentration; Renin; Sodium

The effects of orchiectomy and testosterone replacement on the plasma concentration and the atrial stores of atrial natriuretic peptide (ANP) were studied in the rats. Male rats were orchiectomized (Orc) three weeks before replacement with testosterone propionate (TP, 20 mg/ml/kg body weight) or sesame oil for five days. Immunoreactive ANP (IR-ANP) in the extracted right atria and plasma of experimental rats was measured. Plasma ANP concentrations were 206 +/- 22, 927 +/- 151, and 264 +/- 61 pg/ml in normal control, Orc, and Orc + TP rats, respectively. ANP contents in right atria were higher in Orc (108 +/- 9 ng/mg tissue) and TP-treated Orc rats (123 +/- 9 ng/mg tissue) than in normal animals (32 +/- 7 ng/mg tissue). These results indicate an increased plasma concentration and atrial stores in the castrated male rats. Replacement of testosterone in the castrated male rats does not decrease the atrial ANP stores, but decreases the plasma ANP concentration.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Castration; Heart Atria; Male; Organ Size; Rats; Rats, Wistar; Seminal Vesicles; Testosterone

Atrial natriuretic factor (ANF) promotes natriuresis and diuresis, increases vascular permeability and may induce peripheral vasodilatation. Endothelium-derived relaxing factor (EDRF), which is nitric oxide (NO), promotes local vasodilatation. ANF and EDRF-NO both cause vascular relaxation by generating cGMP via the activation of the particulate and soluble guanylate cyclases, respectively. This study examines the in vivo effect of exogenous ANF administration in normal Wistar rats, and of increased endogenous ANF in an experimental model of heart failure, on plasma and tissue cGMP concentrations. Low-dose ANF increased plasma and pulmonary cGMP concentrations, whereas 10-fold higher doses were necessary to increase aorta cGMP concentrations. Rats with a myocardial infarction had increased plasma ANF and cGMP and pulmonary cGMP concentrations, but aorta cGMP concentration remained similar to that of sham-operated rats. NG nitro L-arginine methyl ester (L-NAME) was administered chronically to sham-operated and myocardial infarction rats to block NO-synthase: soluble guanylate cyclase activity. L-NAME did not lower the increase in plasma ANF concentration or in urinary, plasma or pulmonary cGMP concentration. In contrast, L-NAME reduced the aorta cGMP concentration 6-fold, despite an increased level of circulating ANF. In summary, the pathophysiological range of plasma ANF concentrations greatly increases plasma and pulmonary cGMP concentrations (by activating particulate guanylate cyclase), but has little influence on the aorta cGMP concentration (which remains mainly dependent on NO-synthase: soluble guanylate cyclase activity).

Topics: Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Arginine; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Disease Models, Animal; Infusions, Intravenous; Lung; Male; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar; Renin

Because clinical indices of hydration state are insensitive, the estimation of correct postdialysis dry weight is still major problem. Recently, some new techniques have been introduced to assess postdialysis dry weight more accurately. The plasma concentrations of the biochemical markers atrial natriuretic peptide (ANP) and cGMP are related to intravascular hydration state. The echographically measured inferior caval vein diameter (VCD) is linked to right atrial pressure and blood volume (BV). Regional noninvasive conductivity measurements provide information about regional extracellular fluid volume (EFV). In this study of postdialysis ANP and cGMP concentrations, VCD and EFV yielded postdialysis diagnoses of hydration state in 18 patients on maintenance dialysis. In order to verify the established diagnosis, hemodynamic and BV changes during dialysis were studied. In postdialysis underhydrated patients, differentiated according to VCD and EFV standards, a pronounced decrease in BV, stroke volume, and left ventricular end-diastolic diameter compared with postdialysis normohydrated patients was observed. Hemodynamic and BV changes during dialysis were identical in the groups selected according to postdialysis ANP level. Only a difference in BV decrease was demonstrated between the groups selected according to postdialysis cGMP. Predialysis and postdialysis VCD correlated well with the corresponding EFV (r = 0.7 and r = 0.8, respectively). Because VCD and EFV were related and interpretation yielded diagnoses of postdialysis hydration state that were substantiated by the finding of classical hemodynamic features of underhydration, both are an asset in the diagnosis of postdialysis dry weight. cGMP values are less informative, and ANP does not provide any information at all.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Weight; Cyclic GMP; Electric Conductivity; Female; Hemodynamics; Humans; Male; Middle Aged; Renal Dialysis; Ultrasonography; Veins

Hypercholesterolemia and hypertension are frequently associated risk factors for cardiovascular diseases. The interactions between hypercholesterolemia and the regulatory mechanisms of blood pressure are poorly understood. In this study we investigated the effects of hypercholesterolemia on salt metabolism and its hormonal control mechanisms in spontaneously hypertensive rats (SHR). Six-week-old SHR were randomly assigned to either a high (1%) cholesterol diet or a matched regular diet for 6 weeks, followed by a 2-week dietary washout. A group of normotensive Wistar-Kyoto rats received the high cholesterol diet and was used as a control. Plasma cholesterol increased significantly (P < 0.001) in both cholesterol-fed SHR and Wistar-Kyoto rats. Blood pressure was unaffected by 6 weeks of a high cholesterol diet. Hypercholesterolemia caused a significant increase in aldosterone (by analysis of variance: F = 8.40; P < 0.01) associated with a significant decrease in corticosterone (F = 4.64; P < 0.05) in the SHR, but not in the normotensive rats. In addition, in the cholesterol-fed SHR, urinary sodium excretion was reduced (P < 0.01), and the urinary potassium/sodium ratio was increased (P < 0.01) compared to those in the remaining groups of rats. The hormonal and urinary differences between the hypertensive subgroups were not detectable after withdrawal of cholesterol. These results demonstrate that diet-induced hypercholesterolemia specifically promotes reversible mineralocorticoid accumulation and sodium retention in SHR.

Topics: Adrenal Cortex Hormones; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cholesterol, Dietary; Corticosterone; Hypercholesterolemia; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Water-Electrolyte Balance

1. The effects of a high calcium diet (2.5%) on blood pressure, electrolyte balance, plasma and tissue atrial natriuretic peptide (ANP), cytosolic free Ca2+ concentration ([Ca2+]i), and arterial smooth muscle responses were studied in one-kidney deoxycorticosterone (DOC)-NaCl hypertensive Wistar rats. 2. Calcium supplementation for 8 weeks markedly attenuated the development of DOC-NaCl hypertension and the associated cardiac hypertrophy, and prevented the DOC-NaCl-induced sodium-volume retention as judged by reduced plasma Na+, and decreased plasma and ventricular ANP concentrations in high calcium-fed DOC-NaCl rats. However, calcium supplementation did not affect the DOC-NaCl-induced rise in platelet [Ca2+]i. 3. Smooth muscle contractions of isolated mesenteric arterial rings in response to depolarization by K+ (20-30 mM) were enhanced in DOC-NaCl-treated rats, this enhancement being abolished by concurrent oral calcium loading. The Ca2+ entry blocker nifedipine (10 nM) inhibited the contractions induced by K+ (30-125 mM) more effectively in DOC-NaCl rats than in controls, while the inhibition in calcium-loaded DOC-NaCl rats was significantly greater than in controls only with 30 mM K+. 4. The contractions of mesenteric arterial rings induced by omission of K+ from the organ baths were used to evaluate cell membrane permeability to ions. In chemically denervated rings the onset of the gradual rise in contractile force in K(+)-free medium occurred earlier, and the rate of the contraction was faster in DOC-NaCl-treated rats than in controls and high calcium-fed DOC-NaCl rats. Smooth muscle relaxation induced by 0.5 mM K+ upon K(+)-free contractions was clearly slower in DOC-NaCl rats than in controls and calcium-supplemented DOC-NaCl rats. 5. The functions of arterial smooth muscle Na+, Ca2+ exchange and Ca(2+)-ATPase were evaluated by the aortic contractions elicited by low Na+ medium, and the subsequent relaxation responses induced by Ca(2+)-free solution (in the presence of 5 mM caffeine, 1 microM nifedipine and 10 microM phentolamine). The rate of aortic low Na+ contractions (evaluating Ca2+ influx via Na+, Ca2+ exchange), as well as that of subsequent relaxations was slower in DOC-NaCl-treated rats than in controls, whether the relaxation was induced in normal (144.0 mM) or low (1.2 mM) organ bath Na+ concentration (reflecting Ca2+ extrusion by both Ca(2+)-ATPase and Na+, Ca2+ exchange, and by Ca(2+)-ATPase alone, respectively). However, in calcium-s

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood Platelets; Blood Pressure; Body Weight; Calcium, Dietary; Cell Membrane; Cell Membrane Permeability; Desoxycorticosterone; Heart; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Wistar; Water-Electrolyte Balance

The aims were (1) to characterise plasma and tissue atrial natriuretic factor (ANF) levels, haemodynamic variables, and renal function at different stages of moderate chronic high output heart failure in the rat; and (2) to assess the contribution of the atria and ventricles to plasma ANF levels.. Plasma and tissue ANF levels, haemodynamics, and renal function were evaluated at 1, 2, 4, 8, and 16 weeks after the development of aorto-caval shunts. Sham operated animals served as controls at identical time points. Male Sprague-Dawley rats weighing 225-275 g were used in all experiments.. Mean arterial blood pressure was lower and right atrial pressure was higher in the aorto-caval shunt groups than in sham operated controls at all time periods. Left ventricular end diastolic pressure was increased significantly in aorto-caval shunt rats at 1, 2, and 4 weeks when compared with their control counterparts. Plasma COOH terminal and NH2 terminal ANF concentrations were increased significantly in aorto-caval shunt animals. Plasma ANF was positively correlated with right atrial pressure and left ventricular end diastolic pressure in aorto-caval shunt rats but not in sham operated controls. Aorto-caval shunt animals also developed marked cardiac hypertrophy with decreased atrial ANF concentration, but not content, and increased ventricular ANF concentration and content. Despite high plasma ANF concentrations, aorto-caval shunt rats had a lower packed cell volume at all observed periods and reduced urinary sodium excretion and urinary volume at 1 and 2 weeks, with trends to a reduction at 4, 8, and 16 weeks. Body weight was higher in aorto-caval shunt animals at 16 weeks than in sham operated controls.. (1) Chronically increased cardiac filling pressure stimulated not only ANF release but also ANF synthesis in each cardiac chamber, which in turn contributed to raised plasma ANF concentrations in aorto-caval shunt rats; (2) an attenuated renal response to endogenous ANF and sodium and water retention were apparent in A-C shunt rats. Activation of neurohormonal vasoconstrictor systems and gradually decreased plasma ANF concentrations may contribute to sodium and water retention at different stages of this experimental model of heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Output; Cardiac Output, Low; Heart Atria; Heart Ventricles; Kidney; Male; Rats; Rats, Sprague-Dawley; Urine

Plasma atrial natriuretic peptide (ANP) and cyclic 3'5'-guanosine monophosphate (cGMP) were investigated as indicators of fluid volume overload in children and adolescents with chronic renal failure. Plasma ANP and cGMP were measured in both paediatric patients with chronic renal failure (n = 17, mean serum creatinine 371 +/- 242 mumol/l) and those with end-stage renal disease on haemodialysis (n = 18). cGMP was higher in children with chronic renal failure than in 45 healthy controls (1.0 +/- 0.4 vs 2.1 +/- 0.8 nmol/l, P less than 0.01), whereas plasma ANP was similar (26.9 +/- 9.7 vs 34.0 +/- 12.3 pmol/l). Both ANP and cGMP were markedly elevated in children with end-stage renal disease before haemodialysis and fell significantly during dialysis. During dialysis body weight decreased by 1.6 +/- 0.7 kg, corresponding to 4.5 +/- 2.1% of body weight. Plasma ANP correlated positively with plasma cGMP in haemodialysed patients (r = 0.43, P less than 0.05). Reduction in body weight and in mean arterial pressure correlated more closely with plasma ANP than with cGMP. Therefore, elevation of plasma ANP appears to indicate volume overload in children undergoing haemodialysis, but whether it can be used also in children with chronic renal failure requires further investigation.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Volume; Body Weight; Child; Child, Preschool; Creatinine; Cyclic GMP; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Water-Electrolyte Imbalance

The postdialytic plasma level of cGMP, a marker for the release of atrial natriuretic peptide (ANP) in humans, is closely related to hypervolemia in chronic hemodialysis patients. In order to test the practicability of routine postdialysis cGMP determination for the detection of fluid overload, ANP and cGMP levels in the total hemodialysis population of 81 patients were measured with blood samples drawn immediately after hemodialysis. Twenty-three patients had a cGMP level of more than 20 pmol/mL. In 13 of these, pulmonary congestion was present on the chest roentgenogram. Two of these patients refused a gradual reduction of their dry body weight. In the remaining 21 patients, the weight reduction was associated with a decrease in cGMP levels in all cases and with a decrease in ANP levels in all but two cases. Fourteen of the 21 patients reached a cGMP level below 20 pmol/mL after weight reduction, and at that time, none of these showed signs of pulmonary congestion on chest x-ray. All seven patients, whose cGMP levels remained above 20 pmol/mL despite the reduction, had documented heart disease with impairment of left ventricular function. These results suggest that the plasma cGMP level after hemodialysis is more apt for the determination of dry body weight than is ANP or a chest roentgenogram.

Topics: Adult; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Body Weight; Cardiovascular Diseases; Cyclic GMP; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Predictive Value of Tests; Pulmonary Edema; Radiography; Renal Dialysis; Ventricular Function, Left; Water-Electrolyte Imbalance

Atrial natriuretic peptide (ANP) is a hormone involved in fluid and blood pressure homeostasis. We studied the effects of left-to-right shunting through a patent ductus arteriosus on blood pressure changes and plasma ANP concentrations in newborn piglets. In five experimental piglets, the ductus arteriosus was bathed with PGE1 and infiltrated with formalin to maintain its patency. In four age-matched control piglets, the ductus arteriosus was ligated. Plasma ANP concentrations and blood pressure determinations were obtained prior to (base-line) and 25 +/- 1 h (day 1), and 48 +/- 1 h (day 2) after surgery. Radionuclide-microsphere determinations of left-to-right patent ductus arteriosus shunts were performed on days 1 and 2 in the 5 piglets with a patent ductus arteriosus. Plasma ANP concentrations were significantly elevated in the left atrium on day 1 and the right atrium on day 2 in the PDA piglets. No correlation was demonstrated between plasma ANP concentrations and right or left atrial pressures. We conclude that left and right plasma atrial ANP concentrations are significantly elevated in newborn piglets with left-to-right patent ductus arteriosus shunts.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Body Weight; Ductus Arteriosus, Patent; Hemodynamics; Swine

Diabetes mellitus (DM) is frequently associated with hypertension for which an independent pathomechanism has been suggested. We studied 26 patients with insulin-dependent (IDDM) and 18 patients with non-insulin-dependent (NIDDM) uncomplicated DM; all patients were in metabolic balance and none of them had hypertension. Exchangeable body sodium (NaE was estimated by isotope dilution, using appr. 1.1 Mbq 24NA. In a subset of 8 IDDM and 8 NIDDM patients atrial natriuretic peptide (ANP) plasma concentration was determined prior to and after the infusion of 2000 ml physiological saline over 2 hr. NaE was significantly increased both in IDDM and NIDDM patients (104.4 +/- 11.4% and 109.9 +/- 8.0% of the normal value for healthy subjects of identical body surface area; p < 0.05 and < 0.001 resp.). Mean blood pressure (MBP) correlated significantly with NaE in both groups (r = 0.364 and r = 0.520; p < 0.05 and < 0.025, resp.) but not in healthy control subjects (r = 0.112; N.S.). Resting ANP levels were not significantly different in IDDM (34.9 +/- 11.3 pg/ml), NIDDM (42.6 +/- 11.7 pg/ml) or control subjects (40.9 +/- 17.2 pg/ml) however the infusion of saline resulted in a significantly greater increase of plasma ANP in the NIDDM patients (to 82.9 +/- 43.2 pg/ml; P < 0.01) than in the controls (55.6 +/- 23.7 pg/ml; P < 0.01) which was associated with a significantly less increase in sodium excretion (UNAV) in the NIDDM patients (+86% vs. 3170%; P < 0.02) indicating down-regulation of ANP receptors in the kidney of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Sodium

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.

Topics: Amino Acid Oxidoreductases; Animals; Aorta; Arginine; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Organ Size; Rats; Rats, Inbred Strains

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Body Weight; Female; Humans; Kidney Transplantation; Male; Renin; Water-Electrolyte Balance

To test the effect of converting enzyme inhibition (CEI) on diabetes, with or without renal insufficiency, we studied streptozotocin-induced diabetic rats, with or without reduced renal mass, which were treated with insulin in sufficient amounts to maintain glucose values in the mild to moderately hyperglycemic range. We found that diabetes increased glomerular filtration rate (GFR) (inulin clearance, 2.3 +/- 0.5 ml/min vs 1.9 +/- 0.1 ml/min; p < 0.05) and blood pressure (137 +/- 15 mm Hg vs 116 +/- 6 mm Hg; p < 0.05) but did not increase plasma atrial natriuretic peptide (ANP) values, when compared with control rats (72 +/- 38 vs 68 +/- 24 pg/ml). CEI decreased GFR and blood pressure to control values. In rats with diabetes and concomitantly reduced renal mass, hypertension, elevated ANP values, proteinuria, and glomerulosclerosis were prominent features. CEI was associated with reduced blood pressure (172 +/- 17 mm Hg vs 138 +/- 15 mm Hg; p < 0.05), without a concomitant decrease in GFR (1.1 +/- 0.1 ml/min vs 1.1 +/- 0.1 ml/min). Further, CEI reduced the elevated ANP values (140 +/- 34 pg/ml vs 66 +/- 19 pg/ml; p < 0.05) to those of control rats. CEI reduced proteinuria by 50% and ameliorated the histopathologic changes. In separate experiments, rats with 5/6th nephrectomy and hypertension but without diabetes were also found to have elevated ANP levels that decreased to control values with CEI. The data speak for a renal protective effect of angiotensin I-converting enzyme inhibition in this model but do not support a specific role for ANP in the model of diabetes with concomitantly reduced renal mass.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glomerular Filtration Rate; Kidney; Male; Nephrectomy; Rats; Rats, Wistar; Renal Insufficiency

1. Effects of potassium (K) supplementation (100 mEq/day) on urinary sodium (Na) excretion and on the secretion of atrial natriuretic polypeptide (ANP) during salt loading (350 mEq/day) were studied in 12 healthy salt-resistant normotensives under strictly controlled metabolic ward conditions. 2. Urinary volume and Na excretion on the first day of the high salt period (HSP) were significantly greater in the K-supplemented group (KG) than in the control group (CG). 3. There was a significant gain in bodyweight after salt loading in both groups, with a significantly greater gain in CG on the second day of HSP. Haematocrit decreased significantly during salt loading in both groups, the degree of which was significantly greater in CG. 4. Plasma norepinephrine decreased significantly during salt loading in both groups, the degree of which was significantly less in KG than in CG. A significant increase in plasma ANP was observed in CG on and after the second day of HSP, while a significant increase in plasma ANP was observed on the fifth day of HSP in KG. 5. These findings indicate that K supplementation accelerates diuresis and natriuresis, resulting in moderate suppression of volume expansion induced by salt loading and that this accelerated diuresis and natriuresis is not a result of the action of ANP.

Topics: Adult; Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuresis; Hematocrit; Humans; Male; Natriuresis; Norepinephrine; Potassium, Dietary; Sodium

Previous studies have shown that microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii produces significant increases in local neuronal firing rate associated with reductions in arterial pressure in anesthetized Wistar rats. Single units excited by microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii were also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading. To test the hypothesis that endogenous atrial natriuretic peptide in caudal nucleus tractus solitarii is involved in the tonic control of blood pressure in the rat, we administered a blocking monoclonal antibody to atrial natriuretic peptide in a volume of 50 nl artificial cerebrospinal fluid via microinjection into the caudal nucleus tractus solitarii of spontaneously hypertensive and Wistar-Kyoto rats and observed the effects on mean arterial pressure and heart rate. Control injections of monoclonal antibody were administered into the rostral nucleus tractus solitarii, hypoglossal nucleus, spinal trigeminal nucleus, and cuneate nucleus of spontaneously hypertensive rats. Microinjection of monoclonal antibody into the caudal nucleus tractus solitarii caused significant increases in mean arterial pressure in spontaneously hypertensive rats but not in Wistar-Kyoto rats. There was no concomitant change in heart rate. Control injections of purified mouse immunoglobulin into the caudal nucleus tractus solitarii and of monoclonal antibody into the control neuronal groups listed above had no effect on mean arterial pressure. These results suggest that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii mediates tonic control of blood pressure in spontaneously hypertensive rats but not in normotensive Wistar-Kyoto rats.

Topics: Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart Rate; Injections; Medulla Oblongata; Muscimol; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Human atrial natriuretic peptide (HANP) is a hormone with the physiological characteristics of a regulator of body fluid volume. We studied whether, or not, it is possible to use HANP as a parameter to determine the so-called dry weight (D.W.) in patients on maintenance dialysis. Subjects for experiments included 117 hemodialysis (HD) patients, 18 chronic renal failure (CRF) patients under conservative treatment and 20 normal controls. Plasma HANP level was much higher in HD patients than in controls. In CRF patients treated conservatively, there was no significant correlation between plasma HANP and the degree of renal dysfunction. In HD patients plasma HANP showed a significant positive correlation with CTR (r = 0.408, p less than 0.001), but no correlation with the age or duration of hemodialysis. During hemodialysis, the plasma HANP level fell with the lapse of time significantly (p less than 0.001). In HD patients without complications, plasma HANP level after HD were significantly higher (p less than 0.001) in ones with CTR of 50% or more than with CTR of less than 50%. Plasma HANP may play an important part in regulating the balance of body fluid volume. These findings suggest that plasma HANP is useful as a parameter to determine the D.W. in patients on hemodialysis.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Body Fluids; Body Weight; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

The volume regulating hormones were studied during a 4-week head-down tilt (CNES HDT) in five subjects with and without (controls) lower body negative pressure (LBNP). LBNP was applied 3 times a day for 3 weeks, 4 times a day for 4 d, and 6 times a day for 3 d the last week. In both groups we observed a significant decrease in body weight (3% in controls, 0.8% in LBNP), a significant increase in plasma renin activity and aldosterone (with an amplification of their rhythms), and a significant decrease in norepinephrine with no difference between the two groups. The only major hormonal difference was observed for atrial natriuretic factor (ANF), which decreased significantly in the control group and increased in the LBNP group. These results are compared with the improvement in orthostatic tolerance (OT) after HDT in the LBNP group in the same protocol (17). We conclude that many factors could be involved in the improvement of OT. The results suggest that better conservation of plasma volume in the LBNP group might have prevented a decrease in ANF. Whether ANF plays a role in the regulation of baroreceptor reflex with an improvement in OT is currently unknown.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Volume; Body Fluids; Body Weight; Catecholamines; Exercise; Humans; Hypotension, Orthostatic; Lower Body Negative Pressure; Posture; Pressoreceptors; Renin; Sodium; Space Flight

The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Magnesium; Male; Myocardium; Norepinephrine; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To determine whether weight gain due to renal sodium and water retention occurs in the luteal phase of the normal menstrual cycle.. Prospective observational study.. Research laboratory installed with modified spa bath.. Ten normal healthy women.. Each subject underwent two experiments, one in each phase of the menstrual cycle, involving 3 h head-out water immersion and a pre- and post immersion control hour. 25 ml blood samples were obtained every hour before, during and after water immersion.. Renal and hormonal responses to water immersion during the luteal and proliferative phases of the cycle.. There was no change in weight, creatinine clearance, basal sodium excretion or plasma atrial natriuretic peptide between the two phases of the cycle. There was a significant rise in basal progesterone, plasma aldosterone and plasma renin activity in the luteal phase of the ovulatory cycles. Renal and hormonal responses to immersion including sodium and calcium excretion, elevation of atrial natriuretic peptide (ANP) and suppression of plasma aldosterone and plasma renin activity were identical in the two phases of the menstrual cycle.. We found no evidence to support the hypothesis that renal sodium and water retention occurs in the luteal phase of the normal menstrual cycle.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Body Weight; Calcium; Female; Humans; Immersion; Luteal Phase; Prospective Studies; Sodium

Urea kinetic modeling (UKM) was carried out to evaluate the water control in patients undergoing long-term hemodialysis. In 21 patients on chronic dialysis, the results of two different determinations of the total body water, i.e. by the deuterium oxide (D2O) method and by UKM, were compared. A correlation was observed with Y = 0.98X + 5.9 (P less than 0.01, r = 0.91) for males and Y = 0.97X + 6.2 (P less than 0.01, r = 0.90) for females, indicating that UKM is useful for determining the total body water. In addition, the 21 patients were classified into two groups based on their ECG findings, and UKM was performed in the two groups for comparison. The values of the total body water were 68.5 +/- 4.0% and 68.6 +/- 6.2% of body weight, respectively, with no significant difference between them. However, the CTR was 50.2 +/- 2.8% and 46.2 +/- 4.4%, respectively. Thus, not only X-ray examinations but also UKM should be carried out to determine the standard weight (SW-DW) in the presence of cardiac dysfunction. Instructions for water control were given when the total body water exceeded 73% during the UKM measurements over 5 years, which allowed an optimal total body water to be maintained thereafter. The possible influence of erythropoietin (EPO) was also examined by performing UKM in 8 cases receiving EPO and 7 cases without EPO. No noticeable difference was observed between the two groups. 17 patients using a polyacrylonitrile (PAN) membrane were further divided into those with and those without EPO to evaluate the possible influence of the PAN membrane-EPO combination. As a result, no significant difference was demonstrated, suggesting that UKM can be satisfactorily performed under such conditions. In 11 patients on chronic dialysis, the levels of alpha-human atrial natriuretic peptide (alpha-hANP) were measured pre- and post-dialysis to examine the relationship between the change in alpha-hANP and rate of weight loss (%). A significant correlation was observed with Y = 12.8X + 5.1 (P less than 0.05, r = 0.68). In conclusion, UKM was found to be useful for evaluating the water control and for assessing the optimal dialysis in patients receiving long-term hemodialysis.

Topics: Acrylic Resins; Adult; Atrial Natriuretic Factor; Body Water; Body Weight; Deuterium; Deuterium Oxide; Erythropoietin; Female; Humans; Male; Membranes, Artificial; Middle Aged; Renal Dialysis; Time Factors; Urea; Water

We studied the hormonal, renal and hemodynamic effects of prolonged treatment with SCH 39370, a new neutral endopeptidase (NEP) inhibitor, in experimental congestive heart failure (CHF). Coronary-ligated CHF rats and sham-operated controls received vehicle or SCH 39370 30 mg/kg s.c. twice daily for six days. In rats with heart failure, SCH 39370 elevated the high plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) levels 2-fold both initially and at the end of the experiment. Initially, water balance was more negative in SCH 39370-treated CHF rats than in those treated with vehicle. In all SCH 39370-treated rats, ANP, cGMP and electrolyte excretion and diuresis were pronounced for 6 h after injection but attenuated thereafter. Blood pressure and pulse remained unchanged. On reverse phase high performance liquid chromatography (HPLC), ANP-(99-126) appeared to be the only circulating form of ANP in rats with heart failure. Three forms have been discovered in patients with heart failure. HPLC revealed only intact ANP in plasma of rats with heart failure during SCH 39370 treatment. NEP inhibitors may provide a new tool for treating chronic heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Cyclic GMP; Dipeptides; Endopeptidases; Heart Failure; Hemodynamics; Kidney; Kidney Function Tests; Male; Metalloendopeptidases; Protease Inhibitors; Pulse; Rats; Rats, Inbred Strains; Renin; Water-Electrolyte Balance

Topics: Atrial Natriuretic Factor; Blood Volume; Body Weight; Cyclic GMP; Electric Conductivity; Female; Humans; Male; Peritoneal Dialysis, Continuous Ambulatory; Pulmonary Wedge Pressure; Renal Dialysis; Vena Cava, Inferior

The antihypertensive and tissue-protective effects of nitrendipine were studied after long-term treatment of rats with experimental hypertension. Nitrendipine had opposite effects in comparison with vasodilators like hydralazine or minoxidil. Nitrendipine lowered heart weights, plasma atrial natriuretic peptide levels, and plasma renin activity, and was diuretic. Also, in spontaneously hypertensive rats that had been hypertensive for more than half of their life span prior to treatment, nitrendipine still had these effects. Nitrendipine prevented hypertension-induced mortality, even at subantihypertensive doses. Nitrendipine inhibited endothelin-1-induced DNA synthesis in isolated vascular smooth muscle cells as well as atherosclerotic plaque formation in cholesterol-fed rats.

Topics: Animals; Arteriosclerosis; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Endothelins; Hydralazine; Hypertension; Minoxidil; Muscle, Smooth, Vascular; Nitrendipine; Organ Size; Rats; Rats, Inbred SHR; Renin

Since acute mountain sickness (AMS) is associated with rapid ascent and with fluid retention, we assessed clinical status and fluid homeostasis in men slowly ascending on foot over 3 d to 4559 m and remaining at this altitude 5 d. We studied 15 male mountaineers, 6 of whom had previously had repeated, severe AMS or high altitude pulmonary edema (HAPE), at 1170 m, 3611 m, and 4559 m. We found that four of the six subjects with previous AMS or HAPE compared with none of nine with no such history, developed these conditions. Those who remained well had a diuresis that could not be overcome by increasing fluid intake and no change in renin activity, plasma aldosterone, or atrial natriuretic peptide (ANP). Those who became ill showed considerable weight gain independent of fluid intake, and a great increase in ANP which correlated with measurements of right atrial cross section. We conclude that mountaineers who have previously experienced repeated AMS or HAPE get fluid retention despite slow ascent and that this is associated with widening of the atrium and an increase in ANP.

Topics: Adult; Altitude Sickness; Atrial Natriuretic Factor; Body Fluids; Body Weight; Diuresis; Echocardiography; Heart Atria; Homeostasis; Humans; Male; Middle Aged; Pulmonary Edema; Radiography; Urinary Retention; Water-Electrolyte Balance

Atrial natriuretic peptide (ANP) and plasma renin activity (PRA) were studied in 19 patients with end-stage renal disease (ESRD) under haemodialysis (HD). On the basis of clinical findings, patients were divided into three groups: group A, 6 patients, of mean age 41 +/- 15 years, without heart failure and in need of ultrafiltration (658 +/- 282 ml h-1); group B, 6 patients, of mean age 54 +/- 15 years, without heart failure under isovolaemic HD; group C, 7 patients, of mean age 60 +/- 3 years, with heart failure (NYHA III-IV) and in need of ultrafiltration (607 +/- 120 ml h-1). The highest predialysis ANP levels were found in group C (1534 +/- 471 pg ml-1) followed by group A (476 +/- 168 pg ml-1) and group B (236 +/- 138 pg ml-1) (normal range 62 +/- 27 pg ml-1). Systolic and diastolic blood pressure and heart rate did not correlate with ANP levels in either of the groups. However, iso-osmotic reduction of the body weight by ultrafiltration was correlated with decreasing ANP levels during HD (for groups A and C, r = 0.88 and 0.98, respectively). Isovolaemic HD did not alter ANP concentrations (group B). All patients received a volume bolus at the end of HD, and they responded with an instant increase in ANP concentration, which was most pronounced in patients with concomitant heart failure. PRA was not significantly correlated with ANP levels during HD. In conclusion, the results of this study indicate that there is a sensitive response of ANP levels to changes in body fluid status in ESRD.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Weight; Diuresis; Female; Heart Failure; Homeostasis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin; Statistics as Topic; Time Factors; Water-Electrolyte Balance

The effects of calcium and the mineralocorticoid deoxycorticosterone (DOC) on blood pressure were studied in four groups of spontaneously hypertensive rats (SHR): (1) control; (2) calcium; (3) deoxycorticosterone and; (4) deoxycorticosterone + calcium. Calcium was given as 1.5% calcium chloride in drinking fluid and deoxycorticosterone by weekly subcutaneous injections (25 mg kg-1). During the nine weeks of treatment the increase in systolic blood pressure was enhanced in the deoxycorticosterone and attenuated in the calcium group, whereas the deoxycorticosterone + calcium group did not deviate from control. Total plasma calcium was elevated in the calcium group. Plasma concentrations of sodium and atrial natriuretic peptide (ANP) were increased by deoxycorticosterone while neither of the calcium-treated groups differed from control in these respects. Urinary excretions of calcium and sodium were increased in both groups receiving calcium, and also the deoxycorticosterone group excreted more calcium into urine than the control. Adrenergic nerve density in a section of the mesenteric artery and the urinary excretion of noradrenaline and adrenaline were similar in all study groups. The results indicate that calcium supplementation can attenuate the development of hypertension and prevent the deoxycorticosterone-induced blood pressure rise in SHR, possibly by influencing sodium metabolism as seen in increased natriuresis, and by preventing the actions of deoxycorticosterone on sodium balance.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium, Dietary; Desoxycorticosterone; Electrolytes; Epinephrine; Kinetics; Male; Norepinephrine; Organ Size; Rats; Rats, Inbred SHR

Atrial natriuretic peptide (ANP), a recently discovered cardiac hormone, is an important regulator of body fluid homeostasis. Twenty patients with established chronic renal failure and on maintenance haemodialysis were studied before and after dialysis with capillary dialysers. ANP was determined by RIA after extraction. Mean (+/- SD) pre-dialysis ANP concentration was 146 +/- 51 pg/ml and decreased significantly during dialysis to 68 +/- 38 pg/ml (p less than 0.001). Per cent and absolute changes in plasma ANP level correlated significantly with concomitant changes in body weight (r = 0.764; p less than 0.001 and r = 0.558; p less than 0.01, resp.) but not with changes in serum creatinine, blood pressure or serum electrolytes. The obtained results indicate that ANP levels in patients with chronic renal failure are elevated mainly due to fluid overload, and the rapid fall in ANP concentration observed during haemodialysis is caused by the removal of excess fluid from the body.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatinine; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Renal Dialysis; Sodium; Time Factors

To examine the role of prostaglandins on pressure natriuresis in Dahl salt-sensitive (DS) rat, the pressure-natriuresis relationships in DS and Dahl salt-resistant (DR) rats were characterized with or without indomethacin (2 mg/kg/h) by utilizing an in vivo renal perfusion study. When untreated, in the DS rat the pressure-natriuresis curve was blunted (P less than .05) and excretion of prostaglandin E2 (38 +/- 11 to 109 +/- 43 pg/min) was decreased in comparison to the DR rat. With indomethacin, the pressure-natriuresis curve in the DR rat was blunted, while no significant changes were observed in the DS rat. Plasma renin activity and concentration of atrial natriuretic peptide were not changed by the treatment of indomethacin in both strains. These results suggest that the decrease in renal prostaglandins, at least in prostaglandin E2, plays some role in blunting pressure natriuresis in DS rat.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Dinoprostone; Hypertension; Indomethacin; Natriuresis; Prostaglandins; Rats; Renin; Sodium

The purpose of this study was to determine if the reflex response to a saline load is altered in the obese Zucker rat. The obese Zucker rat is a genetic model of obesity and insulin-resistant diabetes that has been reported to have high blood pressure. We examined the reflux renal responses to volume expansion in both anesthetized obese and lean Zucker rats. Initial blood pressure was significantly elevated in the obese Zucker rats compared with the lean controls. Urine flow and sodium excretion from innervated and denervated kidneys were measured before and after volume expansion with normal saline. Volume expansion resulted in significantly less urine flow and sodium excretion in the obese than the lean Zucker rats. This response was evident in both the intact and denervated kidneys. Rats were then infused with atrial natriuretic peptide (ANP) to determine if natriuretic and diuretic responses were altered in these rats. The diuretic action of ANP was not significantly reduced in the obese Zucker rat. However, the natriuretic action of ANP was significantly attenuated in the obese rats. These results indicate that the reflux response to an acute saline load is attenuated in the obese Zucker rat and that this decreased response may be due to a reduction in the direct action of ANP on the kidney.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Denervation; Glomerular Filtration Rate; Heart Rate; Insulin; Kidney; Obesity; Organ Size; Rats; Rats, Zucker; Reference Values; Renal Circulation; Sodium; Sodium Chloride

The aims were (1) to study the influence of afterload relief on the rise in atrial natriuretic factor (ANF) which occurs during acute volume expansion in the spontaneously hypertensive rat (SHR); (2) to assess the contribution of the atria and the ventricles to ANF release under these circumstances.. In the first series of experiments, SHR were treated with captopril (150 mg.kg-1.d-1) orally for 10 d. Untreated SHR and Wistar-Kyoto (WKY) rats served as controls. Volume expansion, equivalent to 10% of the total blood volume, was performed three times with human plasma protein fraction at 15 min intervals on conscious animals. Some haemodynamic variables and plasma ANF were measured. Tissue ANF measurements were conducted on another series of treated and control SHR not submitted to volume expansion. In another series of experiments, conscious SHR and WKY rats were submitted to repetitive 30% volume expansion (three times at 15 min intervals). Non-expanded animals served as controls. At the end of the experiments, tissue ANF measurements were performed.. All experiments were conducted on 15 week old SHR and WKY rats.. Captopril treatment reduced systolic blood pressure and cardiac hypertrophy in SHR. During volume expansion, changes in left ventricular end diastolic pressure were greater in control SHR than in treated SHR or WKY rats. Central venous pressure was affected similarly by volume expansion in both SHR groups. Plasma ANF rises induced by volume expansion were equal in all groups. Captopril treatment had no effect on right or left auricular ANF content prior to volume expansion. Repetitive 30% expansion reduced both right and left auricular ANF concentrations to the same extent (approximately 300-1500 ng.mg-1 protein) in SHR and WKY groups. Ventricular ANF was not affected by volume expansion in SHR, whereas volume expanded WKY rats had higher right and left ventricular ANF concentrations than their non-expanded controls.. (1) The increase in plasma ANF during volume expansion is not impaired in SHR with newly established hypertension; (2) captopril treatment decreases afterload and the changes in left ventricular end diastolic pressure during volume expansion in SHR, without affecting plasma ANF increases; (3) both the auricles, but not the ventricles, contribute to enhanced ANF secretion caused by acute volume expansion in SHR and WKY rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Captopril; Heart Atria; Hypertension; Male; Myocardium; Organ Size; Plasma Volume; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Indirect evidence suggest that volume overload is the major determinant of plasma atrial natriuretic factor (ANF) elevation in hemodialysis patients. Correlations between plasma ANF levels and extracellular volume (ECV) were investigated by simultaneously measuring both parameters in 30 pediatric hemodialysis patients (aged 1 to 17.5 years; 18 M, 12 F) 24 hours after a dialysis session. Plasma ANF was determined using a commercially available RIA (Amersham) after plasma extraction (SEP-Pack C18); ECV was estimated by determining the volume of distribution of inulin and expressing the result as the % of body weight. In hemodialysis children, ANF levels ranged from 43 to 427 pg/ml (versus 30-70 pmoles/ml in age-matched controls) and EVC ranged from 17 to 33% BW. A significant positive correlation was found between plasma ANF levels and ECV (r = 0.66; p less than 0.001). Patients who exhibited falls in blood pressure during the dialysis session had lower mean ANF and ECV values (133 +/- 90 pg/ml and 23 +/- 3% BW, respectively) than those who did not (211 +/- 123 pg/ml and 26 +/- 4% BW, respectively). Conversely, patients who needed chronic antihypertensive therapy had higher mean plasma ANF and ECV values (204 +/- 122 pg/ml and 26 +/- 4% BW, respectively) than those who did not (149 +/- 100 pg/ml and 23. 5 +/- 4.5% BW, respectively). In a small subgroup of patients who had repeated determinations, individual plasma ANF and ECV changes were closely matched and both parameters were well correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Atrial Natriuretic Factor; Body Weight; Child; Child, Preschool; Humans; Infant; Kidney Failure, Chronic; Plasma Volume; Renal Dialysis

Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN).. Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval.. Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Topics: Administration, Cutaneous; Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Drug Administration Schedule; Female; Heart Rate; Hematocrit; Humans; Male; Nitroglycerin; Norepinephrine; Renin; Sodium

The influence of mild dehydration on plasma levels of atrial natriuretic peptide (ANP) was studied in both young (aged 18 to 25 years) and elderly (aged 72 to 86 years) subjects. We expected that dehydration would lower ANP concentrations due to the ensuing volume contraction. A different response of the ANP hormonal system in the elderly might help to explain the observation that elderly subjects are more predisposed to dehydration as compared to young subjects. Dehydration was induced by restriction of fluid intake to 25% of normal for one day. During the study, urinary osmolality increased while osmolar clearance and body weight decreased. Basal ANP concentrations were higher in the elderly subjects. However, these levels did not change during the dehydration study neither in the young nor in the elderly subjects. This may be explained by the activation of counter-regulatory systems preventing a decrease in central blood volume and hence a decrease in ANP concentration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Body Weight; Dehydration; Female; Humans; Male; Osmolar Concentration; Vasopressins

A 28-year-old woman had hypothalamic disorders (amenorrhea, obesity, psychiatric abnormalities, polydipsia and fever) and chronic glomerulonephritis. She also suffered from general edema associated with cyclical oliguria and polyuria. Her body weight and plasma osmolality increased during the oliguria phase lasting 2 to 8 days and decreased after paroxysmal polyuria accompanied by the natriuresis. These episodes occurred repeatedly, regardless of the treatment with or without diuretics. The release of arginine vasopressin in response to increased plasma osmolality was exaggerated, but changes in plasma volume did not affect arginine vasopressin release. Plasma atrial natriuretic hormone increased in response to a rise in plasma arginine vasopressin and plasma volume during the oliguria phase, thereby resulting in the diuresis and natriuresis. The renin-angiotensin-aldosterone system was secondarily activated by body fluid depletion and diuretics, and this might play an additive role in general swelling. Plasma gonadal hormones did not change to explain the edema. The mechanism of this cyclical edema remains unknown, but it is likely that hypothalamic dysfunction related to psychiatric abnormalities may exaggerate arginine vasopressin release, and enhanced renal sympathetic activity may cause retention of Na and water, and the increase in atrial natriuretic hormone release responding to the plasma volume expansion may bring about the diuresis and natriuresis.

Topics: Adult; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Body Weight; Chronic Disease; Edema; Female; Follicle Stimulating Hormone; Glomerulonephritis; Growth Hormone; Humans; Hydrocortisone; Hypothalamic Diseases; Luteinizing Hormone; Oliguria; Osmolar Concentration; Plasma; Polyuria; Prolactin; Thyrotropin; Thyroxine; Water-Electrolyte Balance

Cadmium (Cd) exposure is known to alter cardiovascular function and has been implicated in the etiology of hypertension. Atrial natriuretic peptide (ANP), a hormone secreted by the heart, has been established as a diuretic, natriuretic, smooth muscle relaxant and may be a modulator of central cardiovascular regulation. The effects of Cd treatment on ANP levels in select tissues were studied as a possible mechanism underlying Cd-induced cardiovascular toxicity. Male rats were injected with CdCl2 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.), twice a day for 7 days and then maintained for a period of 30 days. On experimental day 38 plasma renin activity and plasma ANP content were not significantly altered. The high dose of Cd significantly decreased plasma aldosterone levels and atrial ANP levels on day 38. Hypothalamic ANP was significantly decreased at the 0.1, 0.5 and 1.0 mg/kg doses. Throughout the 37-day period, water consumption was not altered. Urine output was decreased in all treatment groups on day 37. The results indicate that Cd can alter select tissue content of the ANP and this interaction may play an important role in the cardiovascular effects of CD.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Body Weight; Cadmium; Cadmium Chloride; Hypothalamus; Injections, Intraperitoneal; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Renin

To clarify the possible role of elevated atrial natriuretic peptide (ANP) in the pathophysiology of preeclampsia, we measured ANP, renin activity (PRA), angiotensin II (Ang II), TXB2 (a stable metabolite of TXA2) and 6-keto-PGF1 alpha (a stable end product of PGI2) concentrations in the plasma of 19 normal pregnant women and 35 severe preeclamptic patients at term. Plasma ANP levels in the preeclamptic patients (n = 35, 71.5 +/- 3.8 pg/ml, mean +/- S.E.) and also umbilical plasma ANP (n = 35, 83.0 +/- 4.2 pg/ml) were significantly (p less than 0.01) higher than those of normal pregnant women plasma (n = 19, 58.7 +/- 3.7 pg/ml) and umbilical plasma (n = 19, 47.6 +/- 4.7 pg/ml). There was a significant (p less than 0.01) positive correlation between maternal ANP levels and fetal ANP levels (n = 54, r = 0.44). Plasma PRA and 6-keto-PGF1 alpha levels in preeclampsia were significantly (p less than 0.05) lower than those of normal pregnancy. The ratio of 6-keto-PGF1 alpha/TXB2 in preeclampsia was significantly (p less than 0.01) lower than that of normal pregnancy as we reported previously. There was no significant correlation between plasma ANP level and plasma PRA, Ang II, plasma TXB2 and 6-keto-PGF1 alpha concentrations. Moreover there was no significant correlation between plasma ANP level and the severity of preeclampsia. These data suggest the possibility of a transplacental crossing of ANP secreted by feto-placental unit, which might be, at least in part, responsible for the high ANP levels observed in preeclampsia. The ANP in preeclampsia is not related directly to hypertension, but it may play a substantial role in the regulation or normalization of blood volume and vascular reactivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Renin; Thromboxane A2

Lead exposure alters cardiovascular function and has been implicated in the etiology of hypertension. Therefore it was of interest to study the short term effect of lead treatment on atrial natriuretic factor (ANF), a hormone which produces vascular smooth muscle relaxation and natriuresis. Male Sprague Dawley rats were randomly divided into 5 groups containing 4 animals each and injected intraperitoneally with normal saline (control), 0.01, 0.1, 0.5 or 1.0 mg/kg of body weight with lead acetate solution twice a day for 7 days, and then maintained for a period of 30 days. During this period water consumption and urine volume were measured daily. At the end of the 30 day period, immunoreactive levels of ANF in hypothalamus, atria and plasma were measured by radioimmunoassay. Lead treatment did not alter water consumption, but significantly decreased urine output. At all doses, lead produced a decrease in hypothalamic content of ANF and slightly increased atrial levels. The content of ANF in plasma was decreased. The changes in ANF content indicate that lead interacts with the hormonal regulation of the cardiovascular system and these observations may relate to the cardiovascular toxicity of this heavy metal.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Dose-Response Relationship, Drug; Drinking; Heart Atria; Hypothalamus; Lead; Male; Organometallic Compounds; Random Allocation; Rats; Rats, Inbred Strains; Urination

The influence of pregnancy on the circulating concentrations of atrial natriuretic factor, the 28 amino acid carboxy (C)-terminal end of the 126 amino acid atrial natriuretic factor prohormone, and the amino (N)-terminus of the prohormone was studied with three specific radioimmunoassays recognizing: (1) atrial natriuretic factor (i.e., amino acids 99 through 126), (2) the 98 amino acid N-terminus, and (3) amino acids 31 through 67 from the midportion of the N-terminus of the prohormone. Plasma atrial natriuretic factor in normal pregnant women gradually increased as pregnancy progressed, with the mean +/- SEM being 58 +/- 4 pg/ml in the first trimester, 74 +/- 5 pg/ml in the second trimester, and 89 +/- 7 pg/ml in the third trimester. Likewise, proatrial natriuretic factor 31 through 67 increased from 1421 +/- 76 pg/ml (first trimester) to 1509 +/- 84 pg/ml (second trimester) to 1758 +/- 83 pg/ml in the third trimester, whereas the whole N-terminus of the prohormone increased from 1804 +/- 98 pg/ml (first trimester) to 1909 +/- 111 pg/ml (second trimester) to 2160 +/- 79 pg/ml in the third trimester. These results suggest that release of the N-terminus of the prohormone, as well as atrial natriuretic factor, increases with the rise in blood volume associated with a normal pregnancy. The circulating concentrations of both the C-terminus and N-terminus of the atrial natriuretic factor prohormone increased further in the 48 hours after delivery. Because both the C-terminus and N-terminus of the atrial natriuretic factor prohormone contain diuresis-producing peptides, these results suggest that postpartum diuresis may be mediated by these peptides.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chemical Phenomena; Chemistry; Female; Heart Rate; Humans; Labor, Obstetric; Natriuresis; Osmolar Concentration; Peptide Fragments; Pregnancy; Pregnancy Trimester, Third; Protein Precursors; Radioimmunoassay; Reference Values

The effect of streptozocin-induced diabetes (STZ-D) on right atrial structure was investigated in male Wistar rats. STZ (55 mg/kg) or saline (1 ml/kg) was administered by intravenous injection 12 wk before the experimental studies. Tissue was sampled from four regions of the atrium, processed, and embedded in plastic. Quantitative stereological analysis indicated that in STZ-D rats, there was a significant diminution in size of the musculi pectinati (muscular ridges), which form a network making up the wall of the atrium. In addition, within the muscular ridges, there was a significant reduction in the relative proportion of cardiocytes within the cardiac tissue. The rest of the cardiac tissue consisted of interstitial regions, connective tissue, and blood vessels, which correspondingly increased. This suggests there was some form of cardiomyopathy. When atrial granularity was determined relative to cardiocyte volume density, a significant decrease (54%) was found in tissue from STZ-D rats. The blood pressure of conscious STZ-D rats was significantly lower than control rats, whereas right atrial pressure was not different. The level of resting plasma immunoreactive atrial natriuretic factor (ANF) in conscious STZ-D rats (98 +/- 5 pg/ml) was significantly higher than in control rats (52 +/- 7 pg/ml). The decreased atrial granularity could be related to the higher resting plasma ANF levels, suggesting a more rapid turnover or increased synthesis bypassing storage in the granular form.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Heart Atria; Heart Rate; Male; Myocardium; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values

The effect of aging on responses of vascular smooth muscles to atrial natriuretic peptide (ANP) and other vasodilator substances was investigated in isolated rat aortae, rat renal arteries and monkey renal arteries which were precontracted with norepinephrine. There was no significant difference in the ANP-induced maximum relaxation between young and old rat aortae. However, the concentration of agonists causing a 50% relaxation (ED50) value for the old rats was 7.3 times greater than that for the young ones. In rat and monkey renal arteries, the ED50 ratios were 6.2 and 3.8, respectively. The relaxant responses of the rat aortae to isoproterenol and acetylcholine also decreased with increasing age. The ED50 ratios for isoproterenol and acetylcholine were more than 40 and 17, respectively. The maximum relaxation induced by 10(-5) M isoproterenol also decreased significantly in the aortae from the older rats. On the other hand, the ED50 for nitroprusside, nifedipine- and potassium-induced relaxation was not affected by increasing age. These results suggest that ANP-induced relaxation of vascular smooth muscles is reduced with increasing age in rat aortae, rat renal arteries and monkey renal arteries. The mechanisms by which the ANP-induced relaxation decreased in association with the aging process may be quite different from those in acetylcholine-induced and beta adrenoceptor-induced relaxation.

Topics: Acetylcholine; Aging; Animals; Aorta; Atrial Natriuretic Factor; Body Weight; Dose-Response Relationship, Drug; Female; Isoproterenol; Macaca; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Inbred Strains; Renal Artery; Species Specificity

The influence of prolonged high salt intake on intravascular volume, right atrial pressure, plasma atrial natriuretic factor, and extra-atrial tissue (lung, kidney, and liver) COOH- and NH2-terminal atrial natriuretic factor content was investigated in normotensive rats. Despite prolonged high salt (8% NaCl) intake for 5 weeks, total intravascular volume was not impaired. However, right atrial pressure was increased by 54% (p less than 0.01) after salt loading. Although this increment in right atrial pressure should favor atrial natriuretic factor release after NaCl intake, plasma atrial natriuretic factor (COOH-terminal) concentrations markedly decreased from 97.8 +/- 27 to 38.9 +/- 8 pg/mL. Sodium and circulatory homeostasis was, however, well preserved. The lungs contained the highest levels of COOH- and NH2-terminal atrial natriuretic factor. Salt loading resulted in increased concentrations of low as well as high molecular weight atrial natriuretic factor in the lung but not in the kidney or the liver. Our study indicates a limited role of atrial natriuretic factor in adaptation to prolonged salt consumption in rats. Dissociation between right atrial pressure and plasma atrial natriuretic factor after salt intake implicates other factors regulating circulating peptide levels. Prolonged salt intake increases lung generation of atrial natriuretic factor.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Rats; Rats, Inbred Strains; Sodium; Sodium, Dietary

In advanced chronic obstructive lung disease (COLD), sodium retention is common, associated with reduction in renal plasma flow (RPF) and stimulation of the renin-aldosterone (PRA-PA) system, two abnormalities due to or influenced by hypercapnia: the independent role of hypoxemia in perturbing sodium homeostasis is unknown. In five stable patients with COLD (FEV1 = 0.9 +/- 0.21, mean +/- SE) with mild edema, during two weeks of a low sodium diet (one week on room air: pH = 7.39 +/- 0.02; PaO2 = 55 +/- 4 mm Hg; PaCO2 = 49 +/- 4 mm Hg; and one week on O2: pH = 7.38 +/- 0.01; PaO2 = 72 +/- 6 mm Hg; PaCO2 = 52 +/- 4 mm Hg) we monitored sodium balance, systemic and renal hemodynamics, plasma sodium and potassium, PRA, PA, and atrial natriuretic hormone (ANH). During air breathing, patients uniformly showed a depression of RPF despite normal cardiac output; plasma hormone levels did not differ from controls but there was elevation (greater than 2 SD above the normal mean) of PRA in four patients, PA in two patients, and ANH in two of five patients. During O2 breathing, urinary sodium increased significantly from 67 +/- 7 to 102 +/- 10 mEq/24 h. Surprisingly, the patients experienced a small but significant weight gain (0.6 +/- 0.1 kg). None of the other variables was affected by O2 therapy. The following conclusions were reached: in advanced COLD, correction of hypoxemia results in sodium diuresis, indicating that hypoxemia (in the presence of hypercapnia) contributes to sodium retention. The mechanism for this beneficial effect of O2 will require further investigation.

Topics: Aldosterone; Atrial Natriuretic Factor; Body Weight; Glomerular Filtration Rate; Hemodynamics; Humans; Hypoxia; Lung Diseases, Obstructive; Middle Aged; Oxygen Inhalation Therapy; Renal Circulation; Renin; Sodium

1. Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive-ANP (IR-ANP) as well as ANP messenger RNA (mRNA), and the release of IR-ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil-treated Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. IR-ANP levels in the ventricles of untreated, 12 month-old SHR with severe ventricular hypertrophy were increased when compared to age-matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR-ANP concentrations (in WKY from 133 +/- 20 to 281 +/- 34 pg ml-1, P less than 0.01; in SHR from 184 +/- 38 to 339 +/- 61 pg ml-1, P less than 0.05), and in ventricular IR-ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR-ANP content and ventricular weight to body weight ratio (r = 0.59, P less than 0.001, n = 26). 3. When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil-treated SHR, control SHR, minoxidil-treated WKY and control WKY, respectively. A significant correlation was found between the IR-ANP release from ventricles and ventricular weight to body weight ratio (r = 0.56, P < 0.01, n = 24). 4. These studies demonstrate that the ventricles contribute substantially to the circulating level of ANP, and that the amount released depends on the degree of ventricular hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Hemodynamics; In Vitro Techniques; Kidney; Male; Minoxidil; Myocardium; Norepinephrine; Organ Size; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sodium

Plasma immunoreactive human atrial natriuretic peptide (hANP) levels were measured in 9 patients with chronic renal failure treated with maintenance hemodialysis in order to evaluate the effects of fluid removal and osmotic pressure. Under hemodialysis without fluid removal plasma hANP levels remained unchanged, but the levels were significantly decreased during extra-corporeal ultrafiltration (p less than 0.01). The present study provided strong evidence that the fall in plasma hANP levels in hemodialysis patients is mainly due to the reduction in circulating plasma volume.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Weight; Extracorporeal Circulation; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Ultrafiltration; Vasopressins

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Humans; Indomethacin; Male; Natriuresis; Sulindac; Time Factors

To define the relationship between atrial natriuretic polypeptide and the physiological changes of water and electrolytes after burns, the changes in plasma hormonal levels, including atrial natriuretic polypeptide, and urinary water and sodium excretions were examined in burned rats. Further, to elucidate the physiological significance of atrial natriuretic polypeptide after burns, the effects of a specific antiserum against atrial natriuretic polypeptide were determined in burned rats. Plasma atrial natriuretic polypeptide levels in rats following 30 per cent BSA full skin thickness burns were elevated for sustained periods (432.3 +/- 156.5 pg/ml, P less than 0.01 on day 1 postburn, 244.5 +/- 73.7 pg/ml, P less than 0.05 on day 3 postburn). Urine volume and sodium excretion decreased significantly during the first 72 h after burns. On day 3 postburn, urine volume and sodium excretion began to increase significantly. Specific rabbit antiserum against atrial natriuretic polypeptide was injected into the burned rats during this diuretic phase. Significant inhibition of diuresis and natriuresis was observed after the injection of antiserum (27.5 +/- 2.4 per cen decrease in urine volume, 57.1 +/- 10.4 per cent decrease in sodium excretion). These results suggest that atrial natriuretic polypeptide plays a physiological role in the regulation of urinary water and sodium excretion after burns.

Topics: Aldosterone; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Body Weight; Burns; Diuresis; Epinephrine; Male; Natriuresis; Norepinephrine; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium; Time Factors

To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine.. Single blind, placebo controlled study in patients receiving fixed sodium and potassium intakes.. Blood pressure unit of a teaching hospital in south London.. Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks.. Withdrawal of nifedipine and replacement with matching placebo for one week.. Urinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure.. During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained.. Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Renin; Single-Blind Method; Sodium

We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control, Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.

Topics: Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart Rate; Hypertension; Hypothalamus, Anterior; Hypothalamus, Posterior; Immunotherapy; Microinjections; Rats; Rats, Inbred SHR

We determined plasma and cardiac immunoreactive atrial natriuretic polypeptide (ir-ANP) levels in rats treated with deoxycorticosterone acetate (DOCA) and sodium chloride for 1, 7, and 28 days. Systolic blood pressure of DOCA-salt rats began to increase from the 7th day and reached 191 +/- 7 mmHg at the 28th day. One day after treatment with DOCA-salt, plasma levels of ir-ANP were increased compared to that of control rats. This was accompanied by decreased cardiac ir-ANP content. However, at the 7th day of DOCA-salt treatment, both plasma and cardiac ir-ANP levels of DOCA-salt rats were not different from those of control animals. At the 28th day, DOCA-salt rats had high plasma ir-ANP levels and no significantly different cardiac ir-ANP content compared to the controls. These data suggest that there are time-related changes in plasma ANP concentration during the development of DOCA-salt hypertension and higher plasma ANP levels might not necessarily be associated with a decreased cardiac ANP content.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatinine; Desoxycorticosterone; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Systole; Time Factors

About 30% of hemodialyzed patients are suffering from chronic fluid overload despite advice to restrict the oral fluid intake. To investigate the cause of the abnormal drinking behaviour a clinical study was performed in 51 non-diabetic patients with endstage renal disease exhibiting lower interdialysis weight gain (less than 3 kg, n = 17) and increased interdialysis weight gain (greater than 3 kg, n = 34). Blood pressure, body weight self-estimated thirst intensity before and after hemodialysis were analyzed. Biochemical and behavioral variables were measured including hormonal factors of water and sodium metabolism. Significant differences of dry weight, creatinine, urea nitrogen and thirst intensity were found between the two groups. Catecholamines, renin, angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide exhibited a similar pattern in both groups. Atrial natriuretic peptide decreased during hemodialysis in both groups, angiotensin II, however, and norepinephrine showed an exaggerated response to ultrafiltration rate in polydipsic patients. These results suggest that changes in serum osmolality during hemodialysis did not contribute to thirst and drinking behaviour. It seems that postdialytic hypovolaemia together with higher plasma-angiotensin II-levels is responsible for increased oral intake of fluid and excessive weight gain.

Topics: Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Chemical Analysis; Body Weight; Drinking Behavior; Humans; Kidney Failure, Chronic; Norepinephrine; Renal Dialysis; Renin; Thirst

Obesity is usually associated with expansion of blood volume. Therefore, we studied whether obesity affects cardiac and plasma atrial natriuretic peptide (ANP) levels in experimental animal model. Mice made obese with gold thioglucose developed cardiac hypertrophy associated with increases in ANP in atrial tissue and plasma. There were significant (p less than 0.01) correlations between the cardiac ANP concentration and body weight or cardiac weight. These data suggest that enhanced synthesis of atrial ANP in obese mice can be mainly ascribed to increased blood volume associated with cardiac hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Aurothioglucose; Body Weight; Heart; Male; Mice; Mice, Obese; Myocardium; Obesity; Organ Size; Radioimmunoassay; Ventromedial Hypothalamic Nucleus

Based on studies in laboratory animals and on measurements of the urinary metabolites (allo)tetrahydrocortisol and tetrahydrocortisone in human volunteers it has been claimed that liquorice-induced mineralocorticoid excess is caused by a unique defect in the conversion of cortisol to cortisone. To further evaluate this hypothesis we have investigated the influence of glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice, on plasma cortisol and cortisone in 10 healthy young normotensive volunteers. Pure GA (500 mg/day), administered orally from days 3-10 of the study, exerted pronounced mineralocorticoid activity. Ingestion of GA resulted in an elevated urinary excretion of free cortisol and virtually unchanged plasma cortisol levels in the presence of markedly decreased levels of both plasma cortisone and urinary free cortisone. These results provide direct clinical support for the hypothesis that GA induces an inhibition of the activity of 11 beta-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Adult; Aldosterone; Atrial Natriuretic Factor; Body Weight; Cortisone; Creatinine; Female; Glycyrrhetinic Acid; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Male; Potassium; Receptors, Mineralocorticoid; Receptors, Steroid; Renin-Angiotensin System; Sodium

We investigated whether cGMP might be a suitable marker of ideal weight in chronic haemodialysis patients. In 20 patients on chronic haemodialysis (10 males, 10 females, mean age 55.5 +/- 7.4 years; mean interdialytic weight gain 2.4 +/- 1.1 kg) we determined plasma ANP and cGMP values before and after several haemodialysis treatments. ANP and cGMP before haemodialysis were markedly elevated (ANP 255 +/- 190 pg/ml; cGMP 28.6 +/- 16.2 pmol/ml). A significant decrease was found after haemodialysis (ANP 169 +/- 88 pg/ml; cGMP 13.5 +/- 7.4 pmol/ml). These values were still well above normal. There was a significant positive correlation between excessive body-weight delta P (difference between actual weight and estimated ideal weight), indicating fluid overload and ANP before (r = 0.57; P less than 0.001) and after haemodialysis (r = 0.47; P less than 0.001) as well as cGMP before (r = 0.42; P less than 0.01) and after haemodialysis (r = 0.85; P less than 0.0001). With cGMP and delta P after haemodialysis, the correlation appeared to be close enough for clinical application. All patients with a cGMP value of 18 pmol/ml or more after haemodialysis had an excessive body-weight of at least 0.5 kg. We conclude from these data that the plasma cGMP value determined immediately after haemodialysis is a sensitive marker for hyperhydration in patients with end-stage renal disease.

Topics: Atrial Natriuretic Factor; Biomarkers; Body Water; Body Weight; Cyclic GMP; Female; Humans; Male; Middle Aged; Renal Dialysis

Bilateral renal clearance experiments were performed to examine the effects of synthetic rat atrial natriuretic peptide (ANP, atriopeptin II) on the arterial blood pressure (BP) and individual kidney function in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 14) and normotensive rats (n = 15). Bolus administration of graded doses of ANP from 2.5 to 10 micrograms/kg produced dose-related reductions in BP in hypertensive and normotensive rats. Despite profound reductions in BP, there were significant increases in glomerular filtration rate, urine flow, absolute and fractional excretion rates of sodium and potassium, osmolar clearance, and free water clearance in the nonclipped kidney, whereas no significant changes in these renal indices occurred in the clipped kidney. The enhanced renal responses were dose-dependent. The normal kidney responded to ANP with similar magnitude. When ANP was infused intravenously (0.3 microgram/kg.min i.v.) during 2 h, BP maximally reduced by 36 +/- 2 mm Hg (24 +/- 1%) in the hypertensive group and by 27 +/- 2 mm Hg (22 +/- 2%) in the control group. Again, there were distinct renal responses between the two kidneys of hypertensive rats. These results indicate that ANP effectively reduces BP and preferentially increases the excretory function of the nonclipped kidney without compromising the function of the clipped kidney in this hypertensive model.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuresis; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Male; Rats; Rats, Inbred Strains

Plasma concentrations of atrial natriuretic peptides (ANP) in female Wistar rats were measured by radioimmunoassay at oestrus, during pregnancy, during parturition and between 3 h and 4 days post partum. Concentrations of ANP in rats on days 10, 15 and 17 of pregnancy were not significantly different from those in non-pregnant animals in oestrus (32.5 +/- 2.2 pmol/l; mean +/- S.E.M., n = 9), but levels near term (days 20 and 21 of pregnancy) were reduced by approximately 50%. However, plasma concentrations of ANP at 6, 12 and 24 h post partum were approximately twice those of non-pregnant animals in oestrus, but returned to normal levels within 4 days after parturition. Maternal plasma volume increased significantly during pregnancy, and fell 15-20% 6-24 h post partum. These results suggest that the relationship between plasma volume and the plasma concentration of ANP is reset during pregnancy and changes rapidly post partum. The results do not necessarily, however, imply any changes in the relationship between atrial pressure and the concentration of ANP.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Estrus; Female; Plasma Volume; Postpartum Period; Pregnancy; Pregnancy, Animal; Rats; Rats, Inbred Strains; Urine

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gen

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Heart Atria; Heart Ventricles; Hemodynamics; Hypothalamus; Male; Myocardium; Organ Size; Plasma Substitutes; Radioimmunoassay; Rats; Rats, Brattleboro; Rats, Inbred Strains; Rats, Mutant Strains; RNA, Messenger; Vasopressins

We investigated the influences of captopril (CAP) and hydralazine (HYD) on the ANP mRNA level in the hypertrophied left ventricle (LV) of spontaneously hypertensive rats (SHR). Male SHRs (16 weeks of age) were given CAP (35 mg/kg/day) or HYD (3.5 mg/kg/day) for two weeks. Both drugs reduced blood pressure by a similar magnitude. Treatment with CAP caused a reduction in the ANP mRNA level in LV by 62%, and a reduction in the weight of the LV. The ANP mRNA level in LV of the HYD-treated rats was also decreased, but only by 31%. HYD did not affect LV hypertrophy. ANP gene expression in LV of SHR might be effectively suppressed by a reduction of blood pressure and also by the concomitant attenuation of hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Captopril; Gene Expression Regulation; Heart Ventricles; Hydralazine; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; RNA, Messenger

Studies were carried out to determine if the release of atrial natriuretic factor (ANF) is altered in the inbred Dahl salt-sensitive (SS/Jr) rat. Isolated heart-lung preparations of prehypertensive young SS/Jr rats (6-8 weeks of age) and age-matched inbred Dahl salt-resistant (SR/Jr) rats were used. At this relatively young age the blood pressure difference between strains (SS/Jr, 108 +/- 3 mm Hg; SR/Jr, 103 +/- 2 mm Hg) was minor. ANF release was stimulated with preload-induced or afterload-induced atrial stretch. Increased preload produced increases in right and left atrial pressures that were equivalent between young SS/Jr and SR/Jr rats; increased afterload produced increases only in left atrial pressures, which again were equivalent for young rats of the two strains. At any preload-induced change in atrial pressure SS/Jr rat hearts released less ANF than those of SR/Jr rats. Similarly, at any afterload-induced increase in left atrial pressure, SS/Jr rat hearts released less ANF than those of SR/Jr rats. In contrast to the above results in young rats, the strain differences were dramatically reversed when older rats (5-6 months of age) were used; at this age SS/Jr rats were markedly hypertensive (SS/Jr, 211 +/- 8 mm Hg; SR/Jr 130 +/- 4 mm Hg). Hearts from adult hypertensive SS/Jr rats released more ANF than hearts from adult normotensive SR/Jr rats at any left atrial pressure as afterload was increased. This reversal of SS/Jr rats from hyposecreters to hypersecreters of ANF is probably a consequence of hypertension-induced changes such as cardiac hypertrophy and recruitment of the ventricles to produce ANF. It is concluded that the hyposecretion of ANF by prehypertensive SS/Jr rats may represent a genetic trait relevant to the pathogenesis of genetic hypertension and that this is obscured by adaptive changes in the heart as hypertension progresses.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiac Output; Heart; Heart Rate; Rats; Rats, Inbred Strains; Sodium Chloride; Stroke Volume

The changes in plasma level of alpha-atrial natriuretic polypeptide (alpha-ANP) and the relaxing responses to exogenous alpha-ANP of strips of rat aorta pretreated with methoxamine were examined at one, four and eight weeks after myocardial infarction induced by left coronary ligation. Responses to a beta-adrenergic stimulant, isoprenaline, and sodium nitroprusside of the vessel pretreated with high potassium were also evaluated up to twelve weeks. Plasma concentrations of immunoreactive alpha-ANP, which were measured at one, four and twelve weeks, were significantly elevated in rats with myocardial infarction (MI-rats) as compared with sham-operated rats (sham-rats). The relaxation responses of the aorta to exogenenous alpha-ANP in MI-rats were significantly reduced at one and four weeks as compared with sham-rats. The difference was, however, less obvious at eight weeks. The responses to isoprenaline tended to be reduced from the 1st week to the 12th week, and the difference was significant at eight weeks, whereas those to methoxamine and sodium nitroprusside were unchanged. It is concluded that the MI-rats are partially resistant to the vasodilating effects of alpha-ANP and isoprenaline without any change in responses to the alpha-stimulant and sodium nitroprusside, although these changes are transient.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Body Weight; Heart; In Vitro Techniques; Isoproterenol; Male; Methoxamine; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Infarction; Nitroprusside; Organ Size; Rats; Rats, Inbred Strains

The effects of 4 h haemodialysis (15 patients) or 4 h haemofiltration (five patients) on plasma concentrations of atrial natriuretic peptide (ANP) were compared by means of a sensitive radioreceptor binding assay, and related to accompanying changes in body weight, blood pressure and plasma renin activity. Before dialysis, plasma ANP concentrations were considerably elevated: haemodialysis group 10-484 pmol/l (mean 156 pmol/l); haemofiltration group 72-320 pmol/l (mean 170 pmol/l). Although plasma concentrations of ANP fell markedly with treatment in both groups: post-haemodialysis 2-187 pmol/l (mean 67 pmol/l); post-haemofiltration 47-135 pmol/l (mean 79 pmol/l), after treatment it remained above the normal range in 14 of the 20 patients. Pretreatment plasma ANP was related to systolic blood pressure (r = 0.459; P less than 0.05) but bore no relationship to mean or diastolic blood pressure, or plasma renin activity. The fall in plasma ANP concentration during treatment correlated with the postural blood pressure drop after dialysis (r = 0.505; P less than 0.05), but was unrelated to changes in weight or plasma renin activity with haemodialysis or haemofiltration. Plasma ANP concentrations rose rapidly again in the 60 min after dialysis treatment, without change in body weight. These results show that high levels of biologically active ANP circulate in end-stage renal disease. The fact that these are not reduced to normal by haemodialysis or haemofiltration, despite restoration to normovolaemic or hypovolaemic state, suggests that the increased levels of ANP in end-stage renal failure are due to both hypervolaemia and other factors, which may include occult cardiac dysfunction and loss of renal clearance.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Hemofiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plasma Volume; Renal Dialysis; Renin

To assess possible roles of atrial natriuretic factor (ANF) in the regulation of blood pressure in spontaneously hypertensive rats (SHR), we performed two series of experiments. First, we studied acute hypotensive, natriuretic and diuretic effects of ANF in pentobarbital-anesthetized SHR and age-matched Wistar-Kyoto rats (WKY). A synthetic ANF of 25 amino acid residues was intravenously administered as a bolus at doses of 0.1, 1.0, 2.5 and 5.0 micrograms/kg. In SHR group, a significant decrease in mean arterial pressure (MAP) was observed at a dose of 1.0 micrograms/kg, and the decrease was dose-dependent. On the other hand, in WKY group, the hypotensive effect of ANF was not observed until a dose of 5.0 micrograms/kg. The diuretic and natriuretic effects of ANF were observed at a dose of 2.5 micrograms/kg in SHR and 5.0 micrograms/kg in WKY, respectively. Second, we also studied chronic effect of ANF on the development of hypertension in 6-week-old SHR. The SHRs, on regular diet or given 1% NaCl solution for drinking, were continuously infused into the jugular vein by osmotic minipumps with ANF (15, 75 and 150 micrograms/kg/day) or vehicle (physiological saline) as controls for up to 14 days. ANF at a dose of 150 micrograms/kg/day attenuated transiently the development of hypertension in the sodium-loaded SHR. However, the blood pressure returned to control levels by day 5. ANF at doses of 15 and 75 micrograms/kg/day did not affect the development of hypertension. In SHR on regular diet, ANF at a dose of 150 micrograms/kg/day did not affect the development of hypertension. In addition, ANF did not induce any significant changes in urine volume, fluid intake, and urinary excretion of sodium and potassium in SHR, whether they were sodium-loaded or not, when compared to those in vehicle-infused SHR. These results indicate that there may be a significant difference in the sensitivity to diuretic, natriuretic and hypotensive actions of ANF between SHR and WKY. Moreover, it is suggested that ANF may play significant roles by its vascular effect at the early stage of development of hypertension in sodium-loaded SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Hypertension; Male; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium

Using a cross-over protocol we repeatedly measured the plasma levels of alpha-hANP (atrial natriuretic peptide) during one week by radio-immunoassay in eight patients with end-stage renal disease treated with chronic hemodialysis or hemofiltration. Before each hemodialysis or hemofiltration session mean plasma ANP levels (353 +/- 112, and 337 +/- 99 pg.ml-1, respectively) were significantly above normal (50 - 166 pg.ml-1). In all but one patient, the values fell significantly towards but not reaching the normal range. Plasma ANP concentrations returned to normal at the end of the treatment in only two of the eight subjects. There was a positive correlation between the increase in body weight from one treatment to the next and the plasma ANP concentration (r = +0.35, p less than 0.05). The net loss of fluid volume during each treatment did not correlate significantly with the change in plasma ANP levels. There was no difference between hemodialysis and hemofiltration. Plasma ANP measurement may be helpful in the judgement of volume status in patients with end-stage renal disease treated by hemodialysis or hemofiltration.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Body Weight; Female; Heart Rate; Hemofiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Plasma levels of immunoreactive alpha human atrial natriuretic peptide (IR-ANP) and left atrial diameter were measured in 6 normal subjects before and after 6 days of sodium loading using salt supplements and 9-alpha-fluorohydrocortisone. During chronic sodium loading, which increased mean body weight by 1.5 kg and markedly reduced plasma renin and aldosterone levels, plasma IR-ANP increased from 21 +/- 3 to 36 +/- 7 pmol/l (P less than 0.02). Increase in atrial diameter correlated with gains in body weight (r = 0.93, P less than 0.01) but not with increase in plasma IR-ANP. After chronic sodium loading for 6 days, further volume expansion (2 litres of saline infused over 2 hours) significantly increased left atrial diameter but did not affect plasma IR-ANP levels. We conclude that chronic sodium loads increase plasma IR-ANP. However, the failure of further acute atrial distension to increase hormone levels suggests that factors in addition to atrial stretch are important in regulating atrial peptide secretion in man.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart; Humans; Male; Middle Aged; Norepinephrine; Renin; Sodium; Ultrasonics

Plasma concentrations of human atrial natriuretic peptide (hANP) were determined in children with persistent hypertension and in age-matched normotensive controls. We studied 40 children 6-7 years of age (Group A), and 74 children 13-14 years of age (Group B). There was no significant difference in plasma hANP concentration between hypertensives and normotensives in group A. In group B, the plasma hANP concentration in hypertensives (86.5 +/- 44.9 pg/ml: mean +/- SD) was significantly higher than in normotensives (58.8 +/- 40.4 pg/ml) (p less than 0.01). In group B, 24-hour urinary excretion of sodium and fractional excretion of sodium were not significantly different between hypertensives and normotensives. The plasma hANP correlated significantly with the fractional excretion of sodium (p less than 0.05) and the 24-hour urinary excretion of sodium (p less than 0.01) in normotensives. No such correlation was evident in the case of the hypertensives. The pathogenesis of increased plasma hANP concentration in older children with persistent hypertension remains to be investigated. In regard to the effects of hANP on renal function, hANP may contribute to the regulation of sodium handling in normotensive adolescents, whereas other regulatory mechanisms need to be considered in the case of hypertensives.

Topics: Adolescent; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Child; Creatinine; Humans; Hypertension; Japan; Potassium; Sodium

To determine whether pharmacological control of blood pressure could affect the renal function and levels of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) with renal ablation, and to ascertain the benefits of antihypertensive drugs, we studied effects of oral administration of captopril (50 mg/kg/day), an inhibitor of angiotensin converting enzyme, benidipine (3 mg/kg/day) and nilvadipine (10 mg/kg/day), newly developed blockers of calcium channel, and indapamide (10 mg/kg/day) for 14 days on systolic blood pressure, serum creatinine, blood urea nitrogen, and plasma ANP concentration in SHR subjected to surgical removal of the left kidney and infarction of two-thirds of the right kidney (5/6 nephrectomy) a week before. Three weeks after the surgery, systolic blood pressure (mmHg) in the untreated group was 253 +/- 9 (n = 10), in the captopril group 156 +/- 9 (n = 7, p less than 0.05), in the benidipine group 197 +/- 9 (n = 7, p less than 0.05), in the nilvadipine group 146 +/- 9 (n = 7, p less than 0.05) and in the indapamide group 206 +/- 5 (n = 7, p less than 0.05). Serum creatinine (mg/100 ml) was lower in the captopril group (0.58 +/- 0.02, n = 7, p less than 0.05) and in the benidipine group (0.50 +/- 0.03, n = 7, p less than 0.05) but not in the nilvadipine group and in the indapamide group 3 weeks after 5/6 nephrectomy compared to the untreated group. Blood urea nitrogen was also lower in the captopril group and in the benidipine group but not in the nilvadipine group and in the indapamide group. Plasma ANP concentration was significantly reduced by the treatment with captopril and benidipine but not with nilvadipine and indapamide. These results suggest that the reduction of blood pressure by the inhibition of angiotensin converting enzyme with captopril has the potential to ameliorate renal function of the SHR with remnant kidney, a model of chronic renal failure with hypertension, associated with the decreased concentration of plasma ANP. However, it remains to be determined whether the reduction of blood pressure by calcium channel blockers may be involved in the delayed progression of renal failure in this model since there were disparate effects on renal function and plasma ANP concentration with these two calcium channel blockers.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium Channel Blockers; Captopril; Dihydropyridines; Indapamide; Kidney; Male; Nephrectomy; Nifedipine; Rats; Rats, Inbred SHR; Reference Values

The present study was designed to determine the possible involvement of atrial natriuretic factor (ANF) in the hypotensive action of a high-calcium diet. The effects of increased dietary calcium (2.9% calcium, HCa) on blood pressure, urinary sodium excretion, and ANF were examined in 30 spontaneously hypertensive rats (SHR) and 30 Wistar-Kyoto rats (WKY). Control groups of 30 SHR and 30 WKY were fed normal calcium lab chow (0.4% calcium, NCa). The HCa diet reduced blood pressure and serum phosphorus concentration and increased urinary excretion of sodium and calcium in SHR and WKY. The HCa diet also caused a sustained increase in plasma ANF concentration and, finally, a decrease in atrial ANF concentration in both groups. A significant inverse correlation was observed between ANF concentrations in plasma and atria of the four experimental groups. Plasma ANF concentration was positively correlated with daily calcium consumption, and blood pressure was inversely correlated with daily calcium consumption in HCa- and NCa-SHR groups and in HCa- and NCa-WKY groups, respectively. Furthermore, a significant inverse correlation between blood pressure and plasma ANF concentration was observed in SHR groups and in WKY groups, respectively. The observed sustained increment in endogenous plasma ANF concentration, which is probably caused by increased secretion from the atrium, may contribute, in part, to the blood-pressure-lowering effects of the HCa diet.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium; Calcium, Dietary; Drinking; Eating; Heart Atria; Hypertension; Natriuresis; Phosphorus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium

Atrial natriuretic factor (ANF) and angiotensin II (ANG II) have been demonstrated in close vicinity in forebrain areas involved in the central fluid and electrolyte regulation. Previous reports suggested an inhibitory effect of ANF on some of the central actions of ANG II, such as water intake and vasopressin release. In the present study in conscious, unrestrained, sodium-repleted rats we investigated the effects of intracerebroventricularly (i.c.v.) administered ANF (alpha r-APIII) on the central natriuretic action of ANG II. Urine was collected through a novel chronically implanted ureteral catheter. I.c.v. injections of ANG II (100 pg) produced a marked natriuresis of rapid onset without altering urinary volume or blood pressure. Pretreatment with ANF (100 pg, 1 ng, 100 ng i.c.v.) 5 min before ANG II dose-dependently antagonized the ANG II-induced natriuretic effect. The lowest dose caused approximately 50% reduction, the intermediate dose a complete abolition and the highest dose even a reversal of the ANG II-induced natriuretic effect to salt retention. Urinary volume and blood pressure were not altered by the combined treatment with ANG II and ANF. Our results support the idea of a functional antagonism between ANG II and ANF in the central fluid and electrolyte control.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Injections, Intraventricular; Male; Natriuresis; Rats; Rats, Inbred Strains

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and aldosterone were consecutively measured during methimazole treatment in patients with hyperthyroidism due to Graves' disease. ANP values of untreated hyperthyroid patients varied greatly from patient to patient, but decreased progressively with a decrease of serum thyroid hormone concentration during methimazole treatment. PRA was elevated in hyperthyroid patients but less aldosterone was secreted as evidenced by lower aldosterone/PRA ratio in these patients than in normal subjects and in hypertensive patients treated with thiazide. In addition, aldosterone/PRA ratio increased progressively with a decrease of ANP during methimazole treatment. The data indicated that ANP secretion was increased and ANP thus secreted depressed aldosterone secretion in hyperthyroid patients. Propranolol depressed pulse rate but failed to affect ANP secretion. It is suggested that thyroid hormone specifically acts on myocytes to stimulate ANP secretion but physiologic significance of such increased ANP secretion remains to be solved.

Topics: Adolescent; Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Graves Disease; Humans; Hyperthyroidism; Male; Methimazole; Middle Aged; Propranolol; Pulse; Renin; Thiazines; Thyroid Gland

Plasma levels of atrial natriuretic factor (ANP) were examined in 12 patients with liver cirrhosis (6 with ascites) and 6 controls before and after the administration of the infusion of 2000 ml of saline solution per 70 kg of body weight during 2 hours. Basal concentration of ANF tended to be slightly, but nonsignificantly higher in patients with ascitic liver cirrhosis (5.5 +/- 1.3 fmol/ml) than in controls (3.0 +/- 1.0 fmol/ml) and in patients with non-ascitic liver cirrhosis (4.6 +/- 1.3 fmol/ml). Saline administration led to the comparable increase of plasma ANF in ascitic (14.2 +/- 4.0 fmol/ml) and non-ascitic cirrhotics (15.7 +/- 3.7 fmol/ml) and in controls (12.4 +/- 4.3 fmol/ml). The increase of plasma ANF was accompanied by the suppression of plasma renin activity (PRA) and plasma aldosterone (PA) in all groups; in ascitic patients, however, PRA and PA remained above the normal range. While in controls and non-ascitic cirrhotics saline administration led to the increase of urine flow rate /from 0.74 +/- 0.13 to 2.04 +/- 0.44 ml/min, P less than 0.01, in controls; from 0.83 +/- 0.05 to 1.28 +/- 0.07 ml/min, P less than 0.01, in non-ascitic cirrhotics) and urinary sodium excretion (from 110.7 +/- 21.3 to 364.8 +/- 74.4 umol/min, P less than 0.01, in controls; from 125.0 +/- 16.7 to 218.7 +/- 24.3 umol/min, P less than 0.01 in non-ascitic cirrhotics), in patients with ascitic liver cirrhosis neither urine flow rate (from 0.66 +/- 0.1 to 0.72 +/- 0.15 ml/min, n.s.), nor urinary sodium excretion (from 16.7 +/- 9.9 to 54.2 +/- 40.3 umol/min, n.s.) changed significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Volume; Body Weight; Humans; Liver Cirrhosis; Renin

There are differences in the renal handling of sodium between spontaneously hypertensive rats (SHR) and their normotensive controls. We investigated whether this difference may be associated with changes in plasma and tissue atrial natriuretic factor (ANF) levels and with alterations in glomerular ANF receptors at 4, 8, 12, and 16 weeks of age. Age-matched Wistar-Kyoto (WKY) and Wistar rats were used as normotensive controls. Systolic blood pressure was higher in SHR at 8, 12, and 16 weeks, and cardiac hypertrophy was also present in these animals at 4 weeks. Plasma ANF C- and N-terminal concentrations were greater than in both normotensive groups at 8 and 16 weeks. ANF in the right atrium was higher in SHR than in WKY rats and identical to that in the Wistar group at 4 and 8 weeks. ANF in the left atrium was lower in SHR than in both control groups at week 12. No differences were found in ventricular ANF content. The density of glomerular ANF binding sites increased with age in WKY and Wistar rats but not in SHR. At weeks 8, 12, and 16, both normotensive groups had a higher density of binding sites than SHR, but binding site affinity was greater in SHR at weeks 8 and 12. After incubation with increasing concentrations of ANF, the production of cyclic guanosine monophosphate (cGMP) by isolated glomeruli from 16-week-old rats was lower in SHR than in both normotensive groups. We conclude that the development of hypertension in SHR is associated with higher plasma ANF levels and decreased glomerular ANF receptor density and glomerular cGMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Heart Atria; Hematocrit; Kidney Glomerulus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Time Factors

We studied the effects of chronic treatment with a novel angiotensin converting enzyme inhibitor, alpha-[(2S,6R)-6-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2- (2-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid.HCl (CS622), and a vasodilator, hydralazine, on plasma atrial natriuretic factor (ANF) levels and kidney ANF receptors in spontaneously hypertensive rats (SHR). Plasma ANF level was decreased and cardiac hypertrophy reduced in CS622 treated SHR, but not in hydralazine treated SHR, although blood pressure was lowered similarly in both SHR groups. The binding capacity of kidney ANF receptors increased and the affinity decreased in CS622 treated SHR compared to untreated SHR. These results suggest that decrease of plasma ANF results from decreased cardiac load but not from lowered blood pressure, and that changes in ANF receptors result from increased plasma ANF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart; Hydralazine; Kidney; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Thiazepines

Atrial natriuretic peptide (ANP) is released from the cardiac atria in response to acute volume loads; when infused acutely ANP causes diuresis and natriuresis. Cyclic GMP (cGMP) appears to be the second messenger for ANP in the kidney. The role that ANP plays in the long-term regulation of salt and water balance is unclear, however, since resistance to ANP's natriuretic and diuretic activity develops during prolonged administration. The purpose of the present study is to examine the relationship between the rate of cGMP excretion in response to ANP and the development of resistance to ANP's diuretic and natriuretic activity. Following a 30-min baseline period of infusion of Ringer's solution conscious rats received ANP at 15 micrograms/kg/hr (n = 6) or Ringer's alone (n = 5) for 240 min. ANP-infused rats had a significant diuresis and natriuresis during the first hour of infusion; urinary cGMP excretion also increased compared to baseline. By 120 min after initiating the infusion in ANP-rats urinary volume and sodium excretion had declined to values not significantly different from those of baseline or control. In contrast, urinary cGMP excretion remained elevated for the duration of the ANP infusion, whether compared to baseline values or the control group. Resistance to the diuretic and natriuretic activity of ANP is not a result of mechanisms that involve cGMP generation.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Female; Glomerular Filtration Rate; Heart Rate; Hematocrit; Infusions, Intravenous; Rats; Rats, Inbred Strains; Renal Circulation; Sodium; Urination

The immature kidney appears to be less responsive to atrial natriuretic peptide (ANP) than the mature kidney. It has been proposed that this difference accounts for the limited ability of the young animal to excrete a sodium load. To delineate the effects of age on the renal response to exogenous ANP, Sprague-Dawley rats were anesthetized for study at 31-32 days of age, 35-41 days of age, and adulthood. Synthetic rat ANP was infused intravenously for 20 min at increasing doses ranging from 0.1 to 0.8 microgram/kg/min, and mean arterial pressure, glomerular filtration rate, plasma ANP concentration, urine flow rate, and urine sodium excretion were measured at each dose. Since cyclic GMP acts as a second messenger for ANP action, urinary cyclic GMP excretion also was measured. Increasing doses of ANP caused a similar decrease in MAP at all ages studied, and increased glomerular filtration rate in adult but not young rats. Increasing the dose of ANP from 0.1 to 0.4 microgram/kg/min caused a greater rise in urine flow and urinary cyclic GMP excretion in adult than young rats, and urine sodium excretion increased more in adults at all doses (p less than 0.05). However, the rise in plasma ANP concentration also was greater in adults than in young rats (p less than 0.05), indicative of greater systemic clearance of ANP in young animals. Increasing levels of plasma ANP concentration were correlated with a greater rise in urine flow in adult than young (31-32 day old) rats (p less than 0.05), but there was no differential effect on urinary cyclic GMP excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic GMP; Glomerular Filtration Rate; Hematocrit; Infusions, Intra-Arterial; Kidney; Natriuresis; Organ Size; Rats; Rats, Inbred Strains; Reference Values

To evaluate the role of extra-atrial atrial natriuretic peptide (ANP) in volume and blood pressure regulation, the plasma, atrial, ventricular, and hypothalamic levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured simultaneously in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at the ages of 2, 6, and 12 months. Plasma IR-ANP in the 12-month-old, conscious SHR was significantly higher than that of the WKY (300 +/- 18 versus 200 +/- 20 pg/ml, p less than 0.05, n = 9), while no differences in plasma IR-ANP levels were found between the strains in younger rats. Acute volume expansion with saline (1.1 ml/100 g body wt) in hypertensive as well as in normotensive rats resulted in marked increases in right atrial pressure and plasma IR-ANP concentration. The older SHR had attenuated ANP release to volume loading as shown by the shift of the ANP versus right atrial pressure curve to the right. Right auricular IR-ANP concentration decreased, while that of left auricle increased with increasing age in both strains. No substantial differences were noted in auricular ANP concentration between SHR and WKY. However, the total atrial IR-ANP content (micrograms/atria) was consistently lower in SHR compared with WKY. In both ventricles, IR-ANP concentrations and contents increased with increasing age in WKY and SHR, but the ventricular levels of ANP were reduced in ventricles of the SHR heart compared with normotensive controls. The depletion of total ventricular IR-ANP was greatest in SHR with greatest ventricular hypertrophy and coincided with the attenuated ANP release to acute volume load. The increase of left but not right ventricular weight occurring secondary to 6 weeks minoxidil treatment was accompanied by higher ANP concentration in both strains. In contrast to the ventricles, the hypothalamic IR-ANP concentration was significantly increased in SHR compared with that of WKY and decreased in both strains after 6 weeks' treatment with antihypertensive drugs. Thus, ventricular and hypothalamic, as well as atrial, ANP respond to increased pressure overload in genetically hypertensive rats. Our results suggest that chronic stimulation of ANP release from ventricles is associated with depleted stores of ANP from both ventricles and reduced response to acute volume load. Our findings that ventricular ANP increased with increasing weight and in response to a hypertrophic stimulus in WKY and was decreased in SHR with severe v

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Heart Rate; Hypertension; Hypothalamus; Kidney; Male; Methyldopa; Minoxidil; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Eleven patients with acute congestive heart failure were studied during treatment with a loop diuretic. Plasma concentrations of atrial natriuretic peptide were considerably increased before treatment and with successful treatment returned progressively towards normal values. There was a statistically significant correlation between plasma atrial natriuretic peptide concentration and both jugular venous pressure and change of body weight. These results support the hypothesis that atrial distension is an important stimulus to atrial natriuretic peptide release. Furthermore, the close relation between plasma concentrations of atrial natriuretic peptide and clinical improvement in these patients suggests that measurement of plasma atrial natriuretic peptide concentration could provide a clinically useful and non-invasive method of monitoring the response to treatment.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Body Weight; Female; Furosemide; Heart Failure; Humans; Longitudinal Studies; Male; Middle Aged; Venous Pressure

To explain how converting enzyme inhibition could improve the prognosis in cardiac insufficiency, the effect of converting enzyme inhibition (CEI) by S9490-3 (Perindopril) treatment for 2 months (treated infarctions, n = 18) on hormonal plasma variables and the quantitative and qualitative changes in myocardium were studied in an experimental model of left ventricular infarction in rats (untreated infarctions, n = 18) and compared to a sham-operated control group (n = 15). Induction of myocardial infarction was associated with a transient decrease in blood pressure. CEI treatment maintained a lower blood pressure throughout the experimental period. Plasma renin concentration was not significantly increased in the untreated infarct group (155.4 +/- 136.7 ng AI/ml/hr) as compared to the sham-operated group (47.6 +/- 15.9 ng AI/ml/hr). Plasma aldosterone did not change in the three experimental groups. The plasma level of immunoreactive atrial natriuretic factor increased in the untreated infarct group (185 +/- 245 pg/ml) as compared with the control group (76 +/- 40 pg/ml) and was normalized by CEI (66 +/- 60 pg/ml). Body weight was slightly decreased in both treated and untreated infarct groups, whereas the heart weight was significantly increased in the untreated group (1,540 +/- 310 mg) and normalized by treatment (1,145 +/- 180 mg) as compared with sham-operated controls (1,071 +/- 80 mg). The combined atria and right ventricular mass was significantly increased in the untreated infarct group (660 +/- 210 mg) and decreased by treatment (443 +/- 106 mg) but was not completely normalized (controls, 343 +/- 40 mg). Left ventricular isomyosin profiles were modified by myocardial infarction as compared with controls: V1 form decreased from 62.4 +/- 9.4% in the sham-operated group to 41.6 +/- 13.4% in the infarct group, and the V3 form increased from 13.0 +/- 4.7% in sham-operated animals to 27.4 +/- 11.8% in untreated infarct animals. CEI treatment partially, but significantly, reversed this modification of the isomyosin profile (V1, 53.0 +/- 14.4%; V3, 17.5 +/- 8.0%). Volume density of collagen was significantly increased in the untreated infarct rats (4.14 +/- 0.81% versus 2.68 +/- 0.49% in controls), and this was reversed by treatment (2.95 +/- 0.66%). Messenger RNA encoding for atrial natriuretic factor, measured by dot blot hybridization, was significantly increased in both the atria and the ventricles in the untreated infarct group, and treatment by CE

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Collagen; Heart; Hormones; Isoenzymes; Male; Myocardial Infarction; Myocardium; Myosins; Rats; Rats, Inbred Strains; RNA, Messenger

Atrial natriuretic peptide (ANP) is a recently discovered cardiac hormone involved in blood-volume homeostasis. Known stimulating factors for ANP release are rise in atrial pressures or atrial distension, suggesting that blood volume regulates ANP release. This study was undertaken to test the hypothesis that plasma levels of ANP are high and increase during normal pregnancy secondary to the expanding plasma volume. In a cross-sectional study plasma concentrations of ANP were measured in 99 normal pregnant women at different gestational ages and compared with the values found in an age-matched non-pregnant control group. Mean plasma ANP was already significantly increased in the first trimester as opposed to the non-pregnant women, but despite a continuously expanded plasma volume there was no further increase during pregnancy. Our findings suggest that other factors must interact with plasma volume in regulating plasma ANP during pregnancy.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Heart Rate; Humans; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third

Glucocorticoid-induced hypertension in rats has been studied using long-term, low-dose dexamethasone treatment. Dose-related increases in systolic blood pressure were achieved, without loss in body weight, with subcutaneous continuous infusions of 1, 2 and 5 micrograms dexamethasone per day, respectively, for 4 weeks. Rats treated with 10 micrograms dexamethasone per day lost weight at a rate of 10 g per week. Lower doses caused a significant reduction in weight gain compared with controls. Renin, aldosterone, plasma sodium and potassium concentrations were unaffected by dexamethasone treatment. Plasma atrial natriuretic peptide (ANP) concentrations were decreased by 40-50% by dexamethasone. These decreases were negatively correlated with increases in systolic blood pressure and haematocrit. Glucocorticoid-induced decreases in ANP contrast with ANP increases in response to mineralocorticoid treatment in rats with deoxycorticosterone-induced hypertension. Plasma concentrations of the endogenous glucocorticoid, corticosterone, were suppressed to the same very low levels by 5 and 10 micrograms dexamethasone per day; 1 and 2 micrograms doses were less effective. Unlike mineralocorticoid-induced hypertension, the pressor effects of dexamethasone were ameliorated but not abolished by dietary sodium restriction and were unaffected by sodium loading. Two micrograms of dexamethasone reduced plasma ANP in rats on either high- or low-sodium diets by 29 and 34%, respectively. We conclude that low-dose infusions (less than 5 micrograms/day) of dexamethasone are suitable for studying glucocorticoid-induced hypertension without the complications of weight loss that have been reported by others or of the mineralocorticoid-like side effects which endogenous glucocorticoids may exhibit.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Corticosterone; Dexamethasone; Hypertension; Male; Potassium; Rats; Rats, Inbred Strains; Sodium; Sodium, Dietary

Blood was withdrawn from rats injected 1, 3, 6 and 12 weeks previously with the diabetogenic agent streptozotocin (55 mg/kg, I.V.) or saline. Analysis of plasma showed that while the streptozotocin-treated animals displayed significantly (p less than 0.05) diminished triiodothyronine levels and significantly (p less than 0.05) elevated osmolalities at all time points after injection, immunoreactive-ANF levels were unchanged. Thus, there would appear to be no direct relationship between plasma atrial natriuretic factor levels and plasma triiodothyronine levels or plasma osmolalities in the diabetic rat.

Topics: Animals; Atrial Natriuretic Factor; Blood; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Male; Osmolar Concentration; Potassium; Rats; Rats, Inbred Strains; Sodium; Triiodothyronine

The effect of short- and long-term sodium loading and sodium restriction on the gene expression as well as on circulating plasma levels of atrial natriuretic factor (ANF) was evaluated in normotensive Wistar rats. These rats were fed either a low-, a regular-, or a high-sodium diet (regular diet and 1% saline as drinking fluid) and studied after 1 and 3 wk. The ANF mRNA was determined in pooled atria and ventricles of the different groups of rats, using the dot-blot technique. Plasma ANF levels were measured with a radioimmunoassay. After 1 wk on the high-sodium diet, ANF mRNA was increased in right atria and ventricles together with circulating ANF levels when compared with animals maintained for the same period on a low-sodium diet. After 3 wk on the various diets, the differences in cardiac ANF mRNA and in plasma ANF levels had disappeared. Gene expression of ANF was also looked for in different areas of the brain, lung, thyroid, adrenals, and the kidney; no hybridization was detected in any of these organs. These data suggest that in rats, the transcription of the ANF gene and peptide release in enhanced only during short-term adaptation to dietary sodium loading.

Topics: Animals; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart; Male; Myocardium; Organ Size; Organ Specificity; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Sodium, Dietary; Transcription, Genetic; Ventricular Function

The present study was designed to examine the possible effect of long-term treatment with diltiazem on plasma and atrial concentrations of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR). Diltiazem treatment reduced blood pressure and ventricular weight in SHR. Plasma ANP concentration in untreated SHR was higher than Wistar-Kyoto rats (WKY). Diltiazem treatment decreased plasma ANP concentration in SHR near to the level of WKY; moreover, plasma ANP concentration was correlated with blood pressure and ventricular weight in treated and untreated SHR. Left atrial ANP concentration in untreated SHR was lower than WKY. Diltiazem treatment increased left atrial ANP concentration in SHR, but this effect was not noted in WKY. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that the prevention of an increase in plasma ANP by diltiazem treatment may be, in part, attributed to the improvement of cardiac overload induced by reductions in blood pressure and cardiac hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diltiazem; Heart Atria; Heart Ventricles; Hypertension; Male; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Experiments were carried out in normotensive, saline-drinking, 60% reduced renal mass rats to determine the effect of an in vivo blockade of endogenous atrial natriuretic factor (ANF) on blood pressure. We used a 60% reduction in renal mass because blood pressure in these normotensive animals is extremely sensitive to any slight further reduction of renal excretory function. Six weeks following the reduction of renal mass and documentation of normotension, rats were injected intraperitoneally twice daily for 12 days with ANF antibody prepared against the C-terminal heptapeptide of AP III conjugated to bovine thyroglobulin. Control rats similarly prepared, received normal rabbit serum (NRS). Blood pressure progressively increased in rats receiving the antibody, and its withdrawal returned blood pressure to control levels within 4-5 days. Serum from either normal rabbits or rabbits immunized with bovine thyroglobulin or peptides unrelated to ANF had no effect on blood pressure in the control animals. These experiments show that in the normotensive saline-drinking rat with reduced renal mass, an antibody to AP III raises blood pressure. This suggests that ANF here is acting to prevent the rise in blood pressure.

Topics: Animals; Antibodies; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Hypertension; Kidney; Male; Rabbits; Rats; Rats, Inbred Strains; Sodium, Dietary

1. Diabetes was induced in 32 adult Wistar-Kyoto rats with streptozotocin (60 mg/kg). Fourteen rats remained untreated, 10 received insulin three times per week, and eight received insulin daily. Fourteen non-diabetic rats served as controls. 2. Exchangeable sodium and plasma volume were elevated in the untreated diabetic rats. Treatment normalized these parameters. 3. Glomerular filtration rate (GFR) was elevated in the untreated diabetic group and the group receiving insulin three times per week compared with the control group. Daily insulin treatment restored GFR towards control values. 4. Plasma atrial natriuretic factor was similar in untreated diabetic rats and non-diabetic rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Volume; Body Weight; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Insulin; Rats; Rats, Inbred WKY; Sodium

Plasma alpha-atrial natriuretic peptide (alpha-ANP) concentration and levels of cyclic nucleotides [guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP)] were studied in 23 runners before and after a marathon race. Blood samples were drawn from an antecubital vein the morning before the race (base line), at 3 P.M. (i.e., 2 h before the start), on arrival, and 12 and 36 h and 7 days later. Compared with the base-line values of plasma alpha-ANP (5 pmol/l), cGMP (3.8 nmol/l), and cAMP (15.8 nmol/l), the plasma levels of alpha-ANP, cGMP, and cAMP were increased immediately after the marathon, respectively, to 12.0 pmol/l, 12.7 nmol/l, and 50.5 nmol/l. The increase in the plasma alpha-ANP concentration was related (r = 0.85; P less than 0.001) to the changes in plasma cGMP, plasma lactate, hematocrit, and body weight. The plasma cGMP and cAMP concentrations had returned to the prerace levels 12 h after the marathon, whereas the plasma alpha-ANP concentration was significantly lower (3.1 pmol/l) than the base-line values and increased above the prerace values 36 h (7.5 pmol/l) and 7 days (6.8 pmol/l) after the marathon. The plasma cGMP level was also higher 36 h (5.4 nmol/l) and 7 days (5.0 nmol/l) after the marathon race.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cyclic AMP; Cyclic GMP; Erythrocyte Count; Heart Rate; Hematocrit; Hemoglobins; Humans; Lactates; Male; Physical Exertion; Running

The effect of changes of dietary sodium chloride intake and posture on plasma atrial natriuretic peptide concentration and renal function was studied in 11 normal human volunteers. Plasma atrial natriuretic peptide concentration was higher in the upright posture on a high than it was on a medium or low salt diet. On the medium and high but not on the low salt diet the concentration increased significantly on adoption of the supine posture. Creatinine, sodium, lithium and fractional lithium clearances, fractional distal sodium excretion and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, were significantly higher on the high than on the low salt diet. The medium salt intake gave intermediate values. Heart rate while upright was significantly higher on the low than on either the medium or the high salt diets. Systolic blood pressure was unaffected by salt intake. Diastolic blood pressure in the supine position was significantly higher on the low than on the medium or high salt diets. Both plasma noradrenaline concentrations and plasma renin activity were significantly higher on the low than on the high salt diet. Values on the medium salt intake were intermediate. Plasma concentrations of both hormones were higher in the upright than in the supine posture on all three salt intakes. The data are consistent with the hypothesis that atrial natriuretic peptide contributes to the cardiovascular and renal adjustments to changes in dietary sodium chloride, and the possible role of the peptide is discussed.

Topics: Adult; Atrial Natriuretic Factor; Body Weight; Creatinine; Diet, Sodium-Restricted; Female; Hematocrit; Hemodynamics; Humans; Kidney; Male; Norepinephrine; Posture; Renin; Sodium Chloride

The relationship between plasma atrial natriuretic peptide (ANP) and mineralocorticoid escape was examined in six normal men (age, 20-32 yr) treated with 0.4 mg/day fludrocortisone acetate for 9-14 days. Urinary sodium excretion decreased from 162 +/- 15 (SEM) meq/24 h before to 97 +/- 10 meq/24 h during fludrocortisone acetate administration (P less than 0.05). Despite continued fludrocortisone acetate administration, sodium excretion subsequently returned to baseline (escape). Plasma ANP increased from 33 +/- 6 pg/ml (control) to 55 +/- 14 pg/ml on the first day of escape (P less than 0.05). Escape was associated with a decrease in PRA from 0.90 +/- 0.22 (control) to 0.26 +/- 0.08 ng/ml X h (escape, P less than 0.05). The escape phenomenon was not associated with a significant change in mean arterial pressure or glomerular filtration rate. This study demonstrates that mineralocorticoid escape is temporally related to a significant increase in circulating ANP.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Drug Tolerance; Fludrocortisone; Glomerular Filtration Rate; Humans; Male; Natriuresis; Renin

In order to investigate the pathophysiological role of atrial natriuretic polypeptide (ANP) in genetic hypertensive rats, the atrial content and plasma concentration of ANP were measured by a sensitive radioimmunoassay (RIA) for rat ANP in 5-, 10- and 20-week-old spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared to age-matched Wistar Kyoto rats (WKY). Atrial content of immunoreactive ANP (ir-ANP) tended to be higher in SHR and was already significantly higher in SHRSP than in WKY at 5 weeks of age. Atrial content in the hypertensive strains became significantly higher than in WKY when hypertension developed at 10 and 20 weeks. On the other hand, plasma ir-ANP in SHR was significantly lower than in WKY at 5 weeks, however, it became significantly higher in both SHR and SHRSP than in WKY at 10 and 20 weeks. These findings suggest that ANP release may increase to compensate for the elevation of blood pressure in SHR and SHRSP and that biosynthesis of ANP may be concomitantly stimulated, resulting in an increase in atrial ANP.

Topics: Aging; Animals; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Heart; Heart Atria; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

A highly sensitive radioimmunoassay for alpha-human atrial natriuretic peptide (alpha-hANP) was established and applied to measure the human plasma alpha-hANP levels. In our assay system, anti-alpha-hANP antiserum was raised in albino rabbits by intradermally injecting synthetic alpha-hANP which was conjugated with bovine serum albumin. The final antiserum dilution was 1:50,000. Sensitivity was 2 pg/tube and the 50% intercept was at 28 pg/tube. The plasma alpha-hANP was extracted using a Sep-Pak C-18 cartridge. According to this procedure, the mean recovery was 73.8 +/- 3.4% (mean +/- SE). The averaged plasma levels of immunoreactive alpha-hANP (i alpha-hANP) in normal subjects were 24.8 +/- 2.1 pg/tube. In patients with chronic renal failure undergoing hemodialysis, the averaged plasma i alpha-hANP levels were 56.4 +/- 5.0 pg/ml before hemodialysis. Plasma i alpha-hANP levels were significantly higher in the patients with chronic renal failure than in the normal subjects. After hemodialysis, plasma i alpha-hANP levels decreased significantly (32.2 +/- 2.8 pg/ml). These results suggest that the alteration in extracellular fluid volume (ECFV) may affect the plasma levels of i alpha-hANP in patients with chronic renal failure under hemodialysis; i.e., an increase in ECFV elevates and a decrease in ECFV lowers the circulating levels of alpha-hANP.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Humans; Middle Aged; Rabbits; Radioimmunoassay; Renal Dialysis; Uremia

We investigated the effects of captopril on the plasma atrial natriuretic polypeptide (ANP) level and the renin angiotensin system in rats. A single oral administration of captopril decreased the plasma ANP level and increased the plasma renin activity (PRA). Chronic administration of captopril for 2 weeks caused no changes in plasma ANP level, but PRA was increased. This suggests the hypothesis that the hemodynamic changes rather than changes in the renin angiotensin system caused by captopril may affect the plasma ANP level.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Captopril; Kidney; Male; Myocardium; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System

The mammalian atrial hormone atrial natriuretic factor (ANF) has been shown to have potent natriuretic and diuretic actions as well as vasodilator effects when released into the circulation. To investigate how the levels of the circulating form of this peptide change with alteration of intravascular fluid volume, we measured immunoreactive ANF in the plasma of Wistar rats after acute saline load, acute furosemide treatment, and chronic water restriction. Circulating levels of immunoreactive ANF increased significantly (p less than 0.001) 1 minute after acute saline load and returned to normal levels within 5 minutes. Volume contraction induced by furosemide treatment of chronic water restriction significantly reduced the circulating immunoreactive ANF. These data indicate that acute volume expansion causes an immediate release of immunoreactive ANF into the general circulation and acute volume contraction results in a decline of circulating levels of immunoreactive ANF, which is maintained during chronic volume contraction. These results suggest that the atria detect alterations in intravascular fluid volume and respond by changing the levels of ANF acutely as well as chronically and thereby participate in the regulation of body fluids and, perhaps, of blood pressure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Fluids; Body Water; Body Weight; Furosemide; Hematocrit; Male; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Water

To study the effects of volume overload and renal failure on plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH), we measured levels of this hormone in normal subjects, in patients with advanced chronic renal failure (CRF) with and without clinically evident volume overload, and in patients with end-stage renal disease (ESRD) treated with chronic hemodialysis. The levels were 13 +/- 2 pmol/l in normal volunteers, 77 +/- 24 pmol/l in patients with CRF without volume overload, and 219 +/- 50 pmol/l in patients with CRF and clinically evident volume overload (analysis of variance, p less than 0.001, alpha = 0.05 compared to normals). In patients with ESRD, the levels of IR-ANH were 145 +/- 46 pmol/l before dialysis and decreased to 87 +/- 31 after dialysis (p less than 0.025). No correlation was found between the decrease in IR-ANH levels and the decrease in weight during dialysis. A significant positive correlation was found between the IR-ANH levels and blood urea nitrogen in patients with CRF (r = 0.658, p less than 0.01). Volume overload appears to be the most important stimulatory factor for ANH secretion in renal failure patients but other mechanisms, especially a decrease in metabolic clearance, may also contribute to elevated plasma levels. The increased secretion of ANH in patients with renal failure may be an important adaptive response to volume overload and hypertension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Female; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Studies were performed on anesthetized adult Münich-Wistar rats to investigate the role of angiotensin II in the natriuretic response to synthetic atrial natriuretic peptide (ANP, 28 amino acids). For this purpose the whole kidney glomerular filtration rate (GFR) and urinary excretion of electrolytes were measured in groups of animals pretreated with the converting enzyme inhibitor captopril (3 mg h-1 kg-1 body wt) or vehicle and then given a continuous intravenous infusion of ANP at 10 micrograms h-1 kg-1 body wt. In the vehicle-pretreated animals, 45 min of ANP infusion did not change GFR (control value 1.17 +/- 0.11, experimental value 1.17 +/- 0.06 ml min-1 g-1 kidney wt). Sodium excretion (UNaV) increased more than three-fold from 0.036 +/- 0.010 to 0.134 +/- 0.058 mumol min-1 g-1 kidney wt (p less than 0.05) and potassium excretion (UKV) increased from 0.481 +/- 0.055 to 0.946 +/- 0.068 mumol min-1 g-1 kidney wt (P less than 0.05). Urine osmolality (UOsm) remained unchanged, while the blood pressure (BP) decreased by 15%. In animals pretreated with captopril, ANP infusion led to a decrease in GFR from 1.27 +/- 0.11 to 1.05 +/- 0.09 ml min-1 g-1 kidney wt (P less than 0.05). Despite this effect, UNaV increased more than two-fold from 0.076 +/- 0.020 to 0.193 +/- 0.087 mumol min-1 g-1 kidney wt (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Captopril; Glomerular Filtration Rate; Male; Natriuresis; Organ Size; Potassium; Rats; Rats, Inbred Strains; Sodium; Urodynamics

1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy. 2. Plasma ANF was higher, and atrial ANF content lower in rats with renal failure when compared with sham-operated controls. 3. Plasma renin activity (PRA) and ANF were elevated at 1 week following subtotal nephrectomy. After 1 month plasma ANF had risen further, but PRA was suppressed to below control values. 4. Plasma ANF was also measured in six patients with chronic renal failure undergoing routine haemodialysis. 5. Elevated plasma ANF levels in patients with renal failure were lowered by haemodialysis, although extraction of ANF across the dialysis membrane was negligible. 6. Secretion of ANF is increased in chronic renal failure in man and the rat, possibly mediated by increased intravascular volume.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Creatinine; Hematocrit; Humans; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Inbred Strains; Renal Dialysis; Renin; Renin-Angiotensin System

1. Plasma concentrations of human alpha-atrial natriuretic polypeptide (h-alpha ANP) during escape from the effects of mineralocorticoid excess were determined in six healthy volunteers. 2. Escape, as indicated by an abrupt increase in sodium excretion on the third to sixth day of 9 alpha-fludrocortisone acetate administration (0.6 mg/day), was observed in all subjects. 3. The mean plasma h-alpha ANP level was 30.9 +/- SEM 8.8 pmol/l on the control day; it increased exponentially in response to 9 alpha-fludrocortisone acetate administration, reached a significant level (114.0 +/- 22.4 pmol/l, P less than 0.05) on the day before escape and remained elevated during escape. 4. The 24 h creatinine clearance and blood pressure did not change significantly before the escape. Plasma h-alpha ANP increased markedly when the cumulative sodium balance exceeded 220 mmol. 5. These results suggest that h-alpha ANP may play a contributory role in natriuresis and diuresis after mineralocorticoid excess.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatinine; Fludrocortisone; Humans; Male; Osmolar Concentration; Radioimmunoassay; Renin; Sodium

To study the role of atrial natriuretic peptide (ANP) in chronic heart failure, ANP synthesis, storage, and release were examined by measuring atrial ANP messenger ribonucleic acid (mRNA) levels and atrial and plasma ANP concentrations in rats with myocardial infarction produced by coronary artery ligation. Three groups were defined as the following: 1) controls, sham-operated, or operated, but noninfarcted; 2) moderate infarcts, involving 5-30% of the left ventricular circumference; and 3) large infarcts (greater than or equal to 30%). In addition, to determine a possible modulation by dietary Na intake on ANP levels in heart failure, plasma immunoreactive ANP (iANP) levels were measured in rats with and without infarcts given low, regular, or high Na intake for 2 wk, by which time all groups were in neutral balance. Plasma iANP levels varied directly with increasing infarct and atrial sizes, irrespective of Na intake. In contrast, atrial ANP concentration varied inversely with increasing infarct size. The ANP mRNA content index, a measure of total atrial ANP mRNA, was significantly increased in rats with large infarcts compared with control rats. These results indicate that in rats with myocardial infarction, the severity of left ventricular dysfunction, as inferred from infarct size, but not chronic Na intake, is the primary determinant of the extent of activation of the ANP system. Elevated circulating ANP levels are maintained through enhanced atrial synthesis and release. ANP may thus play an important role in the hemodynamic and renal adaptations to chronic heart failure.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Female; Myocardial Infarction; Rats; Rats, Inbred Strains; RNA, Messenger; Sodium; Transcription, Genetic

We have recently shown that circulating atrial natriuretic polypeptide (ANP) in adult spontaneously hypertensive rats (SHR) is higher than that in age-matched Wistar-Kyoto rats (WKY). The present experiment was designed to examine the possible effects of chronic treatment with angiotensin I converting enzyme inhibitors (ACEI) on plasma ANP levels in SHR. Captopril and enalapril lowered blood pressure and reduced relative ventricular weight in SHR but not to the level of WKY. Plasma ANP levels were decreased by captopril and enalapril compared with untreated SHR. These results suggest that the ANP release may be suppressed in ACEI-treated SHR compared with untreated SHR. We speculate that a reduction of cardiac overload by ACEI may in part explain the decline of circulating ANP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Captopril; Enalapril; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY

To investigate the involvement of thyroid hormone on the release of atrial natriuretic polypeptide (ANP), we have measured immunoreactive ANP in the atria and plasma of experimental hyperthyroid and hypothyroid rats. Plasma ANP was higher (p less than 0.05) in hyperthyroid rats and was lower (p less than 0.05) in hypothyroid rats than in euthyroid rats. ANP content and concentration in the atria were lower (p less than 0.01) in hyperthyroid rats than in hypothyroid rats. An inverse correlation was found between the plasma ANP and ANP concentration in the atria (n = 15, r = 0.60, p less than 0.01). The results indicate an increased systemic release of ANP from the atria in hyperthyroidism and a decreased systemic release in hypothyroidism.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Heart Atria; Hemodynamics; Hyperthyroidism; Hypothyroidism; Male; Radioimmunoassay; Rats; Rats, Inbred Strains

Protocols were designed to 1) identify atrial natriuretic factor (ANF) bioactivity in pregnant rats, 2) compare ANF activity in atria from gravid and virgin Sprague-Dawley animals, and 3) assess renal and vascular responsiveness to ANF during gestation. Similar quantities of ANF were extracted from atria of term gravid and age-matched controls (assayed as the natriuretic response in awake virgins). We then purified by high-performance liquid chromatography a peptide identical to the synthetic 23 amino acid atriopeptin II (AP II). With equimolar injections of ANF, gravid rats had a blunted natriuretic response (P less than 0.05). However, when dose was based on estimated extracellular volume, awake virgin and pregnant animals displayed similar highly significant dose-response curves to infused AP II (R's 0.8). When hydropenic rats were assayed, both gravid and virgins required 10 times more ANF to initiate a diuresis; dose-response curves again being similar and highly significant. Decrements in blood pressure were also similar in pregnant and nongravid animals. Thus, despite an increased intravascular volume of 70% during gestation, cardiac content of ANF and the renal and vascular responsiveness to this peptide are similar to those in virgin rats, suggesting resetting of ANF-volume relationships during pregnancy.

Topics: Animals; Atrial Function; Atrial Natriuretic Factor; Biological Assay; Blood Pressure; Body Weight; Extracellular Space; Female; Kidney; Natriuresis; Pregnancy; Pregnancy, Animal; Rats

We measured the immunoreactive atrial natriuretic factor concentrations in plasma and right and left atria of salt-sensitive, salt-resistant Dahl rats and Wistar Kyoto rats, all fed for 5 weeks by 8% salt diet. We found an increase in plasma immunoreactive atrial natriuretic factor (p less than 0.001) in salt-sensitive Dahl rats which became severely hypertensive in comparison with salt-resistant and Wistar Kyoto rats which remained normotensive on the same diet. There were however, no differences in the immunoreactive atrial natriuretic factor concentrations in the atria between the three groups of rats; all rats tended to have lower concentrations in the left than in the right atrium. The data show the presence of increased circulating atrial natriuretic factor immunoreactivity in hypertensive salt-sensitive Dahl rats which may be due either to the hypertension-induced left atrial distention, to volume expansion or indirectly renal hyposensitivity to the atrial natriuretic factor in these rats.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Heart Atria; Hypertension; Male; Natriuresis; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Sodium

Plasma immunoreactive human atrial natriuretic peptide (Ir-ANP) levels were measured in eight patients with chronic renal failure who were volume-expanded and during treatment by sequential ultrafiltration and haemodialysis. One patient was studied at two separate treatment sessions. Plasma Ir-ANP levels were raised in all patients (mean +/- SE 184 +/- 44 pmol/l, n = 9) compared with healthy controls (11 +/- 1.4 pmol/l), but showed considerable inter-patient variability. Plasma Ir-ANP levels fell with fluid removal during ultrafiltration (123 +/- 30 pmol/l, n = 9, P less than 0.02) and again as fluid was removed during haemodialysis (76 +/- 20 pmol/l, n = 9, P less than 0.02). Seven patients studied 48 h later, before their next dialysis treatment, had regained weight and showed a coincident rise in circulating plasma Ir-ANP (130 +/- 33 pmol/l, n = 7). Our data would support the hypothesis that the secretion of ANP is determined by volume or by a stimulus related to volume. However, it does not exclude the possibility that a factor other than extracellular fluid volume expansion contributes to the raised plasma Ir-ANP levels in chronic renal failure.

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Blood; Blood Pressure; Blood Urea Nitrogen; Body Weight; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osmolar Concentration; Potassium; Radioimmunoassay; Renal Dialysis; Sodium; Ultrafiltration

Immunoreactive atrial natriuretic factor (IR-ANF) was measured in plasma and atrial extracts from normal and cardiomyopathic Syrian golden hamsters. Plasma IR-ANF was increased from 84.8 +/- 9.8 pg/ml (n = 17) to 234 +/- 23 (n = 25; P less than .0001) in hamsters with moderate failure, and to 1085 +/- 321 pg/ml (n = 10; P less than .02) in animals with severe failure. Plasma IR-ANF increased with increased atrial hypertrophy. Atrial IR-ANF content was essentially the same in normal animals and in those with moderate heart failure (3.06 +/- 0.28 vs. 3.17 +/- 0.19 microgram/100 g body wt.) and lower in the majority of those with severe failure (1.82 micrograms/100 g body wt., P less than .001). The elevations of IR-ANF in plasma are similar to those seen in patients with congestive heart failure. Our studies do not support bioassay results showing a deficiency of atrial ANF content as being important in the congestive heart failure associated with cardiomyopathy in the hamster.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomyopathies; Cricetinae; Heart Atria; Heart Failure; Male; Mesocricetus; Organ Size; Radioimmunoassay

The mechanisms involved in the diuretic action of the recently discovered group of atrial natriuretic peptides (ANP) are not entirely clear. To determine whether the diuresis and the changes in blood pressure produced by alpha-human ANP (alpha-hANP) involved a concomitant modification of circulating arginine-vasopressin (arg-VP), we evaluated the effects of synthetic alpha-hANP on plasma alpha-hANP, arg-VP, electrolytes, protein, haematocrit, blood pressure and urinary sodium and water excretion in 10 normal subjects on daily sodium intakes of 16, 140 and 310 mmol, respectively. Plasma alpha-hANP levels before and during a 45-min alpha-hANP infusion (0.09 micrograms/kg per min) tended to be slightly, though not significantly, higher on 'normal' or high sodium intake than on low sodium intake. Alpha-human ANP produced a fall in diastolic blood pressure (P less than 0.001) and to a lesser extent mean blood pressure, and a rise in heart rate (P less than 0.001) at all levels of sodium intake. The induction of diuresis, natriuresis and plasma volume contraction caused by alpha-hANP was greater on a high sodium intake than on 'normal' or low sodium intakes (P less than 0.001). Plasma arg-VP concentrations were lower (P less than 0.05) on a high than on a low sodium intake, but were not altered by an alpha-hANP infusion. The data indicate that in healthy humans circulating arg-VP may tend to decrease in response to a high salt diet. However, marked changes in plasma alpha-hANP concentrations have, regardless of sodium intake, no relevant influence on circulating arg-VP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Creatinine; Heart Rate; Humans; Male; Potassium; Sodium; Water-Electrolyte Balance

A natriuretic factor has long been postulated to play a role in renal mineralocorticoid escape. We therefore investigated changes in plasma levels of atrial natriuretic peptide (ANP) during chronic treatment with 9 alpha-fluorohydrocortisone. Five normal subjects were studied on a constant diet (300 meq Na+ and 72 meq K+ per day) and received 0.8 mg 9 alpha-fluorohydrocortisone for up to 14 days. Sodium balance became positive and body weight increased between 1.0-4.5 kg maximally. Serum aldosterone was suppressed and plasma levels of ANP were stimulated up to 10-fold. Increment in plasma ANP was positively correlated with the gain in body weight (r = 0.666, p less than 0.001). Renormalization of sodium balance was seen in two subjects, however the maximum in plasma ANP did not occur during the time of renal escape. ANP-secretion is stimulated during sodium retention induced by mineralocorticoids, however ANP does not seem to trigger the escape mechanism.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Body Weight; Female; Fludrocortisone; Humans; Kidney; Male; Mineralocorticoids; Potassium; Sodium

There are no reliable parameters for the detection of fluid overload in anuric patients. In 70 patients on regular haemodialysis (HD) or haemofiltration (HF) treatment, plasma ANP IR concentrations were determined by radioimmunoassay and compared to 43 controls with normal renal function. ANP IR levels were markedly elevated immediately before HD or HF (m 82 fmol/ml) compared to ANP IR plasma concentrations after HD or HF (m 42 fmol/ml) and to ANP IR levels of healthy controls (m 19 fmol/ml). ANP IR was detected in haemofiltrates and found to be eliminated by HF. During isovolemic HF, ANP IR levels remained constant suggesting that ANP synthesis is much higher than elimination by HF and that the decrease in circulating volume at the end of HF or HD is the main stimulus for a lower secretion rate of ANP. Elevated ANP IR levels at the end of HD/HF were found to be associated with fluid overload even without clinical or radiographic symptoms. Consistent weight reduction was followed by a decrease of ANP IR levels.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Body Weight; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay; Renal Dialysis; Ultrafiltration; Water-Electrolyte Imbalance

The effect of volume changes on the plasma concentration of atrial natriuretic peptide (ANP) in children with chronic renal failure was investigated by the use of a specific and sensitive radioimmunoassay. Predialysis plasma ANP was significantly higher in children with end-stage renal disease than in healthy children and children with advanced renal failure without evidence of volume expansion. During haemodialysis plasma ANP decreased significantly and plasma renin activity rose slightly, whereas plasma arginine vasopressin and aldosterone did not change. Plasma ANP correlated positively with volume status (body weight gain during the interval between two haemodialysis sessions). An expanded extracellular fluid volume thus seems to be a major stimulus for the rise in ANP in children with end-stage renal disease. The findings suggest that ANP may be important in volume homoeostasis.

Topics: Adolescent; Atrial Natriuretic Factor; Body Weight; Child; Diuresis; Female; Humans; Kidney Failure, Chronic; Male; Muscle Proteins; Osmolar Concentration; Plasma Volume; Renal Dialysis

The cardiac content and plasma concentration of atrial natriuretic polypeptide (ANP) in hypertensive rats were measured by using radioimmunoassay for ANP. The animals used in this study were young (5-week-old) and adult (12- to 14-week-old) spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP) and normotensive control Wistar-Kyoto rats (WKY). Most immunoreactive ANP in the cardiac extract of the hypertensive rats (both SHR and SHR-SP) was found to be predominantly gamma-form as well as that of WKY. Cardiac ANP content in adult SHR and SHR-SP was significantly lower than in adult WKY (p less than 0.01), although there were no differences among three groups in young rats. Similar tendencies were also observed for plasma ANP concentration. The level of plasma in adult hypertensive rats was significantly lower or tended to be lower than in adult normotensive rats. Furthermore, a high negative correlation was present between blood pressure and cardiac ANP content (r = 0.748, p less than 0.01) and between blood pressure and plasma ANP concentration (r = 0.608, p less than 0.01) in all adult rats but there were no such relationships in young rats. The present study suggests that atrial natriuretic polypeptide may contribute to the pathogenesis or maintenance of high blood pressure in the genetic hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart; Myocardium; Organ Size; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The diuretic-natriuretic responses of eight assay rats to extracts of atrial tissue obtained 3 months after left coronary ligation were less than the responses to extracts of tissue from sham-operated controls. The mean difference in diuresis (sham-operated response minus ligated response) was 370 (range 22 to 656) microliter/20 minutes (p less than 0.01) and in natriuresis 56 (range -92 to 222) microEq/20 minutes (p = 0.19). The differences in diuretic responses to these extracts was directly related to the severity of elevation of left ventricular end-diastolic pressure in these rats (r = -0.82, p = 0.01). These results in a model with varying degrees of left ventricular dysfunction suggest that myocardial damage is associated with a chronic decrease in atrial natriuretic factor. Reduced circulating atrial natriuretic factor therefore could contribute to the previously observed impaired ability of coronary ligated rats to excrete a saline load and to the sodium retention observed in clinical heart failure. Conclusive evidence will depend on the development of techniques to measure plasma levels of this hormone.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Coronary Disease; Disease Models, Animal; Heart; Male; Natriuresis; Organ Size; Rats; Rats, Inbred Strains

Conscious one-kidney, one-clip hypertensive rats and their normotensive controls were infused during 7 days with synthetic ANF (Arg 101-Tyr 126) at 100 ng/hr/rat (35 pmol/hr/rat) by means of osmotic minipumps. The basal blood pressure of 193 +/- 6 mmHg gradually declined to 145 +/- 6 mmHg at day 4 after the infusion was started. No changes in blood pressure were observed in ANF-infused normotensive rats. A significantly higher diuresis and natriuresis was observed in ANF-infused hypertensive rats when compared to the non-treated hypertensive group. No such changes were observed in ANF-treated normotensive animals. No differences in PRA were seen in any group. Atrial immunoreactive ANF was significantly lower in one-kidney, one-clip rats than in the normotensive animals, but whether this is the reflection of an increased release in the circulation remains to be elucidated. It is suggested that the hypotensive response of one-kidney, one-clip animals to ANF may be secondary to a dual mechanism, vasodilatation and volume depletion.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Disease Models, Animal; Diuresis; Heart Atria; Hypertension, Renal; Male; Muscle Proteins; Natriuresis; Nephrectomy; Rats