atrial-natriuretic-factor and Hypertension--Renal

It is now well accepted that alterations in kidney function, due either to primary renal disease or to inappropriate hormonal influences on the kidney, are a cardinal characteristic in all forms of hypertension, and lead to a reduced ability of the kidneys to excrete sodium and the consequent development of elevated arterial pressures. However, it is also apparent that many extrarenal factors are important contributors to altered kidney function and hypertension. Central to many hypertensinogenic processes is the inappropriate activation of the renin-angiotensin system (RAS) and its downstream consequences by various pathophysiologic mechanisms. There may also be derangements in arachidonic acid metabolites, endothelium derived factors such as nitric oxide and carbon monoxide, and various paracrine and neural systems that normally interact with or provide a counteracting balance to the actions of the RAS. Thus, when the capacity of the kidneys to maintain sodium balance and extracellular fluid volume within appropriate ranges is compromised, increases in arterial pressure become necessary to re-establish normal balance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Carbon Monoxide; Cyclooxygenase Inhibitors; Eicosanoids; Heme; Heme Oxygenase (Decyclizing); Hypertension; Hypertension, Renal; Renin-Angiotensin System

Atrial natriuretic peptide is a recently discovered cardiac hormone with natriuretic, vasodilatory and hypotensive activities. The role of this hormone in the pathophysiology of hypertension is of particular interest. In contrast to an earlier concept, a deficiency of the atrial peptide could not be found in animal models of hypertension or in patients. ANP plasma levels were elevated in SHR with accelerated hypertension, in salt-sensitive Dahl rats, in rats with DOCA-salt-hypertension and in animals with renovascular hypertension. Elevated ANP levels under these conditions can be explained by an expansion of the intravascular volume or by an elevated atrial wall stretch induced by the hypertension itself. In patients with primary hypertension, plasma levels of the peptide are raised in some patients and are normal in others. Plasma ANP levels correlate with age, blood pressure and signs of left ventricular hypertrophy. A negative correlation is described between ANP and renin. Measurement of plasma ANP levels does not allow a differentiation between primary and secondary forms of hypertension. Elevated ANP levels are also found in primary hyperaldosteronism and in renal failure. Stimulation of ANP secretion by physical exercise and dietary salt loading is maintained in hypertension. Infusion of 1-28-hANP leads to a reduction in systemic arterial pressure in normotensives and hypertensives. The natriuresis induced by exogenous ANP is more pronounced in hypertensives. Stimulation of endogenous ANP secretion does not prevent the rise in blood pressure possibly due to a reduction in ANP receptors in target tissues.

Topics: Acromegaly; Animals; Atrial Natriuretic Factor; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney Failure, Chronic; Male; Rats; Rats, Inbred Strains

Topics: Animals; Atrial Natriuretic Factor; Diuresis; Hypertension, Renal; Natriuresis; Rats; Sodium Channels; Sodium Chloride

Topics: Atrial Natriuretic Factor; Endorphins; Humans; Hypertension, Renal; Kidney; Parathyroid Hormone; Renal Dialysis; Renin-Angiotensin System; Sympathetic Nervous System; Water-Electrolyte Balance

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

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 effects of low-dose dopamine infusion on renal hemodynamics, tubular function estimated by the lithium clearance technique and plasma levels of angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) were studied in 11 patients with essential hypertension (HT) and in 10 healthy control subjects (CS). Antihypertensive treatment was terminated at least 2 weeks prior to examination. Dopamine (2 micrograms/kg/min) was infused for two hours. Before dopamine infusion all measured parameters, but blood pressure, did not deviate significantly between the two groups, including 24 h urinary sodium excretion prior to investigation (HT: 166.9 mmol/24 h vs. CS: 183.4 mmol/24 h, medians). Dopamine infusion resulted in an exaggerated natriuresis in the HT group when compared with the CS group; sodium excretion: (HT: from 260 to 759 mumol/min vs. CS: from 255 to 432 mumol/min, p < 0.01) and fractional sodium excretion: (HT: from 1.6 to 4.2% vs. CS: from 1.6 to 2.4%, p < 0.01 median values). Distal fractional sodium reabsorption was significantly lower in the HT patients (HT: from 94.0 to 88.5% vs. CS: from 94.0 to 91.6%, p < 0.01). ANP decreased significantly only in the HT group (HT: from 4.8 to 3.5 pmol/l vs. CS: from 3.2 to 3.4 pmol/l, p < 0.01). Renal hemodynamics, blood pressure, urinary output, Ang II, Aldo, and AVP were changed to the same degree or unchanged in both groups. It is concluded that the exaggerated natriuretic response seen in patients with essential hypertension during low-dose dopamine infusion probably is due to a enhanced dopamine sensitivity mainly in the distal parts of the nephron.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Dopamine; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney Tubules, Distal; Lithium; Male; Middle Aged; Natriuresis; Renal Circulation; Sodium; Urination

We examined the effects of two therapeutic oral (p.o.) doses of cicletanine (50 and 100 mg daily) on renal hemodynamics and segmental tubular handling of sodium. Six normotensive (NT) healthy subjects (group 1) received 50 mg cicletanine, and 12 moderately hypertensive (HT) patients with normal sodium diet and randomly divided into two groups of 6 were treated either with cicletanine 50 mg (group II) or with cicletanine 100 mg (group III). Studies were performed both acutely and after 4 weeks of cicletanine administration. After 28-day treatment, blood pressure (BP) was significantly reduced in HT patients. In NT subjects (group I) and HT patients (groups II and III), acute administration of cicletanine 50 or 100 mg at day 0 did not significantly modify glomerular filtration rate (GFR) or renal blood flow (RBF), but markedly increased fractional excretion of Na (FENa) by 67% in group I and by 62 and 135% in groups II and III, respectively. Fractional distal reabsorption of Na (FDRNa) was significantly reduced in the three groups after cicletanine administration. After 4-weeks treatment, GFR and RBF were not significantly modified. The increase in FeNa and decrease in FDRNa were of the same magnitude as that at day 0. No major changes occurred in hormonal profile [renin, aldosterone, atrial natriuretic factor (ANF)]. Even at low doses, cicletanine has a natriuretic effect in NT and HT subjects. Unchanged fractional reabsorption of lithium and a significant decrease in FDRNa in the three groups suggest that this natriuretic effect occurs at the distal tubule.

Topics: Administration, Oral; Adult; Aldosterone; Analysis of Variance; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Tubules; Male; Middle Aged; Pyridines; Renal Circulation; Renin; Sodium; Vascular Resistance

Hypertension is regarded as a condition of mild inflammation and endothelial imbalance. The aim of the study was to evaluate serum concentrations of biomarkers of inflammation and endothelial function: tumour necrosis factor alpha (TNF-α), endothelin-1 (ET-1), and N-terminal fragment of pro-atrial natriuretic peptide (NTpro-ANP) in hypertensive and normotensive children.. We studied 63 children aged 13.56 ± 3.73 years, divided into two groups: a group with primary hypertension (n = 50) and a group with renal hypertension (n = 13). The control group consisted of 34 normotensive children aged 12.76 ± 3.96 years. Biomarkers were measured with ELISA tests.. ET-1 levels were significantly higher in primary hypertension (9.93 ± 1.73 pg/ml) and renal hypertension (10.77 ± 1.50 pg/ml) in comparison to controls (4.03 ± 0.97 pg/ml), (p < 0.001, p < 0.001, respectively). NT-pro ANP concentrations in primary hypertension (71.03 ± 10.02 pg/ml), and renal hypertension (84.78 ± 6.44 pg/ml) were significantly higher than in the control group (29.62 ± 5.56 pg/ml) (p < 0.001, p < 0.001, respectively). TNF-α concentrations in primary hypertension (8.36 ± 1.60 pg/ml) and renal hypertension (7.35 ± 0.93 pg/ml) significantly exceeded concentrations in controls (4.49 ± 0.93 pg/ml), (p < 0.001, p < 0.001, respectively). ET-1 and NT-pro ANP concentrations in renal hypertension significantly exceeded those in primary hypertension (p = 0.049, p < 0.001, respectively) while TNF-α levels in renal hypertension were significantly lower than in primary hypertension (p = 0.046).. The results of our study show that ET-1, NT-pro ANP, and TNF-a concentrations are increased in hypertension in children. Our investigation indicates significant importance of inflammation and endothelial involvement in hypertension in youth.

Topics: Adolescent; Atrial Natriuretic Factor; Biomarkers; Child; Child, Preschool; Endothelin-1; Essential Hypertension; Female; Humans; Hypertension, Renal; Male; Peptide Fragments; Tumor Necrosis Factor-alpha

Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1μM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1μM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Atrial Pressure; Cyclic GMP-Dependent Protein Kinases; Gene Expression Regulation; Guanylate Cyclase; Heart Atria; Hypertension, Renal; Imidazoles; Losartan; Male; Nitric Oxide; Oligopeptides; Peptide Fragments; Phosphatidylinositol 3-Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Tissue Culture Techniques; Vasodilator Agents

Angiotensin II (Ang II) is released by stretch of cardiac myocytes and has paracrine and autocrine effects on cardiac myocytes and fibroblasts. However, the direct effect of Ang II on the secretion of atrial natriuretic peptide (ANP) is unclear. The aim of the present study is to test whether Ang II affects stretch-induced ANP secretion. The isolated perfused beating atria were used from control and two-kidney one-clip hypertensive (2K1C) rats. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5cmH(2)O to 7.5cmH(2)O. Atrial stretch by volume load caused increases in atrial contractility by 60% and in ANP secretion by 100%. Ang II suppressed stretch-induced ANP secretion and tended to increase atrial contractility whereas losartan stimulated stretch-induced ANP secretion. Neither PD123319 nor A779 had direct effect on stretch-induced ANP secretion. The suppressive effect of Ang II on stretch-induced ANP secretion was blocked by the pretreatment of losartan but not by the pretreatment of PD123319 or A779. In hypertrophied atria from 2K1C rats, stretch-induced ANP concentration attenuated and atrial contractility augmented. The response of stretch-induced ANP secretion to Ang II and losartan augmented. The expression of AT1 receptor protein and mRNA increased but AT2 and Mas receptor mRNA did not change in 2K1C rat atria. Therefore, we suggest that Ang II generated endogenously by atrial stretch suppresses stretch-induced ANP secretion through the AT1 receptor and alteration of Ang II effect in 2K1C rat may be due to upregulation of AT1 receptor.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Hypertrophic; Extracellular Fluid; Gene Expression; Heart Atria; Hypertension, Renal; Imidazoles; Losartan; Male; Myocardial Contraction; Peptide Fragments; Perfusion; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Reflex, Stretch

Cyclooxygenase (COX) is a key enzyme regulating the production of various prostaglandins (PGs) from arachidonic acid. Angiotensin II has been reported to be an important inflammatory mediator, which increases COX-2. The aim of this study was to determine the role of various PGs and COX-2 in the regulation of atrial natriuretic peptide (ANP) secretion. PGF2alpha and PGD2 caused dose-dependent increases in ANP release and intra-atrial pressure. The potency for the stimulation of ANP secretion by PGF2alpha was higher than that by PGD2. In contrast, PGE2, PGI2, PGJ2, and thromboxane A2 did not show any significant effects. The increases in intra-atrial pressure and ANP secretion induced by PGF2alpha and PGD2 were significantly attenuated by the pretreatment with an inhibitor of PGF2alpha receptor. By the pretreatment with an inhibitor for phospholipase C (PLC), inositol 3-phosphate (IP3) receptor, protein kinase C (PKC), or myosin light chain kinase (MLCK), PGF2alpha-mediated increase in ANP secretion and positive inotropy were attenuated. Inhibitor for COX-1 or COX-2 did not cause any significant effects on atrial parameters. In hypertrophied rat atria, PGF2alpha-induced positive inotropy and ANP secretion were markedly attenuated whereas COX-2 inhibitor stimulated ANP secretion. The expression of COX-2 increased and the expression of PGF2alpha receptor mRNA decreased in hypertrophied rat atria. These results suggest that PGF2alpha increased the ANP secretion and positive inotropy through PLC-IP3-PKC-MLCK pathway, and the modulation of ANP secretion by COX-2 inhibitor and PGF2alpha may partly relate to the development of renal hypertension.

Topics: Animals; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Enzyme Inhibitors; Extracellular Fluid; Gene Expression; Heart Atria; Hypertension, Renal; In Vitro Techniques; Membrane Proteins; Perfusion; Prostaglandin D2; Prostaglandins; Rats; Rats, Sprague-Dawley; Receptors, Immunologic; Receptors, Prostaglandin; Renal Artery; Signal Transduction; Xanthones

Cardiac hypertrophy, an adaptive process to an increased hemodynamic overload, includes not only an increase in cell size but also qualitative changes in constituent proteins. Although swelling-activated chloride channels (I(Cl,swell)) chronically activate in hypertrophied atrial myocytes, the role of I(Cl,swell) in regulation of atrial natriuretic peptide (ANP) release is poorly understood. We investigated the effects of I(Cl,swell) on ANP release and contractility and its modification in hypertrophied rat atria. To stimulate I(Cl,swell), hypoosmotic HEPES buffered solution (0.8T, 0.7T and 0.6T) was perfused into isolated perfused beating atria. The hypoosmotic HEPES buffered solution increased ANP release as compared to isoosmotic buffered solution (1T) in an osmolarity-reduction dependent manner. Atrial contractility and extracellular fluid translocation did not change. Exposure to hypoosmotic buffer (0.8T) containing low chloride (8mM), tamoxifen or diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) significantly attenuated hypoosmolarity-induced ANP release. The pretreatment with genistein, okdaic acid, U73122, GF109203x, and staurosporine attenuated hypoosmolarity-induced ANP release whereas orthovanadate augmented it significantly. In hypertrophied atria from renal hypertensive rats, hypoosmolarity-induced ANP release was markedly attenuated and DIDS-induced decrease in ANP release and negative inotropy were augmented as compared to sham-operated rat atria. Therefore, we suggest that I(Cl,swell) may partly participate hypoosmolarity-induced ANP release through protein tyrosine kinase and phospholipase C-protein kinase C pathway. The modification of responses of ANP release to hypoosmolarity and DIDS in hypertrophied atria may relate to changes in I(Cl,swell) activity by persistent high blood pressure.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Animals; Atrial Natriuretic Factor; Cardiomegaly; Chloride Channels; Estrenes; Extracellular Fluid; Genistein; Heart Atria; Hypertension, Renal; Indoles; Maleimides; Okadaic Acid; Osmotic Pressure; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Staurosporine; Tamoxifen; Vanadates

We have known that endothelial nitric-oxide synthase (eNOS) and oxidative stress may play a key role in cardiac performance in failing rat hearts. However, the interactions between eNOS or oxidative stress and bradykinin (BK) under treatment of calcium channel blockers (CCBs) remain unknown. To elucidate the mechanism underlying the cardioprotective effect of long-acting dihydropyridine CCBs, we evaluated the effect of benidipine on the BK-eNOS and NAD(P)H oxidase pathway in Dahl salt-sensitive (DS) rats with heart failure.. 11-week-old DS rats were treated with one of the following drug combinations for 7 weeks until the onset of the failing stage: vehicle, BK B2 receptor antagonist (FR172357 (FR)) alone, hydralazine, benidipine, and benidipine plus FR. The left ventricular end-systolic pressure-volume relationship (ESPVR) (contractility: Ees) was evaluated using a conductance catheter.. Downregulated Ees and per cent of fractional shortening (%FS) assessed by echocardiography and eNOS expression in the failing stage were both significantly increased by using benidipine; this result was not found, however, when using FR alone or hydralazine or benidipine plus FR. Upregulated expression of NAD(P)H oxidase p22phox and p47phox and lectin-like oxidized low-density lipoprotein receptor-1, and downregulated superoxide dismutase-1 (SOD-1) were significantly ameliorated by benidipine, but not by FR alone or by hydralazine or benidipine plus FR. Benidipine effectively inhibited vascular lesion formation and suppressed atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGF-beta1), but this was not the case when using FR alone or hydralazine or benidipine plus FR.. These results suggest that benidipine may be useful for cardioprotective agents in preventing the cardiac dysfunction and remodeling associated with the BK-eNOS and oxidative stress pathway.

Topics: Animals; Atrial Natriuretic Factor; Cardiotonic Agents; Collagen Type I; Dihydropyridines; Gene Expression; Heart Failure; Hypertension, Renal; Intercellular Adhesion Molecule-1; Myosin Heavy Chains; NADPH Oxidases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Inbred Dahl; Scavenger Receptors, Class E; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factor RelA; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1; Vasodilator Agents; Ventricular Function; Ventricular Remodeling

Sympathetic nervous system and atrial natriuretic peptide (ANP) system play fundamental roles in the regulation of cardiovascular functions. Overactivity of sympathetic nervous system can lead into cardiovascular diseases such as heart failure and hypertension. The present study aimed to define which adrenergic receptors (ARs) affect atrial contractility and ANP release and to determine their modification in renal hypertensive rat atria. An alpha(1)-AR agonist, cirazoline increased ANP release with positive inotropism. These alpha(1)-AR agonist-mediated responses were attenuated by the alpha(1A)-AR antagonist, but not by the alpha(1B)- or alpha(1D)-AR antagonist. An alpha(2)-AR agonist, guanabenz and clonidine increased ANP release with negative inotropism and decreased cAMP level. The order of potency for the increased ANP release was cirazoline>>phenylephrine=guanabenz>>clonidine. In contrast, a beta-AR agonist, isoproterenol decreased ANP release with positive inotropism and these responses were blocked by the beta(1)-AR antagonist but not by the beta(2)-AR antagonist. The increased cAMP level by isoproterenol was suppressed by pretreatment with both beta(1)- and beta(2)-AR antagonists. In renal hypertensive rat atria, the effects of isoproterenol on atrial contractility, ANP release, and cAMP level were attenuated whereas the effect of cirazoline on ANP release was unaltered. Atrial beta(1)-AR mRNA level but not alpha(1A)-AR mRNA level was decreased in renal hypertensive rats. These findings suggest that alpha(1A)- and beta(1)-AR oppositely regulate atrial ANP release and that atrial beta(1)-AR expression/function is impaired in renal hypertensive rats.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Atrial Natriuretic Factor; Clonidine; Cyclic AMP; Dose-Response Relationship, Drug; Guanabenz; Heart Atria; Hypertension, Renal; Imidazoles; Isoproterenol; Male; Phenylephrine; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; RNA, Messenger; Time Factors

We have demonstrated that myocardial ATP-sensitive potassium (K(ATP)) channels are implicated in the development of cardiac hypertrophy in hyperlipidemic rabbits. We investigated the effect of pravastatin on development of ventricular hypertrophy in male normolipidemic Wistar rats with two-kidney, one-clip (2K1C) hypertension and whether the attenuated hypertrophic effect was via activation of K(ATP) channels. Twenty-four hours after the left renal artery was clipped, rats were treated with one of the following therapies for 8 wk: vehicle, nicorandil (an agonist of K(ATP) channels), pravastatin, glibenclamide (an antagonist of K(ATP) channels), hydralazine, nicorandil plus glibenclamide, or pravastatin plus glibenclamide. Systolic blood pressure, relative left ventricular (LV) weight, and cardiomyocyte sizes significantly increased in vehicle-treated 2K1C rats compared with those in sham-operated rats. Treatment with either nicorandil or pravastatin significantly attenuated LV hypertrophy/body weight compared with the vehicle, which was further confirmed by downregulation of LV atrial natriuretic peptide mRNA. Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating K(ATP) channels as the relevant target. A dissociation between the effects of blood pressure and cardiac structure was noted because pravastatin and hydralazine reduced arterial pressure similarly. These results suggest a crucial role of cardiac K(ATP) channel system in the development of ventricular hypertrophy in the 2K1C hypertensive rats. Pravastatin is endowed with cardiac antihypertrophic properties probably through activation of K(ATP) channels, independent of lipid and hemodynamic changes.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Natriuretic Factor; Echocardiography; Gene Expression Regulation; Glyburide; Heart Ventricles; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Renal; Hypertrophy, Left Ventricular; Male; Nicorandil; Potassium Channels; Pravastatin; Rats; Rats, Wistar; Vasodilator Agents

Atrial natriuretic peptide (ANP) enhances cardiac vagal baroreflexes in normotensive animals. In spontaneously hypertensive rats (SHRs) this effect of ANP was absent. The reflex actions of ANP were preserved if hypertrophy was completely prevented in SHRs. However even a small amount of cardiac hypertrophy, with no hypertension, in SHRs was accompanied by a loss of the reflex bradycardic actions of ANP. In the present study, we investigated whether pathophysiological cardiac hypertrophy, induced by one-kidney, one-clip renovascular hypertension (1K-1C; n = 6), or physiological cardiac hypertrophy induced by chronic spontaneous, wheel-running exercise training (n = 7), similarly prevented vagal reflex actions of ANP. Cardiac baroreceptor-activated bradycardia was measured during rapid ramp increases ( approximately 5 s) in blood pressure after bolus doses of methoxamine or vehicle in conscious, chronically instrumented rats during infusions of ANP (50 pmol kg(-1) min(-1)). Compared with uninephrectomised control rats (n = 10), rats with 1K-1C had cardiac hypertrophy (approximately 55% increase in left ventricle:body weight (LV:BW) ratio; P < 0.05) and blunted vagal baroreflex gain (-0.93 +/- 0.18 versus-0.50 +/- 0.13 beats min(-1) mmHg(-1); P < 0.05). ANP did not augment baroreflex function in 1K-1C. Compared with their sedentary controls (n = 7), exercise-trained rats with cardiac hypertrophy ( approximately 20% increase LV:BW ratio; P < 0.05) also had blunted ramp baroreflex bradycardia (-1.28 +/- 0.23 versus-0.57 +/- 0.09 beats min(-1) mmHg(-1); P < 0.05). In contrast, ANP more than doubled baroreflex bradycardia in exercise-trained rats (P < 0.05). The aetiology of cardiac hypertrophy therefore influenced whether ANP retained its vagal baroreflex enhancing properties.

Topics: Animals; Atrial Natriuretic Factor; Baroreflex; Cardiomegaly; Hypertension, Renal; Male; Nephrectomy; Physical Conditioning, Animal; Physical Exertion; Rats; Rats, Wistar; Vagus Nerve

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

The plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) become increased in hypertension. However, it is unknown what is the effect of the etiology and the severity of hypertension on the plasma concentrations of ANP and BNP.. We examined plasma levels of ANP (measured as N-terminal fragment of proatrial natriuretic peptide; NT-proANP) and BNP in patients having sustained hypertension of different etiology and severity: in patients with renovascular hypertension (RVHT, n = 12), severe essential hypertension (SEHT, n = 37), and mild essential hypertension (MEHT, n = 29). In addition, we studied the diagnostic value of NT-proANP and BNP to discriminate patients with RVHT from patients with essential hypertension.. The plasma concentrations of NT-proANP and BNP were higher in the RVHT group (593 +/- 80 and 25.0 +/- 9.3 pmol/l, respectively) than in the SEHT group (320 +/- 33 and 4.7 + 0.6 pmol/l, respectively; p < 0.001 for both), in spite of the similar blood pressure level, and also higher than in the MEHT group (356 +/- 30 and 7.0 +/- 1.0 pmol/l; p = 0.004 and p = 0.006, respectively). There was no difference in natriuretic peptide levels between the SEHT and MEHT groups. Plasma NT-proANP and BNP correlated positively with aging and serum creatinine concentration and inversely with left ventricular diastolic filling. In addition, NT-proANP correlated positively with systolic blood pressure and BNP with left ventricular mass index. The areas under receiver operating characteristic curves for plasma NT-proANP and BNP to discriminate RVHT patients from patients with essential hypertension were 0.793 and 0.782, respectively. The best cutoff value was 530 pmol/l for NT-proANP, giving a sensitivity of 67% with a specificity of 86%. The cutoff value of 9.8 pmol/l for BNP resulted in a sensitivity of 58% and a specificity of 90%.. Patients with RVHT have higher plasma levels of NT-proANP and BNP than patients with essential hypertension. In addition to the etiology of hypertension, also left ventricular characteristics are important determinants of NT-proANP and BNP concentrations in hypertension. Due to the low sensitivity, NT-proANP and BNP are not suitable as screening tools for RVHT.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Diagnosis, Differential; Female; Humans; Hypertension, Renal; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Sensitivity and Specificity; Severity of Illness Index

Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP (hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (P<0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the ScaI mutated allele (A(1)) was significantly lower in hypertensive than in control subjects (11% versus 19%, P=0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%; P<0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the A(1) allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59; P=0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele (T(708)) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59; P<0.001). We conclude that the mutated genotypes of the ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.

Topics: Adult; Aged; Albuminuria; Atrial Natriuretic Factor; Cohort Studies; Deoxyribonucleases, Type II Site-Specific; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genes; Genetic Predisposition to Disease; Humans; Hypertension, Renal; Male; Middle Aged; Polymorphism, Genetic

Although left ventricular hypertrophy (LVH) is a common complication which contributes substantially to high cardiovascular mortality and morbidity in end-stage renal failure, whether changes in blood pressure and alterations of circadian variation of blood pressure occur between the hemodialysis (HD) day and the interdialytic day, and if so, whether they influence the left ventricular mass (LVM) remain unknown. Thirty-five consecutive stable patients who had had a hematocrit value greater than 25% for the previous 6 months, who had been on the same antihypertensive drugs during this period, and who underwent HD 3 times a week were included. Echocardiograms were recorded after HD and then ambulatory blood pressure monitoring was recorded every hour for 48 h. The mean interdialytic body weight gain was less than 5% of dry weight. Patients with LVH had a higher average systolic blood pressure (SBP) at predialysis, postdialysis, on the HD day and on the interdialytic day than those without LVH despite the higher antihypertensive therapy rate. The majority of patients with LVH showed concentric hypertrophy and higher plasma natriuretic peptide levels. Irrespective of the presence of LVH, the average blood pressure value did not change between the HD day and the interdialytic day, and a loss of circadian blood pressure variation was observed on both the HD and interdialytic days. Univariate analysis revealed that LVM was significantly correlated with the average SBP at predialysis, postdialysis, on the HD day, on the interdialytic day and over 48 h (r= 0.48, r=0.61, r=0.67, r=0.67, r=0.73, respectively; all p<0.05). Multiple regression analysis revealed that 48-h SBP was independently associated with the LVM index. These results suggest that neither the loss of circadian blood pressure variation nor the changes of blood pressure between the HD and interdialytic days was of major etiologic importance in the development of LVH, and that the absolute value of the 48-hour average SBP may be an important risk factor for concentric LVH in stable HD patients.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Echocardiography; Female; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Regression Analysis; Renal Dialysis

To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS)blockade.. Captopril, an angiotensin-converting enzyme (ACE)inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT1-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP),urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.. Captopril and L- 158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT1-receptor binding in the kidney was inhibited to about 40% of the control value after administration of L- 158,809. The AT2-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.. Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT1-receptor antagonism on cGMP production was not mediated by AT2-receptor-dependent mechanisms, since renalAT2-receptor binding density was suppressed following treatment with L-158,809. AT1-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Autoradiography; Blood Pressure; Captopril; Cyclic GMP; Enzyme Inhibitors; Female; Hypertension, Renal; Imidazoles; Kidney; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Tetrazoles

The potential involvement of the brain renin-angiotensin system in the hypertension induced by subpressor doses of angiotensin II was tested by the use of newly developed transgenic rats with permanent inhibition of brain angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague-Dawley rats (parent strain) (122.5+/-1.5 versus 128.9+/-1.9 mm Hg, respectively; P<0.05). The increase in systolic blood pressure induced by 7 days of chronic angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in comparison with control rats (29.8+/-4.2 versus 46. 3+/-2.5 mm Hg, respectively; P<0.005). Moreover, an increase in heart/body weight ratio was evident only in Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle measured by ribonuclease protection assay were similarly increased in both TGR(ASrAOGEN) (ANP, x2.5; collagen III, x1.8) and Sprague-Dawley rats (ANP, x2.4; collagen III, x2) as a consequence of angiotensin II infusion. Thus, the expression of these genes in the left ventricle seems to be directly stimulated by angiotensin II. However, the hypertensive and hypertrophic effects of subpressor angiotensin II are at least in part mediated by the brain renin-angiotensin system.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Brain Chemistry; Cardiomegaly; Collagen; Gene Expression; Heart Ventricles; Hypertension, Renal; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger

Fragments derived from the prohormone of alpha-human atrial natriuretic peptide (alpha-ANP) in patients with cardiac failure are more closely related to the disease state than intact alpha-ANP.. Specific immunoassays have been developed to detect proANP 1-30, proANP 31-67, and proANP 1-98. Plasma concentrations of these fragments were determined in 122 hemodialysis patients with and without cardiac dysfunction, with and without hypertension, as well as with and without dialysis-associated hypotensive episodes either before or after a regularly scheduled hemodialysis session. The effects of different dialyzer membranes were also evaluated. The results of these assays along with other markers of volume regulation such as alpha-ANP and cyclic 3',5' guanosine monophosphate (cGMP) were compared with those of healthy controls.. Predialytic and postdialytic plasma concentrations of the proANP fragments were markedly higher in uremic patients than in controls (98-fold for proANP 1-98, 56-fold for proANP 31-67, and 35-fold for proANP 1-30). All proANP fragments, alpha-ANP, and cGMP decreased during hemodialysis. A strong linear correlation was found between predialytic and postdialytic plasma levels. There was no correlation, however, with the amount of fluid removed during hemodialysis. Patients with altered left ventricular hemodynamics displayed significantly higher plasma concentrations of all proANP fragments and alpha-ANP, but not cGMP, than patients with normal cardiac function. Hemodialysis patients with moderate or severe hypertension had higher concentrations of proANP fragments, alpha-ANP, and cGMP than patients with normal blood pressure or patients with only mild hypertension. There was no significant difference in circulating levels of proANP peptides, alpha-ANP, and cGMP between patients with and without frequent dialysis-associated hypotensive episodes. Cellulose-triacetate dialyzers reduced plasma levels of proANP 1-30, proANP 31-67, and proANP 1-98 significantly more than polysulfone dialyzers, but alpha-ANP and cGMP levels were not different.. Circulating alpha-ANP and proANP fragments are influenced by a variety of factors such as end-stage renal disease, hemodialysis treatment, dialyzer membrane material, cardiac dysfunction, and hypertension. Therefore, these are not useful markers to accurately estimate volume status in hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cyclic GMP; Female; Heart Failure; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Peptide Fragments; Protein Precursors; Renal Dialysis

Recipients of a kidney from spontaneously hypertensive rats (SHR) but not from normotensive Wistar-Kyoto rats (WKY) develop posttransplantation hypertension. To investigate whether renal sodium retention precedes the development of posttransplantation hypertension in recipients of an SHR kidney on a standard sodium diet (0.6% NaCl), we transplanted SHR and WKY kidneys to SHR x WKY F1 hybrids, measured daily sodium balances during the first 12 days after removal of both native kidneys, and recorded mean arterial pressure (MAP) after 8 wk. Recipients of an SHR kidney (n = 12) retained more sodium than recipients of a WKY kidney (n = 12) (7.3 +/- 10 vs. 4.0 +/- 0.7 mmol, P < 0.05). MAP was 144 +/- 6 mmHg in recipients of an SHR kidney and 106 +/- 5 mmHg in recipients of a WKY kidney (P < 0.01). Modest sodium restriction (0.2% NaCl) in a further group of recipients of an SHR kidney (n = 10) did not prevent posttransplantation hypertension (MAP, 142 +/- 4 mmHg). Urinary endothelin and urodilatin excretion rates were similar in recipients of an SHR and a WKY kidney. Transient excess sodium retention after renal transplantation may contribute to posttransplantation hypertension in recipients of an SHR kidney.

Topics: Animals; Atrial Natriuretic Factor; Diet, Sodium-Restricted; Endothelins; Homeostasis; Hypertension, Renal; Kidney; Kidney Transplantation; Male; Nephrectomy; Peptide Fragments; Postoperative Complications; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Sodium Chloride, Dietary

To investigate effects of angiotensin I converting enzyme (ACE) inhibition in experimental nephritis during chronic inhibition of nitric oxide (NO) synthase.. Rats with and without autoimmune Heymann nephritis were treated with a NO synthase inhibitor L-NAME (50 mg/100 ml) and/or an ACE inhibitor captopril (20 mg/100 ml) in drinking water for 12 weeks. Urinary cGMP excretion was used as an indirect measure of NO activity. Blood pressure, urinary albumin, nitrite and nitrate levels, plasma ANP, and plasma renin activity were measured. Kidneys were examined with light microscopy and immunohistochemical methods.. Captopril treatment protected rats receiving L-NAME and none of the captopril-treated rats died. Mortality was greatest in the nephritis-L-NAME (57%) and L-NAME (43%) groups. Captopril normalized cGMP excretion, blood pressure, and prevented partly the appearance of albuminuria. Peritubular infiltration of mononuclear cells was clearly enhanced in the nephritis-L-NAME group (found in 80% of the rats) as compared with the nephritis (20%), L-NAME (40%), and control (0%) groups. The peritubular cell infiltration caused by L-NAME was prevented by captopril treatment. L-NAME-induced hypertension was associated with cardiac hypertrophy and this was prevented by captopril.. NO may play an important renoprotective role in disease progression of chronic membranous glomerulonephritis. Captopril prevents L-NAME-induced hypertension, improves survival, and ameliorates renal damage in this type of nephritis. Dysfunction of renal NO pathways may be an important factor causing progressive renal damage in chronic nephritis. Our results suggest that the dysfunctional renal NO system may be beneficially activated by ACE inhibitors.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Hypertension, Renal; Kidney Tubules; Myocardium; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Organ Size; Rats; Rats, Wistar; Renin

Cardiac hypertrophy is associated with altered Ca2+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Ca(2+)-ATPase is thought o play a crucial role in the alterations of Ca2+ handling and LV function. We assessed the dose-dependent effect of chronic ACE inhibition or AT1 receptor blockade on cardiac function in relation to the cardiac expression of the SR Ca(2+)-ATPase and ANF.. Renal hypertensive rats (2K-1C) were treated for 12 weeks with three different doses of the ACE inhibitor benazepril, the AT1-receptor antagonist valsartan (each drug 0.3, 3, and 10 mg/kg per day i.p.) or placebo. LV dimensions, hypertrophy and wall stress were determined in vivo by magnetic resonance imaging and the gene expressions of ANF and SR Ca(2+)-ATPase were quantified by Northern blot. Low doses of both drugs did not affect blood pressure, hypertrophy, systolic wall stress and the ANF and SR Ca(2+)-ATPase gene expression. High doses of each drug reduced systolic blood pressure, wall stress, and LV hypertrophy to a similar extent and to values comparable to normotensive, age-matched rats. In addition, high dose treatment reduced LV end-systolic and end-diastolic volume as compared to untreated 2K-1C animals and normalized the mRNA levels of both ANF and SR Ca(2+)-ATPase (as compared to normotensive animals).. We conclude that in this model, high doses of ACE inhibition and AT1-receptor blockade are necessary to normalize systolic blood pressure, LV hypertrophy and systolic LV wall stress which, in turn, is associated with restoration of a normal cardiac phenotype with respect to SR Ca(2+)-ATPase and ANF and normalization of cardiac function.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Benzazepines; Blotting, Northern; Calcium-Transporting ATPases; Dose-Response Relationship, Drug; Heart Ventricles; Hypertension, Renal; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Rats; Rats, Inbred WKY; Sarcoplasmic Reticulum; Tetrazoles; Valine; Valsartan

1. We assessed the changes of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats (RHR). 2. Two-kidney, one-clip hypertensive rats (6-week-old male Wistar) were made and studied 6 (RHR-1) and 10 weeks (RHR-2) after the procedure. Regression of cardiac hypertrophy was induced by nephrectomy at 6 weeks after constriction, and the nephrectomized rats were maintained further for 4 weeks (nephrectomized rat: NEP). Sham operation was performed, and the rats were studied after 6 (Sham-1) and 10 weeks (Sham-2). Atrial natriuretic peptide and brain natriuretic peptide gene expression in the left ventricle was analysed by Northern blotting. 3. Plasma atrial natriuretic peptide and brain natriuretic peptide were significantly higher in RHR-1 and RHR-2 than in Sham-1, Sham-2 and NEP. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels in RHR-1 were approximately 7.2-fold and 1.8-fold higher than those in Sham-1, respectively, and the corresponding levels in RHR-2 were 13.0-fold and 2.4-fold higher than those in Sham-2, respectively. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels of NEP were normalized. Levels of atrial natriuretic peptide and brain natriuretic peptide mRNA were well correlated positively with left ventricular weight/body weight ratios. There was a significant positive correlation between the levels of atrial natriuretic peptide and brain natriuretic peptide mRNA (r = 0.86, P < 0.01). 4. We conclude that the expression of atrial natriuretic peptide and brain natriuretic peptide genes is regulated in accordance with the degree of myocardial hypertrophy and that the augmented expression of these two natriuretic peptides may play an important role in the maintenance of cardiovascular haemodynamics in renovascular hypertension.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Blotting, Northern; Cardiomegaly; DNA Primers; Gene Expression Regulation; Hypertension, Renal; Male; Molecular Sequence Data; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred SHR; Rats, Wistar; RNA, Messenger

To assess the effect of recombinant human erythropoietin (EPO) on the factors regulating blood pressure (BP), we determined the hemoglobin level (Hgb), blood viscosity (BV), plasma renin activity (PRA), plasma concentrations of aldosterone (PAC), adrenaline (Ad), noradrenaline (NAd), and atrial natriuretic peptide (ANP), and serum and intracellular concentrations of cations before and after 3 months of EPO treatment (40 units/kg/week of EPO intravenously after each hemodialysis session) in 11 patients undergoing maintenance hemodialysis. Intracellular sodium concentration ([Na+]i) was measured using erythrocytes with flame photometry. EPO treatment was associated with significant increases in Hgb (7.1 +/- 1.4 to 8.4 +/- 1.8 g/dl, p<0.01), mean BP (103 +/- 11.4 to 116 +/- 19.9 mmHg, p<0.01), [Na+]i (4.99 +/- 0.78 to 6.22 +/- 0.96 mmol/l, p<0.01) and BV (1.39 +/- 0.14 to 1.53 +/- 0.18 c.p., p<0.05), but no significant alteration in PRA, PAC, Ad, NAd, ANP, or in the serum concentration of Na+, K+, and Ca2+. The changes in mean BP (deltaMBP) were significantly correlated with delta[Na+]i (R=0.676, p=0.022) and deltaBV (R=0.668, p=0.034), but not with deltaHgb. By multiple regression analysis, delta[Na+]q and deltaBV independently contributed to deltaMBP; deltaMBP=2.27 X delta[Na+]i+32.2 X deltaBV +3.37 (R=0.695). These data suggest that intracellular sodium accumulation as well as increased blood viscosity may be independently involved in the blood pressure elevation after EPO treatment in patients under maintenance hemodialysis. We found no evidence supporting a role of circulating hormonal factors, such as the renin-angiotensin system, adrenaline, or ANP, in the change in blood pressure.

Topics: Aged; Aldosterone; Anemia; Atrial Natriuretic Factor; Blood Pressure; Blood Viscosity; Calcium; Cations; Epinephrine; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension, Renal; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Potassium; Regression Analysis; Renal Dialysis; Renin; Sodium

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), are two mechanistically similar enzymes involved in the metabolism of several vasoactive peptides. Selective inhibitors of ACE are effective antihypertensive agents in high-renin, renovascular rats and normal-renin, spontaneously hypertensive rats (SHR), but are not effective in the low-renin, deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In contrast, NEP inhibitors are only effective in the low-renin model of hypertension. Treatment with a combination of selective inhibitors or with a dual inhibitor of both enzymes produces an antihypertensive response regardless of basal plasma renin activity. In this study, we compared the activities of MDL 100,173, a novel subnanomolar inhibitor of both ACE and NEP, with those of equimolar doses of captopril, a selective ACE inhibitor, following intravenous administration in these three rat models of hypertension. Treatment with MDL 100,173 significantly lowered blood pressure compared to vehicle treatment in all three models, whereas captopril treatment lowered blood pressure in the renovascular and SHR models only. Administration of MDL 100,173 also significantly elevated diuresis and natriuresis compared to either vehicle or captopril treatment in the SHR and DOCA-salt rats. Urinary excretion of atrial natriuretic peptide (ANP) was increased by MDL 100,173 treatment in all three models of hypertension. Treatment with captopril did not alter urine, sodium, or ANP excretion in any of the models. However, plasma-renin activity was elevated by both MDL 100,173 and captopril '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Blood Pressure; Captopril; Disease Models, Animal; Diuresis; Hypertension; Hypertension, Renal; Male; Neprilysin; Protease Inhibitors; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sodium

The present study was to investigate a role for endothelium-derived nitric oxide (EDNO) system in the development and maintenance of 2-kidney, 1 clip (2K1C) hypertension. Effects of blocking the synthesis or supplementing the precursor of EDNO on the developmental phase of hypertension were examined in 2K1C rats. Responses of the isolated vasculature to phenylephrine, acetylcholine, sodium nitroprusside, and atrial natriuretic peptide were also examined in chronic 2K1C rats. Ingestion of NG-nitro-L-arginine methyl ester or L-arginine did not affect the development of hypertension in 2K1C rats. Contraction response to phenylephrine was enhanced and relaxation response to acetylcholine was attenuated in the thoracic aortic ring isolated from chronic hypertensive rats, both being more marked in the 12-week hypertensive than in the 7-week hypertensive. Indomethacin did not significantly affect the degree of the attenuated vasorelaxation response to acetylcholine. The vasorelaxation response to sodium nitroprusside and atrial natriuretic peptide remained unaltered in the hypertensives. These results indicate that EDNO does not affect the developmental phase of 2K1C hypertension, whereas an impaired endothelium-dependent vasorelaxation is associated with chronic 2K1C hypertension.

Topics: Acetylcholine; Animals; Arginine; Atrial Natriuretic Factor; Chronic Disease; Disease Models, Animal; Hypertension, Renal; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Phenylephrine; Rats; Rats, Sprague-Dawley; Vasodilation

To compare normal pregnancy with pregnancy-induced hypertension (PIH)/preeclampsia with respect to the effects of acute volume expansion on plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP) and fetal-maternal circulation.. Observational study.. University hospital.. Fifteen women with PIH/preeclampsia and 15 healthy pregnant controls.. Before and after 30 minutes' infusion of a crystalloid solution (15 ml/kg), maternal venous blood was sampled for ANP and cGMP analysis and echocardiographic and Doppler investigations were performed.. Basal median (range) ANP and cGMP levels were significantly higher in the PIH/preeclampsia group compared to the controls: 6.5 (3.8-30.4) compared to 3.9 (2.0-6.7) pmol/l, p < 0.01 and 5.8 (2.4-11.6) compared to 4.0 (2.3-10.8) nmol/l, p < 0.05. The response to volume load was enhanced: 4.6 (-4.5-21.8) compared to 0.7 (-4.1-8.8), p < 0.05 and 2.9 (0.1-10.9) compared to 1.2 (-5.0-6.0), p < 0.05, respectively. Systemic vascular resistance was initially higher in the patient group, 22.3 (14.1-36.7) compared to 15.6 (10.0-25.5) peripheral resistance units, p < 0.01 but the response to volume load was similar in both groups (12-13% decrease). The pulsatility index of the uterine artery, 0.85 (0.46-1.38) compared to 0.72 (0.49-1.26) and umbilical artery 0.89 (0.66-1.57) compared to 0.97 (0.74-1.31) did not differ between the groups. Volume expansion did not affect any of these variables.. The pulsatility index of the uterine artery remained unaffected in both preeclamptic patients and healthy controls despite an increase of ANP and cGMP concentration and a systemic vasodilatation during acute volume expansion. This finding may indicate the absence of a vasodilation of the uteroplacental vascular bed.

Topics: Atrial Natriuretic Factor; Blood Circulation; Blood Volume; Cyclic GMP; Female; Fetal Blood; Humans; Hypertension, Renal; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pulsatile Flow; Vascular Resistance

From our perspective, Priscilla Kincaid-Smith's major achievement in the field of hypertension relates to the pathogenesis of vascular lesions. Our own studies of the hypertension of renal parenchymal disease have suggested a role for impairment of the cortisol-cortisone shuttle and decreased activity of the enzyme complex 11-beta-hydroxy-steroid dehydrogenase. We have defined the renal functional consequences of steroid-induced hypertension and shown that the rise in blood pressure produced by steroids with predominant glucocorticoid activity is not dependent on volume shifts or sodium status, although the magnitude of the rise is modulated by dietary sodium content. We have shown that normal pregnant women adapt readily to extremes of sodium intake while women with pre-eclampsia retain sodium, and have shown enhanced capillary permeability. Recent studies have defined an abnormal aldosterone:renin ratio, dopaminergic inhibition of aldosterone, elevations of plasma atrial natriuretic peptide and reduced urinary prostacyclin:thromboxane ratios in women with pre-eclampsia.

Topics: Adrenal Cortex Hormones; Atrial Natriuretic Factor; Australia; Female; History, 20th Century; Humans; Hypertension; Hypertension, Renal; Kidney; Nephrology; Pre-Eclampsia; Pregnancy; Renin-Angiotensin System

Topics: Adrenalectomy; Animals; Atrial Natriuretic Factor; Hypertension; Hypertension, Renal; Hypophysectomy; Hypothalamus; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Sodium, Dietary; Subfornical Organ; Thirst

Diurnal change of plasma atrial natriuretic peptide (ANP) concentration was investigated in 12 patients with hypertension due to chronic renal failure (CRF) and in 12 patients with essential hypertension (EH) of comparable degree. Blood pressure (BP) monitoring was performed at 15-min intervals, while peripheral blood samples were obtained at 4-hour intervals starting from 8.00 h. The mean 24-hour plasma levels (+/- SEM) of ANP were 24.3 +/- 1.8 pmol/l in EH and 23.4 +/- 1.2 pmol/l in CRF. In EH, plasma ANP concentration was highest at 4.00 h (33.5 +/- 0.8 pmol/l) and lowest at 16.00 h (15.5 +/- 0.6 pmol/l). In CRF, no significant circadian change was present (22.2 +/- 3.1 and 20.4 +/- 3.6 pmol/l, respectively), and the nocturnal fall in BP was lost. Our data demonstrate that in CRF the loss and possible reversal of the nocturnal decline in BP is associated with the disappearance of any significant circadian variation in the circulating concentrations of ANP. These findings suggest a role for ANP in the alteration of BP variability of CRF, possibly mediated by autonomic dysfunction, and are further evidence for the existence of a relation between the circadian rhythms of ANP and BP.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Female; Glomerulonephritis; Heart Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Pyelonephritis

The examination comprised 58 patients with essential hypertension and 17 with nephrogenic arterial hypertension. An analysis of the baseline levels of natural natriuretic factor in patients with essential and nephrogenic hypertension revealed no intergroup differences (55.3 +/- 3.0 and 45.7 +/- 5.2 ng/ml, respectively). The concentration of natural natriuretic factor was significantly higher in even patients with mild arterial hypertension than in healthy persons (28.4 +/- 4.7 and 17.4 +/- 2.9 ng/ml). There was a direct correlation between the level of natural natriuretic factor and blood pressure and left ventricular myocardial hypertrophy. There were higher positive correlations between the levels of natural natriuretic factor and those of hormones of the renin-angiotensin-aldosterone system and catecholamines in patients having a diastolic pressure of greater than 115 mm Hg. A significant increase in natural natriuretic factor levels (92.1 +/- 11.8 ng/ml) was found in the presence of hypertensive crisis.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Catecholamines; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Middle Aged; Renin-Angiotensin System; Severity of Illness Index

It has been suggested that the impaired natriuretic response of the clipped kidney in two-kidney, one clip hypertensive rats is related to downregulation of renal atrial natriuretic peptide receptors. To test this hypothesis, blood volume expansion and atrial peptide binding studies were performed in this model. Infusion of 1% and then 1.5% body weight donor blood (n = 6) caused a progressive increase in plasma immunoreactive atrial natriuretic peptide (107 +/- 26 to 168 +/- 31 to 427 +/- 154 pg/ml, p less than 0.001); the sodium excretion of the nonclipped kidney rose from 230 to 2,200 to 4,000 neq/min (p less than 0.01) but that of the clipped kidney did not rise significantly. There was a highly significant correlation between log cyclic guanosine monophosphate and log sodium excretion by the nonclipped (r2 = 0.749) but not the clipped (r2 = 0.046) kidney. Between clipped and nonclipped kidneys, the association constant (5.26 +/- 0.89 versus 5.17 +/- 0.64 x 10(9)/mol) and apparent binding site density (575 +/- 92 versus 500 +/- 74 fmol/mg protein) for atrial peptide binding in isolated glomeruli did not differ. Assay of atrial peptide-induced cyclic guanosine monophosphate release by isolated glomeruli showed that clipped and nonclipped kidneys were equally responsive. Binding affinity and receptor density did not differ in homogenates prepared from inner medullas of clipped and nonclipped kidneys. These results show that the blunted natriuretic response in clipped kidneys was not associated with any relative decrease in number or function of glomerular or papillary atrial natriuretic peptide receptors.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Glomerular Filtration Rate; Hypertension, Renal; Natriuresis; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Topics: Adrenergic beta-Antagonists; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Echocardiography; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

Neuroendocrine activity in normal subjects was compared to patients with chronic renal failure on maintenance hemodialysis (CRF-HD) and to cyclosporine-treated renal transplantation (RT) recipients in an effort to further define the mechanisms underlying their associated fluid, electrolyte, and hemodynamic abnormalities. To evaluate neuroendocrine function in CRF and RT patients, plasma levels of angiotensin II (A-II), vasopressin (AVP), atrial natriuretic peptide (ANP), neuropeptide Y, neuropeptide Y (NPY), epinephrine (E), and norepinephrine (NE) were measured before and after HD and RT. Plasma concentrations of A-II, AVP, ANP, and NPY were significantly elevated in patients with CRF. HD did not produce a significant change in plasma concentrations of AVP, ANP, NPY, E, or NE. NE plasma levels, but not E levels, increased pre- and post-HD. A-II plasma levels were elevated basally in CRF patients and significantly increased following HD. Following RT, plasma levels of A-II, AVP, NPY, and creatinine decreased significantly over the first week, but AVP and NPY did not normalize. Plasma levels of ANP were elevated during the first month, then decreased to normal levels in RT patients. NE levels, but not E levels, were elevated both pre- and post-RT. Despite antihypertensive treatment, the group mean arterial pressure increased post-RT from 100 +/- 4.4 to 116 +/- 3.7 mmHg by POD 6.

Topics: Adult; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Cyclosporine; Epinephrine; Furosemide; Humans; Hypertension, Renal; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Neurosecretory Systems; Norepinephrine; Prospective Studies; Radioimmunoassay; Renal Dialysis; Water-Electrolyte Balance

To study the effects of atrial natriuretic peptide (ANP) on body fluid volume regulation, we estimated the changes in intra- and extravascular fluid volume by measuring hematocrit (Hct), plasma protein concentration and water balance, and the changes in intra- and extracellular fluid volume by the electrical impedance method during intravenous infusion of ANP. We did two studies, as follows: ANP was infused into 18 patients with essential hypertension, 29 with renal parenchymal hypertension and 15 normotensives at 0.025 microgram/kg/min for 40 min. Both hypertensive groups showed greater natriuretic responses to ANP than normotensives. ANP infusion into essential hypertensive patients increased the urinary excretion of water by 125%, Na by 205%, Hct by 4.2% and plasma total protein (TP) by 5.2% (each P less than .001). In 9 patients (1 with renal hypertension and 8 normotensives) who did not show a natriuretic response (-2.1%), the infusion of ANP also significantly increased Hct (3.8%) and plasma TP (3.1%, each P less than .01). The electrical impedance method was applied to 12 subjects to simultaneously detect the intracellular (Ri) and extracellular resistivities (Re), of which reciprocals reflect the fluid volume in the extra- and intracellular spaces, respectively. ANP infusion increased Re in all subjects (3.96 +/- 0.16 [SE] v 4.03 +/- 0.16 omega.m, P less than .05), but decreased Ri in 7. Changes in urinary Na excretion correlated positively with those in both Re (r = 0.62, P less than .05) and Ri (r = 0.75, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Body Fluids; Electrodiagnosis; Extracellular Space; Hematocrit; Humans; Hypertension; Hypertension, Renal; Intracellular Fluid; Middle Aged; Natriuresis; Plasma Volume

Concentrations of atrial natriuretic factor (ANF) were measured in discrete brain nuclei by radioimmunoassay in rats. Alterations in the salt and fluid homeostasis and aldosterone treatment resulted in marked changes of ANF levels in the preoptic-hypothalamic periventricular structures including the organum vasculosum laminae terminalis, in the subfornical organ and the perifornical nucleus. Furthermore, marked changes were observed in ANF levels of these nuclei in various types of renal hypertensions. Altered ANF levels were found in several brain nuclei (locus coeruleus, dorsal raphe nucleus, tegmentum pontis, nucleus of the solitary tract) of animals with diabetes insipidus or spontaneous hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Diabetes Insipidus; Homeostasis; Hypertension, Renal; Hypothalamo-Hypophyseal System; Male; Raphe Nuclei; Rats; Rats, Brattleboro; Rats, Inbred Strains; Sodium Chloride; Water-Electrolyte Balance

In 12 patients with unilateral significant renal ischemia plasma levels of atrial natriuretic peptide (ANP) were estimated in renal vein blood of the ischemic (IK) and contralateral kidney (NK) and in arterial blood under supine and upright conditions. Plasma ANP levels in renal vein blood were compared with plasma renin activity (PRA) of the same blood samples. Plasma ANP levels in renal vein blood of the contralateral kidney (87 +/- 9 pg/ml) were significantly lower than in arterial blood (131 +/- 11 pg/ml) and renal vein blood of the ischemic kidney (139 +/- 16 pg/ml). In contrast plasma ANP concentrations in renal vein blood of the ischemic kidney were slightly or markedly higher than in arterial blood. A positive correlation was found between the ratio of plasma ANP in renal vein blood of the IK to that of the NK under supine condition and the respective ratio of PRA. Data presented in this paper suggest the presence of abnormal handling of ANP by an ischemic kidney and that plasma ANP levels in renal vein blood may be a marker of renal ischemia.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Female; Humans; Hypertension, Renal; Ischemia; Kidney; Male; Middle Aged; Posture; Renal Veins; Renin

In a previous study, we found that a long-term infusion of atrial natriuretic peptide (ANP) produced a sustained reduction of mean arterial pressure and peripheral vascular resistance in two-kidney, one-clip (2K-1C) hypertensive rats, whereas in control rats it had only a transient effect on cardiac output. However, plasma levels of ANP were actually 3-fold higher in normotensive than in hypertensive rats. Previous studies suggested that plasma ANP levels might modulate the vascular reactivity to the peptide. The present study examined whether the lack of chronic hemodynamic effects of ANP in control rats was due to changes in vascular reactivity to the peptide. In control rats, vascular reactivity to ANP was reduced 50% by a chronic infusion of ANP. However, in 2K-1C hypertensive rats, a long-term infusion of ANP had no effect on the vascular reactivity to ANP. The results of the present study indicate that the lack of persistent hemodynamic effects of a chronic infusion of ANP in control rats may be due to a decrease in the vascular reactivity to the peptide. The sustained hypotensive and vasodilatory effects of a long-term infusion of ANP in 2K-1C hypertensive rats are associated with no changes in the vascular reactivity to ANP.

Topics: Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Hypertension, Renal; Infusions, Intravenous; Male; Rats; Rats, Inbred Strains; Vasodilation

The effect of acute volume expansion (2 liters of saline solution in 2 h) on plasma concentrations of atrial natriuretic factor (ANF), plasma aldosterone concentration (PAC), plasma renin activity (PRA) and their relationship to the renal excretion of urine, sodium and potassium were studied in 6 control subjects and 7 patients with essential hypertension (EH) WHO stage I. Saline infusion provoked comparable rise in plasma ANF in both groups (from 2.98 +/- 0.45 to 12.36 +/- 1.74 pmol/l in the control subjects and from 3.80 +/- 0.72 to 15.78 +/- 2.06 pmol/l in EH patients), significant drop in PRA (from 0.915 +/- 0.419 to 0.256 +/- 0.127 nmol/l/h in controls and from 1.711 +/- 0.324 to 0.714 +/- 0.128 nmol/l/h in EH) and in PAC (from 0.30 +/- 0.07 to 0.14 +/- 0.03 nmol/l in control subjects and from 0.53 +/- 0.13 to 0.24 +/- 0.07 nmol/l in EH). The increase of plasma ANF concentrations after volume expansion might be involved in the suppression of PRA and PAC found after this stimulus. Similar increase in plasma ANF after saline infusion in both groups was associated with significantly greater urine and sodium excretion in EH than in controls. From these results it may be suggested that the acute volume expansion during saline infusion evokes a comparable release of ANF into circulation in both EH patients and controls. In EH patients, however, the similar rise in ANF is accompanied by a more pronounced diuretic and natriuretic response. This exaggerated natriuresis after acute volume and sodium loading cannot be explained solely by a rise in ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Creatine; Hemodynamics; Humans; Hypertension, Renal; Kidney; Middle Aged; Natriuresis; Potassium; Renin; Renin-Angiotensin System; Sodium

In 14 patients with arterial hypertension secondary to chronic renal parenchymal disease and impaired renal function, 24-h ambulatory blood pressure, casual blood pressure, plasma concentrations of angiotensin II, aldosterone, arginine vasopressin and atrial natriuretic peptide, serum creatinine, plasma lipids and lipoproteins, and body weight were determined at the end of two consecutive 3-week periods; placebo was administered in the first period and verapamil sustained-release 240 mg was given in the second period. Verapamil reduced mean 24-h ambulatory blood pressure from 152/104 mm Hg (means) to 142/97 mm Hg. Blood pressure was reduced significantly during the daytime, in the evening, and in the early morning, but not at night. Casual blood pressure was also significantly reduced from 176/106 mm Hg to 154/96 mm Hg. No significant changes were determined in the hormones, serum creatinine, plasma lipids and lipoproteins, heart rate, or body weight. Atrial natriuretic peptide was correlated significantly with serum creatinine (p = 0.733, n = 14, p less than 0.01). We conclude that verapamil sustained-release 240 mg in one daily dose has a moderate blood-pressure-lowering effect in patients with chronic renal disease and hypertension without inducing tachycardia, activation of the renin-angiotensin-aldosterone system, or increase in body weight, and without altering renal function and plasma lipids and lipoproteins. The positive correlation between atrial natriuretic peptide and serum creatinine may support the hypothesis that extracellular volume increases during progression of renal disease.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Creatinine; Delayed-Action Preparations; Female; Heart Rate; Humans; Hypertension, Renal; Kidney Function Tests; Lipoproteins; Male; Middle Aged; Verapamil

Atrial natriuretic peptide (ANP, 2 micrograms/min) was infused intravenously into rabbits four weeks after renal wrap or sham operation. Mean arterial pressure (MAP) averaged 132 +/- 4 mmHg in the renal wrapped rabbits and 89 +/- 3 mmHg in the sham rabbits, and glomerular filtration rate (GFR) was significantly lower in the hypertensive rabbits (6.2 +/- 1.0 ml/min) than in sham rabbits (8.9 +/- 0.7 ml/min). In sham rabbits, ANP caused a significant diuresis, natriuresis and increase in GFR. Enalapril pretreatment blunted these responses. In the hypertensive rabbits, ANP reduced mean arterial pressure but did not cause significant diuresis or natriuresis or change in GFR. Enalapril pretreatment did not significantly alter this response to ANP. In separate experiments, nitroprusside was infused to lower arterial pressure in hypertensive rabbits by a similar amount to that achieved with ANP and this reduced GFR, sodium and urine excretion rates. Thus ANP maintained GFR and sodium excretion in hypertensive rabbits compared to an equihypotensive dose of nitroprusside. In summary, ANP did not cause natriuresis or diuresis in renal wrapped kidneys at a dose which was effective in normal kidneys, but did maintain GFR, sodium and water excretion rates, compared to an equally hypotensive dose of nitroprusside.

Topics: Animals; Atrial Natriuretic Factor; Consciousness; Enalapril; Glomerular Filtration Rate; Hypertension, Renal; Kidney; Male; Nitroprusside; Rabbits; Renin

To investigate the involvement of atrial natriuretic peptide (ANP) in secondary hypertension, we examined hormonal and renal responses to ANP infusion (0.025 microgram/kg/min) in 27 patients with renal parenchymal hypertension, 10 with primary aldosteronism, 8 with renovascular hypertension, and 15 normotensive subjects. The preinfusion plasma concentration of ANP was significantly higher in patients with renal parenchymal hypertension (120 pg/ml, p less than 0.01) and in patients with primary aldosteronism (98 pg/ml, p less than 0.05) than in the normotensive subjects (40 pg/ml), but it was not greater than in the patients with renovascular hypertension (73 pg/ml, NS). In the patients with renal parenchymal hypertension, plasma ANP correlated negatively with creatinine clearance (r = -0.76, p less than 0.001). Mean blood pressure (-5%, p less than 0.01) and plasma aldosterone (-40%, p less than 0.001) decreased to a similar degree in the four groups during ANP infusion. However, an increase in urinary sodium excretion caused by ANP was higher in the hypertensive than in the normotensive patients (+250% vs. +70%, p less than 0.01) and correlated positively with mean blood pressure during ANP infusion (r = 0.47, p less than 0.001). The removal of adenomas in the patients with primary aldosteronism significantly lowered both plasma levels of ANP and cyclic guanosine 2',3'-monophosphate and reduced an increase in sodium excretion during ANP infusion, whereas the responses of blood pressure and plasma aldosterone to ANP infusion were not altered by the operation. Thus, these results suggest that elevated ANP secretion and increased natriuretic responses to ANP may modify the blood pressure and body fluid volume status in some types of secondary hypertension.

Topics: Adrenal Gland Neoplasms; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Hormones; Humans; Hyperaldosteronism; Hypertension, Renal; Hypertension, Renovascular; Kidney; Osmolar Concentration; Postoperative Period; Reference Values; Renin

1. The haemodynamic and renal effects of short-term infusion of human atrial natriuretic peptide (ANP) (1-28) were examined in sheep treated with ACTH and compared with the responses previously observed in normotensive sheep. 2. Infusion of ANP at 100 micrograms/h for 60 min in ACTH-treated sheep (5 micrograms/kg per day for 5 days) decreased blood pressure and produced a fall in both cardiac output and stroke volume. No changes were seen in heart rate and total peripheral resistance. 3. ANP produced large increases in urine volume, urinary sodium and chloride excretion, and further decreased plasma potassium concentration in the ACTH-treated sheep. Compared with normal sheep studied previously under the same conditions, the ACTH-treated sheep showed a much greater diuretic and natriuretic response to ANP, although the blood pressure response to ANP was similar in both states. 4. The change in renal responsiveness to ANP in sheep may be related to the increased blood volume of the ACTH-treated animals because volume expansion is known to enhance the renal effects of ANP.

Topics: Adrenocorticotropic Hormone; Animals; Atrial Natriuretic Factor; Blood Volume; Chlorine; Hemodynamics; Humans; Hypertension, Renal; Kidney; Peptide Fragments; Sheep; Sodium

In 14 patients with arterial hypertension secondary to chronic renal parenchymal disease and impaired renal function, 24-h ambulatory and casual blood pressure readings plasma, angiotensin II, aldosterone, arginine vasopressin and atrial natriuretic peptide, creatinine clearance, plasma lipids and lipoproteins, and body weight were determined after consecutive 3-week periods on placebo and sustained release verapamil 240 mg/day. Verapamil reduced the mean 24-h ambulatory blood pressure from 152/104 to 142/97 mm Hg. Blood pressure was significantly reduced during the daytime and the evening, but not at night. Casual blood pressure was also significantly reduced from 176/106 mm Hg to 154/96 mm Hg. No significant changes were found in the hormones, creatinine clearance, plasma lipids and lipoproteins, heart rate or body weight. The atrial natriuretic peptide level was significantly correlated with the calculated creatinine clearance (r = -0.797). Thus, sustained release verapamil 240 mg as a single daily dose had a moderate hypotensive effect in patients with chronic renal disease without inducing tachycardia, activation of the renin-angiotensin-aldosterone system, or increasing body weight, and without altering renal function and plasma lipids and lipoproteins. The negative correlation between atrial natriuretic peptide and glomerular filtration rate supports the hypothesis that the extracellular volume increases during progression of renal disease.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Delayed-Action Preparations; Female; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Verapamil

Plasma levels of immunoreactive atrial natriuretic factor (IR-ANF) were evaluated by radioimmunoassay in several models of experimental hypertension and in human hypertension. Plasma levels of IR-ANF are consistently increased in all models of experimental hypertension studied so far. This is accompanied by a decrease of IR-ANF levels in the left atrium at certain times. Plasma levels of IR-ANF are not increased in human essential hypertension, except in the severe form (diastolic blood pressure above 110 mmHg). Peripheral levels of IR-ANF in renovascular hypertension do not differ from normal but are increased above normal in aortic blood.

Topics: Animals; Atrial Natriuretic Factor; Female; Heart Atria; Heart Ventricles; Humans; Hypertension; Hypertension, Renal; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

Autosomal dominant polycystic kidney disease (ADPKD) has been shown to be associated with a greater than 50 percent incidence of hypertension prior to deterioration in renal function as assessed by glomerular filtration rate. The present study provides evidence for increased cardiac pre-load, as assessed by plasma atrial natriuretic factor (ANF) and cardiac index, in hypertensive as compared to normotensive ADPKD. The hypertensive ADPKD patients exhibited an increased renal vascular resistance as compared to the normotensive patients in spite of comparable glomerular filtration rates. It is hypothesized that the renal involvement of hypertensive ADPKD patients causes an impaired renal response to the observed increase in cardiac index, and also may release a venoconstrictor (such as angiotensin) which contributes to the enhanced cardiac pre-load and thus the hypertension.

Topics: Adult; Atrial Natriuretic Factor; Cardiac Output; Female; Genes, Dominant; Humans; Hypertension, Renal; Male; Middle Aged; Natriuresis; Plasma Volume; Polycystic Kidney Diseases; Renin-Angiotensin System; Sodium, Dietary

The plasma concentration of the immunoreactive (IR) human atrial natriuretic factor (hANF) was measured in 17 patients with primary IgA nephropathy (IgAN) (9 normotensive and 8 hypertensive subjects without impairment of renal function). Furthermore, correlations with the renin-angiotensin II-aldosterone system and hemodynamic alterations were studied. The mean value of IR-hANF was significantly (p less than 0.002) higher in normotensive IgAN patients (68.2 +/- 14.6 pg/ml) than in controls (48.8 +/- 11.5 pg/ml), while it was slightly and not significantly elevated in hypertensive IgAN patients (58.5 +/- 8.4 pg/ml). In the latter the mean plasma renin activity (PRA) was significantly increased (0.92 +/- 0.30 ng/ml/h; p less than 0.002), while in normotensive IgAN patients (0.68 +/- 0.58 ng/ml/h) no difference was observed. Plasma aldosterone levels showed the same behavior pattern as those of PRA. Hemodynamic studies showed that the mean values of the cardiac index (CI) were significantly (p less than 0.002) high in both normotensive (3.55 +/- 0.5 l/min/m2) and hypertensive (3.32 +/- 0.47 l/min/m2) patients, while a significant reduction in the total peripheral resistance index (TPRI) in normotensive (2171 +/- 349 dyn/s/cm-5/m2; p less than 0.02) and a significant increase in hypertensive (2959 +/- 440 dyn/s/cm-5/m2; p less than 0.05) patients were observed. The mean arterial pressure (MAP) had a positive correlation with the TPRI and an inverse correlation with the IR-hANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Female; Glomerulonephritis, IGA; Hemodynamics; Humans; Hypertension, Renal; Male; Radioimmunoassay; Renin-Angiotensin System

The hemodynamic responses to i.v. infusion of 0.3 and 0.6 microgram/kg per min of human atrial natriuretic factor (hANF [102-126]) in intact, conscious, one-kidney, perinephritic, hypertensive beagles were examined and compared with the responses in ganglionic-blocked dogs. Blood pressure and heart rate were not affected but plasma ANF-like immunoreactivity was increased by as much as 627%. After hexamethonium (20 mg/kg, i.v.) blockade, a dose-dependent hypotensive response of up to 29 mmHg with no change in heart rate was observed. It is concluded that the compensatory mechanisms of the neurally mediated baroreflex system masked the depressor actions of hANF.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Dogs; Hemodynamics; Hexamethonium; Hexamethonium Compounds; Hypertension, Renal; Male

We have compared atrial and plasma concentration of atrial natriuretic factor (ANF) in 4 models of non spontaneous experimental hypertension with different pathogenic mechanisms in the rat: two-kidney, one-clip (2-K, 1-C), one-kidney, one-clip (1-K, 1-C), DOCA-NaCl and adrenal regeneration hypertension (ARH) and their respective normotensive controls. All hypertensive groups developed cardiac hypertrophy. In all hypertensive groups plasma ANF was higher than in controls. Atrial ANF concentration was lower in the right and left atrium of 1-K, 1-C rats and in the left atrium of ARH. A good correlation was found between systolic BP and plasma ANF in 2-K, 1-C (r = 0.82; p less than 0.01) and 1-K, 1-C animals (r = 0.70; p less than 0.01). This correlation was less good in DOCA-NaCl (r = 0.41; p less than 0.05) and non existent in ARH (r = 0.28; NS). A negative correlation between plasma ANF and atrial ANF concentrations was found only in the 1-K, 1-C group (r = 0.41; p less than 0.05). A good correlation between plasma ANF levels and cardiac weight was found in all groups: 2-K, 1-C (r = 0.83; p less than 0.01), 1-K, 1-C (r = 0.73; p less than 0.01), DOCA-NaCl (r = 0.69; p less than 0.01) and ARH (r = 0.71; p less than 0.01). We suggest that the release of ANF in experimental hypertension depends of the pathogenesis and could be related either to the level of BP (hence the magnitude of the left ventricular end-diastolic pressure) or to the existence of an expanded blood volume. The correlation between plasma ANF levels and cardiac hypertrophy suggests that ANF could be partially released by the ventricles.

Topics: Adrenal Glands; Animals; Atrial Natriuretic Factor; Cardiomegaly; Desoxycorticosterone; Hypertension; Hypertension, Renal; Male; Nephrectomy; Rats; Rats, Inbred Strains; Regeneration; Sodium Chloride

The relationship between ANF activity and hypertension was determined by measuring ANF atrial content and vascular reactivity in two different models: spontaneous hypertensive rats (SHR) and renal hypertensive rats (RHR). Atrial extracts and aortic strips were prepared from hypertensive and normotensive animals. Relaxant activities of extracts, synthetic ANF and nitroglycerin were assayed on superfused aortic strips previously contracted by norepinephrine. ANF atrial content was statistically significantly lower in both models of hypertension, presumably by increased ANF release into the circulation which results in depletion of tissue storage sites. Vascular subsensitivity to ANF and nitroglycerin was found in both models of hypertension. Diminished ANF vascular reactivity in hypertension could be due to receptor down-regulation and/or to a decrease in the ability of cGMP to induce relaxation.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Female; Heart; Hypertension, Renal; In Vitro Techniques; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Tissue Extracts

Atrial natriuretic peptide (ANP), besides its diuretic and antihypertensive effects, exhibits an "in vitro" inhibitory action on aldosterone. In order to elucidate if these effects are present also "in vivo", we injected 100 micrograms of alpha-human ANP as a bolus in normal volunteers, low renin essential hypertensive subjects (LRH) and in patients with primary aldosteronism (PA). A transient hypotensive effect was seen in all patients, without significant variations of heart rate. The diuretic and saluretic effects of ANP were greater in hypertensive subjects, even in PA where endogenous ANP levels are known to be elevated. Plasma aldosterone values decreased significantly only in normal volunteers. In conclusion, in LRH and PA renal effects of ANP are not diminished, although its aldosterone-inhibiting properties are less evident than in normals.

Topics: Adolescent; Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Diuresis; Humans; Hyperaldosteronism; Hypertension, Renal; Middle Aged; Natriuresis; Renin

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