atrial-natriuretic-factor and Cardiac-Output--Low

Body fluid volume regulation by the kidney relies upon the complex interaction of numerous factors. However, in edematous disorders, extrarenal factors can override the 'innate wisdom' of the kidney. For example, in patients with cardiac failure or liver disease and in pregnant women, the normal kidney continues to retain sodium and water despite expanded blood, plasma and extracellular fluid volumes. Such fluid retention can ultimately lead to pulmonary congestion, ascites or peripheral edema. Understanding the kidney's modulation of total body sodium and water in these patients has been perplexing. Cardiac output cannot provide the sole afferent signal for the kidney to regulate sodium and water balance, as the normal kidney can retain excessive amounts of sodium and water when cardiac output is low (e.g. in low output cardiac failure) or high (e.g. cirrhosis or pregnancy). Therefore the integrity of the arterial circulation, which can be impaired either by a low cardiac output or arterial vasodilation, is an important factor in body fluid composition and volume regulation in health and disease.

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Edema; Female; Humans; Kidney; Myocardial Infarction; Pregnancy; Sodium

The atrial natriuretic peptide (ANP) plays an important role in chronic heart failure (CHF), delaying the progression of the disease. However, despite high ANP levels, natriuresis falls when CHF progresses from a compensated to a decompensated state, suggesting emergence of renal resistance to ANP. Several mechanisms have been proposed to explain renal hyporesponsiveness, including decreased renal ANP availability, down-regulation of natriuretic peptide receptors and altered ANP intracellular transduction signal. It has been demonstrated that the activity of neutral endopeptidase (NEP) is increased in CHF, and that its inhibition enhances renal cGMP production and renal sodium excretion. In vitro as well as in vivo studies have provided strong evidence of an increased degradation of intracellular cGMP by phosphodiesterase in CHF. In experimental models, ANP-dependent natriuresis is improved by phosphodiesterase inhibitors, which may arise as new therapeutic agents in CHF. Sodium-retaining systems likely contribute to renal hyporesponsiveness to ANP through different mechanisms. Among these systems, the renin-angiotensin-aldosterone system has received particular attention, as angiotensin II and ANP have renal actions at the same sites and inhibition of angiotensin-converting enzyme and angiotensin-receptor blockade improve ANP hyporesponsiveness. Less is known about the interactions between the sympathetic nervous system, endothelin or vasopressin and ANP, which may also blunt ANP-induced natriuresis. To summarize, renal hyporesponsiveness to ANP is probably multifactorial. New treatments designed to restore renal ANP efficiency should limit sodium retention in CHF patients and thus delay the progression to overt heart failure.

Topics: Arginine Vasopressin; Atrial Natriuretic Factor; Biological Availability; Cardiac Output, Low; Chronic Disease; Guanylate Cyclase; Humans; Kidney; Renin-Angiotensin System; Signal Transduction; Sympathetic Nervous System; Vasoconstriction

To describe the potential utility of a true surrogate marker of heart failure outcomes, historically investigate the validity of surrogates most commonly evaluated in heart failure, and identify specific end points offering the most potential for future use.. A MEDLINE search (1966-June 2001) was completed to identify relevant literature. Additional references were also retrieved from selected articles. Search terms included b-type natriuretic peptide, cardiac remodeling, end-diastolic volume, heart failure, and surrogate end points.. By definition, true surrogate end points must predict outcomes associated with disease progression and response to therapy. A validated surrogate measure of mortality would render significant utility in both heart failure drug development and clinical practice. Improvements in traditional functional markers of heart failure, including ejection fraction and exercise capacity, have produced inconsistent results in regard to mortality in a number of clinical trials. Numerous measures of cardiac remodeling and neurohormonal activation, however, have proven to be reliable predictors of disease progression and therapeutic response. These findings have contributed significantly to the current understanding of heart failure pathophysiology and approach to treatment. Specifically, measures such as left-ventricular end-diastolic volume (LVEDV) and, potentially, b-type natriuretic peptide (BNP) concentrations may correlate with disease progression and parallel the mortality reductions observed with angiotensin-converting enzyme inhibitor and beta-blocker therapy.. Currently, LVEDV and plasma BNP offer the greatest potential as surrogate end points in heart failure. Further investigation of these measures is required before routine implementation in drug development and clinical practice can be justified.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Humans; Natriuretic Peptide, Brain; Neurotransmitter Agents; Predictive Value of Tests; Stroke Volume; Ventricular Remodeling

Natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide, are key regulators in the homeostasis of salt and water excretion and in the maintenance of blood pressure. During heart failure, these peptides are highly activated because of volume overload and increased myocardial wall tension. Among all natriuretic peptides and neurohormones, brain natriuretic peptide and its N-terminal prohormone fragment have been shown to be the best markers to identify patients with heart failure. They are useful prognostic markers as well. The stability of brain natriuretic peptides and N-terminal prohormones in ethylene-diamine-tetraacetic-acid whole blood is sufficient for routine use. Sensitive and specific assays without the need for plasma extraction are commercially available. The available data indicate that natriuretic peptides are powerful diagnostic and prognostic markers in heart failure patients. First data on treatment guidance are promising.

Topics: Aged; Anticoagulants; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Drug Stability; Edetic Acid; Female; Humans; Male; Natriuretic Peptide, Brain; Prognosis; Sensitivity and Specificity

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Diastole; Endothelins; Hormones; Humans; Myocardial Stunning; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Topics: Ambulatory Care; Atrial Natriuretic Factor; Cardiac Output, Low; Community Health Services; Costs and Cost Analysis; Echocardiography; Hospitalization; Humans; Nursing Care

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Central Nervous System; Dogs; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Rats; Renin; Renin-Angiotensin System; Sheep

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cyclic GMP; Humans; Kidney; Neprilysin; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Heart Defects, Congenital; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Myocardium; Respiratory Distress Syndrome, Newborn

Renal dysfunction is an important independent prognostic factor in heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony, but the impact of CRT on renal function is less defined. We hypothesized that CRT would improve glomerular filtration rate as estimated by the abbreviated Modification of Diet in Renal Disease equation (eGFR).. The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study evaluated CRT in HF patients with NYHA Class III-IV, ejection fraction or=130 ms. Patients were evaluated before and 6 months after randomization to control (n = 225) or CRT (n = 228). Patients were categorized according to their baseline eGFR: >or=90 (category A), 60

Topics: Atrial Natriuretic Factor; Blood Urea Nitrogen; Cardiac Output, Low; Cardiac Pacing, Artificial; Creatinine; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Hematocrit; Hemoglobins; Humans; Kidney; Kidney Diseases; Male; Natriuretic Peptide, Brain; Placebos; Retrospective Studies; Treatment Outcome; Ventricular Function, Left

Oxidative stress plays an important role in the pathogenesis of heart failure and was investigated in the present study of the role of exogenous A-type natriuretic peptide (ANP) in the patients with heart failure and in cultured neonatal rat cardiomyocytes.. The first protocol was to examine if an infusion of human ANP (carperitide) changed serum levels of TRX (thioredoxin) during the treatment of patients with heart failure compared with conventional therapy using furosemide. Protocol 2 investigated whether ANP had a direct antioxidant action on the failing heart by measuring TRX gene expression and reactive oxygen species (ROS) production in cultured neonatal rat cardiomyocytes. In Protocol 1, 8 patients were treated with only an intravenous bolus of furosemide and 11 patients with only an intravenous infusion of carperitide for 24 h. Serum TRX levels significantly decreased at 4 h (p<0.03) and at 24 h (p<0.05) in the carperitide group, whereas they decreased slightly but were not significantly different in the furosemide group. In Protocol 2, it was found that a low dose of exogenous ANP of 10(-9) mol/L significantly suppressed TRX expression and ROS production in cardiomyocytes.. Carperitide infusion has a predominantly antioxidant action, in addition to improving the hemodynamics of patients with acute heart failure. Furthermore, carperitide infusion should have a direct antioxidant effect on the failing heart.

Topics: Aged; Animals; Antioxidants; Atrial Natriuretic Factor; Cardiac Output, Low; Cells, Cultured; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Gene Expression Regulation; Humans; Male; Middle Aged; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Thioredoxins

Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ET(A)/ET(B) receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment ( P <0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Bosentan; Cardiac Output; Cardiac Output, Low; Cardiac Pacing, Artificial; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Female; Infusions, Parenteral; Losartan; Natriuretic Peptide, Brain; Renin; Sheep; Sulfonamides

The prevalence of chronic heart failure (CHF) with systolic dysfunction is increasing. Plasma natriuretic peptides have been envisaged as diagnostic and predictive markers.. To investigate the relationship between the levels of B-type natriuretic peptide (BNP) and A-type natriuretic peptide (ANP) and the clinical and functional parameters of CHF in outpatients with CHF at baseline, compared with normal healthy controls; to find out the differences in a randomised controlled trial between patients treated with an angiotensin-converting enzyme (ACE) inhibitor, captopril, or an angiotensin receptor blocker (ARB), irbesartan. These differences were assessed throughout the six-month treatment period and at the sixth month.. Plasma BNP (pmol/L) and ANP (pmol/L) were determined in 68 hypertensive patients with dilated cardiomyopathy, NYHA class III-IV and ejection fraction (EF) < or = 40%, and in 26 normal controls. Statistical analysis for BNP and ANP was done by Students t-test. The patient group was randomly subdivided into two subgroups of 34 patients, each treated with either an ARB, irbesartan, or an ACE inhibitor (ACE-I), captopril. BNP and ANP were measured in both subsamples and correlated with clinical, functional and neurohormonal parameters throughout a follow-up period of six months and at the sixth month.. The mean EF in the patient sample was 33.43+/-6.52% and in the controls was 61.96 +/-3.53% (p=0.000). The mean BNP (pmol/L) in patients was 44.78+/-54.36 and in the controls was 7.12+/-8.28 (p=0.000) and the mean ANP (pmol/L) was 30.32+/-25.97 in patients and 11.18+/-7.92 in controls (p=0.000). A statistically significant difference was found between patients and healthy controls. Significant correlations were found between natriuretic peptides and EF. Between the baseline phase and the sixth month, BNP and ANP decreased significantly in the ARB group. At the sixth month, both BNP and ANP were lower in the ARB group. Evidence of clinical benefit was found with both ARB or ACE-I treatment throughout the six months, with patients moving from classes III and IV to class II NYHA. Improvement of EF was also found, with transition of patients with lower EF (even <30%) to higher values. EF was higher in the ARB group at the sixth month.. BNP and ANP can be useful diagnostic tools in hypertensive CHF patients with moderate-to-severe LV dysfunction. The decrease in BNP and ANP in the ARB group throughout six months, as well as the lower value at the sixth month, suggest a prognostic value of these parameters.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Biphenyl Compounds; Captopril; Cardiac Output, Low; Chronic Disease; Echocardiography; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Humans; Irbesartan; Male; Middle Aged; Natriuretic Peptide, Brain; Predictive Value of Tests; Radiography, Thoracic; Radionuclide Ventriculography; Tetrazoles; Ventricular Dysfunction, Left

To determine whether the plasma concentration of the putative new cardiac hormone relaxin is predictive of clinical outcome in patients with chronic heart failure (CHF).. Plasma relaxin and N-terminal pro B type natriuretic peptide (NT pro BNP) concentrations were measured in 87 patients admitted in an emergency with CHF caused by left ventricular systolic dysfunction. These were related to death and death or readmission with CHF over the following year.. Western Infirmary, Glasgow, UK.. Plasma concentrations of relaxin and NT pro BNP; time to death or hospitalisation caused by heart failure.. Plasma concentrations of both relaxin and NT pro BNP were greatly increased. Of the 43 patients with NT pro BNP above the group median concentration, 23 (53%) died and 30 (70%) died or were hospitalised with CHF. Among the 44 with concentrations below the median, these numbers were 5 (11%) and 12 (27%), respectively (p < 0.0001 and p < 0.0001, respectively). Plasma NT pro BNP concentration remained an independent predictor of an adverse clinical outcome in a multivariate analysis. Of the 42 patients with a relaxin concentration above the median, 13 (31%) died and 20 (48%) died or were hospitalised. Below the median, these numbers were 15 of 45 (33%) and 22 of 45 (49%) (p = 0.76 and p = 0.84, respectively).. NT pro BNP is a powerful and independent predictor of outcome in CHF, whereas relaxin, also secreted by the heart in increased amounts in CHF, is not.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Chronic Disease; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Predictive Value of Tests; Prognosis; Relaxin; Survival Analysis

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 +/- 0.03 (mean +/- SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits a natriuresis. In HF, WI suppressed ANG II and aldosterone (Aldo) concentrations, increased the release of atrial natriuretic peptide (ANP), and elicited a natriuresis (P < 0.05 for all) compared with seated control. Compared with control subjects (n = 9), ANG II, Aldo, and ANP concentrations were increased (P < 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 +/- 16 vs. 88 +/- 15 micromol/min and 0.42 +/- 0.18 vs. 0.68 +/- 0.12% (mean +/- SE), respectively, both P < 0.05]. When ANG II and Aldo concentrations were further suppressed (P < 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P < 0.05) to the level of control subjects (108 +/- 34 micromol/min and 0.70 +/- 0.23%, respectively). Renal free water clearance increased during WI in control subjects but not in HF, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast, renal free water clearance is attenuated in response to volume expansion in compensated HF despite normalized plasma AVP concentrations.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cardiac Output, Low; Enzyme Inhibitors; Fluid Shifts; Glomerular Filtration Rate; Heart Rate; Humans; Immersion; Kidney; Male; Middle Aged; Natriuresis; Sodium; Urine; Vasopressins; Water-Electrolyte Balance

The purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects.. Fifteen men (age 39+/-2 years [mean+/-SE]) with dilated cardiomyopathy (ejection fraction 18+/-3%) received intravenous ANP (50 microgram bolus, then 50 ng. kg-1. min-1) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at -6 and -12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at -6 mm Hg lowered CVP (P<0.05), whereas LBNP at -12 mm Hg caused significant reductions in CVP, systolic BP, and diastolic BP. These effects of nonhypotensive and hypotensive LBNP on CVP and BP were similar during ANP and NTG infusions, yet MSNA was lower both before and with LBNP during ANP (P<0.02). Nonhypotensive LBNP increased MSNA during NTG (+133+/-68 Units; P<0.001) but not during ANP infusion (+24+/-23 Units; P=NS).. These observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP.

Topics: Adult; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiomyopathy, Dilated; Hemodynamics; Humans; Lower Body Negative Pressure; Male; Middle Aged; Muscle, Skeletal; Nitroglycerin; Reflex; Sympathetic Nervous System

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are both circulating plasma hormones that are secreted by the heart and have similar physiological effects. We have shown previously that abrupt increases in plasma BNP in normal humans impair the clearance of ANP from plasma and result in additive physiological effects. Because large increases in plasma ANP are reported to have no effect on plasma BNP levels in patients with heart failure, we have studied ANP-BNP interactions in eight normal male subjects receiving background infusions of BNP (2 pmol.kg-1.min-1 for 5 h). Each subject also received a coinfusion of ANP ("active" day, 2 pmol.kg-1.min-1 for 2 h) or vehicle ("placebo" day) using a balanced random order, single-blind design. Metabolic clearance rate of ANP (mean 4.1 +/- 0.6 l/min) and disappearance rate from the plasma (t1/2 3.4 +/- 0.3 min) were similar to values measured previously in the absence of exogenous BNP. In contrast, steady-state plasma BNP levels were reversibly increased (mean BNP increment 10 pmol/l) during the administration of ANP (P = 0.038). Associated with these changes were significant (additive) physiological effects. Thus the addition of ANP increased plasma and urine guanosine 3',5'-cyclic monophosphate (P < 0.001 for both) and lowered systolic blood pressure (P = 0.049). When ANP was coinfused, significant differences were also observed in urine volume (P = 0.001) and sodium excretion (P = 0.043) between the infusion period (when urine volume and sodium excretion were enhanced) and postinfusion period (when values decreased). Taken together, our findings of similar interactions between ANP-BNP and BNP-ANP infusions occurring at pathophysiological concentrations of these two peptides, suggest that the interactions result from dissociation of prebound hormone, presumably from biological or clearance receptors.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclic GMP; Hormones; Humans; Infusions, Intravenous; Male; Natriuresis; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Osmolar Concentration; Reference Values; Urine

C-type natriuretic peptide (CNP) is a newly identified peptide that is structurally related to atrial natriuretic peptide (ANP). Although it has been suggested that CNP is released from the endothelium for the regulation of local vascular tone, no data are available concerning the vasodilatory response to CNP in humans.. Strain-gauge plethysmography was used to determine the vasodilatory effects of intra-arterially infused CNP compared with the effects of ANP infusion in 11 patients with chronic heart failure (CHF) and 11 age-matched healthy controls. Graded doses of CNP and ANP (8, 16, 32, and 48 pmol.min-1.dL-1 tissue volume) were administered randomly into the nondominant brachial artery, and forearm blood flow (FBF) was measured. No significant changes in systemic blood pressure and heart rate were found during the study. Both the absolute and percent FBF responses to ANP relative to the baseline value were significantly lower in CHF patients than in healthy controls (P < .01), whereas the responses to CNP were similar. The calculated forearm spillover of cyclic GMP (cGMP) was significantly lower in CHF patients receiving the highest dose of ANP (P < .02), whereas changes in cGMP spillover after the equimolar dose of CNP were significantly higher (P < .02), despite the lesser potency of CNP.. In patients with CHF the peripheral vasodilatory effect of ANP is attenuated, but CNP-induced peripheral vasorelaxation is preserved, with CNP being less potent for equimolar doses.

Topics: Atrial Natriuretic Factor; Blood Vessels; Cardiac Output, Low; Chronic Disease; Cyclic GMP; Female; Forearm; Humans; Injections, Intra-Arterial; Male; Middle Aged; Natriuretic Peptide, C-Type; Plethysmography; Proteins; Regional Blood Flow; Vascular Resistance; Vasodilation

This study was conducted to evaluate the degree of neurohumoral activation around the time of hospital discharge after myocardial infarction.. Because pharmacologic interventions that block the effects of neurohumoral activation improve the prognosis after infarction, we hypothesized that widespread neurohumoral activation persists in some patients until at least the time of hospital discharge and that the determinants of activation vary from one system to another.. Five hundred nineteen patients in the Survival and Ventricular Enlargement Study (SAVE) had plasma neurohormones measured before randomization at a mean of 12 days after infarction. All patients had left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt heart failure.. Although all neurohormones except epinephrine were increased compared with values in age-matched control subjects, plasma norepinephrine (301 +/- 193 vs. 222 +/- 87 pg/ml, p < 0.001), renin activity (3.0 +/- 3.7 vs. 1.2 +/- 1.2 ng/ml per h, p < 0.001), arginine vasopressin (1.9 +/- 6.9 vs. 0.7 +/- 0.3 pg/ml, p < 0.001) and atrial natriuretic peptide (75 +/- 75 vs. 21 +/- 9 pg/ml, p < 0.001) values ranged from normal to very high, indicating a wide spectrum of neurohumoral activation. Activation of one system did not correlate with activation of another. The clinical and laboratory variables most closely associated with neurohumoral activation were Killip class, left ventricular ejection fraction, age and use of diuretic drugs. The association between neurohumoral activation and clinical and laboratory variables varied from one neurohormone to another.. Neurohumoral activation occurs in a significant proportion of patients at the time of hospital discharge after infarction. Which neurohormone is activated and which clinical and laboratory variables determine this activation vary from one neurohormone to another.

Topics: Aged; Aldosterone; Atrial Natriuretic Factor; Cardiac Output, Low; Dopamine; Female; Humans; Male; Middle Aged; Myocardial Infarction; Neurotransmitter Agents; Norepinephrine; Renin; Stroke Volume; Vasopressins; Ventricular Function, Left

Seven patients with chronic heart failure were treated in single-blind crossover fashion with placebo and 10 mg, 50 mg, and 200 mg doses of the neutral endopeptidase inhibitor candoxatril to determine the effects of candoxatril on the elimination kinetics of exogenously infused atrial natriuretic peptide (ANP). An incremental dose-response effect was observed on the mean maximum observed plasma concentration (Cmax) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled active versus placebo comparisons showed that candoxatril reduced the clearance (p = 0.021) and elimination rate constant (p = 0.006) and increased Cmax (p = 0.002) and time to reach Cmax (p = 0.01) of exogenous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP. The most favorable effects were observed in response to 200 mg candoxatril, although even this dose may not have achieved the maximal modulating effect on elimination of circulating ANP.

Topics: Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Dose-Response Relationship, Drug; Heart Rate; Humans; Indans; Infusions, Intravenous; Male; Middle Aged; Prodrugs; Propionates; Single-Blind Method

A study was undertaken to examine the effects of the angiotensin-converting enzyme inhibitor lisinopril on exercise performance in 18 patients with major impairment of left ventricular systolic function. The study was a randomized, double-blind, crossover design, and patients received treatment with either once-daily lisinopril (2.5-10 mg) or placebo for a period of 6 weeks. A total of 15 patients completed the study. Compared with placebo, lisinopril had no significant effect on supine or standing blood pressure or heart rate. Although lisinopril had no effect on exercise duration during a low-intensity exercise protocol, in patients undergoing a high-intensity exercise protocol, there was a trend toward improved exercise time and peak oxygen consumption improved significantly. In addition, treatment with lisinopril resulted in an increase in renal blood flow and a reduction in glomerular filtration rate. Moreover, administration of once-daily lisinopril 10 mg resulted in a decrease in plasma concentrations of angiotensin II, aldosterone, and atrial natriuretic peptide, and an increase in plasma concentrations of active renin.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Dipeptides; Double-Blind Method; Exercise Test; Glomerular Filtration Rate; Humans; Lisinopril; Male; Middle Aged; Oxygen Consumption; Placebos; Renal Circulation; Stroke Volume; Ventricular Function, Left

+/- Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.. This was a single blind, randomised comparison of +/- candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of +/- candoxatrilat and two placebo doses on four consecutive days.. A teaching hospital department of cardiology.. Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37.5% and mean peak oxygen consumption was 20.4 ml/min/kg.. Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after +/- candoxatrilat and placebo.. +/- Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0.005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6.7 to 4.7 mmHg (NS) and pulmonary artery wedge pressure fell from 9.2 to 6.7 mmHg (p < 0.05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39.5 to 34.2 cm/s (p < 0.05), along with a non-significant rise in peak atrial filling velocity from 39.7-41.6 cm/s after +/- candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1.04 to 0.87 (p < 0.05).. +/- Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclohexanecarboxylic Acids; Heart Rate; Humans; Male; Middle Aged; Neprilysin; Pulmonary Wedge Pressure; Random Allocation; Single-Blind Method; Ventricular Function, Left

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double-blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run-in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l-1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l-1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atrial Natriuretic Factor; Captopril; Cardiac Output, Low; Double-Blind Method; Female; Follow-Up Studies; Gait; Humans; Male; Oxygen Consumption; Physical Exertion; Walking

This study reports the effects of the new beta 1 adrenoceptor partial agonist, xamoterol, on neuroendocrine activity after acute myocardial infarction (AMI). Fifty-one consecutive patients with AMI were randomized to treatment with xamoterol, 200 mg twice a day, or placebo; patients were also stratified as to whether or not diuretic therapy was given for left ventricular dysfunction. Noradrenaline, plasma renin activity (PRA), and atrial natriuretic factor (ANF) were measured over a 10-day period. Noradrenaline concentrations are higher (p less than 0.05) in patients treated with diuretics at the time of admission and fell over the subsequent 10 days (p less than 0.01). Treatment with xamoterol did not affect this noradrenaline response to myocardial infarction. PRA was also significantly higher in the patients treated with diuretics, and there was a nonsignificant trend for xamoterol to blunt the PRA response in these patients. There was no difference in ANF levels between those patients who were treated with diuretics and those who were not; xamoterol did not affect ANF. Thus xamoterol does not further elevate noradrenaline levels as do conventional beta blockers, and it does not activate the renin-angiotensin system as do potent nonselective beta agonists. Furthermore, xamoterol does not increase ANF levels, probably because it is not negatively inotropic. We conclude that xamoterol does not cause deleterious neuroendocrine changes in patients with AMI even in those treated for heart failure.

Topics: Adrenergic beta-Agonists; Adult; Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Female; Humans; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Propanolamines; Randomized Controlled Trials as Topic; Renin; Xamoterol

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Carbamates; Cardiac Output, Low; Chronic Disease; Cyclohexanecarboxylic Acids; Diuresis; Dose-Response Relationship, Drug; Hemodynamics; Humans; Kidney; Male; Middle Aged; Natriuresis; Neprilysin; Propionates; Pulmonary Wedge Pressure; Renin; Sodium

Timely diagnosis, early introduction of appropriate treatment, accurate risk stratification, and optimal titration of therapy are all key to the management of acute and chronic heart failure (HF). Plasma concentrations of the cardiac natriuretic peptides (NPs) are valuable aids in each of these elements of care. However, most data are derived from cohorts with undifferentiated HF or HF with reduced ejection fraction (HFREF), and the performance and best application of NPs in HF with preserved ejection fraction (HFPEF) is less certain. This review outlines the evidence for use of NPs in the evaluation and management of HFPEF.

Topics: Acute Disease; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Case-Control Studies; Chronic Disease; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Reference Values; Sensitivity and Specificity; Stroke Volume; Syndrome

A 64-year-old man presented with chief complaints of exertional dyspnea and palpitation. He had previously undergone left nephrolithotomies twice. A chest roentgenogram showed pleural effusion on both sides with cardiac dilation, and electrocardiography showed a frequent occurrence of ventricular premature contractions. An echocardiogram showed diffuse hypokinesis of the left ventricular wall motion (ejection fraction, 45%) and dilation of the left ventricle (left ventricular end-diastolic dimension, 61 mm). We administered diuretics, ACE inhibitors and a beta-adrenergic blocking agent after making a diagnosis of cardiac insufficiency. Because coronary angiography showed 90% stenosis of the left anterior descending coronary artery (No. 7), we performed coronary angioplasty in this locus. Though both the left ventricular wall motion and ejection fraction improved, and the clinical symptoms disappeared, the left ventricular end-diastolic dimension, and arrhythmia did not improve. Furthermore, the brain natriuretic peptide increased despite these treatments. Thereafter, a left renal artery aneurysm (extrarenal aneurysm measuring 5 cm in diameter and an intrarenal aneurysm measuring 3 cm in diameter) and a left renal arteriovenous fistula were discovered when abdominal echography was performed because of epigastric discomfort. As a result, a left total nephrectomy was performed. Subsequently, the left ventricular end-diastolic dimension and arrhythmia improved, and the brain natriuretic peptide returned to a normal value. We herein report a case that developed cardiac insufficiency due to a renal aneurysm and renal arteriovenous fistula after undergoing left nephrolithotomies twice.

Topics: Aged; Aneurysm; Arteriovenous Fistula; Atrial Natriuretic Factor; Cardiac Output, Low; Humans; Kidney; Kidney Diseases; Male; Natriuretic Peptide, Brain; Renal Artery

As indicated in ancient Chinese medical books, Corydalis yanhusuo has therapeutic effects on cardiovascular diseases. The analgesic effect of this plant has been fully elucidated, and l-tetrahydropalmatine has been shown to be the main active principle. The aim of this investigation was to evaluate its protective effects in a rat heart failure model. Rats were subjected to coronary artery ligation, and orally administered with ethanolic extract of Corydalis yanhusuo 50, 100, or 200 mg kg(-1) daily, from the 7th day after surgery. We measured cardiac function, plasma atrial natriuretic peptide (ANP), relative heart and lung weights, infarct size and ventricular dilatation after treatment for 8 weeks. Administration with Corydalis yanhusuo led to a significant reduction in infarct size and improvement in cardiac function as demonstrated by lower left ventricular end diastolic pressure (LVEDP) and elevated +/-dp/dt(max). We also found that Corydalis yanhusuo significantly reduced left ventricular (LV)/body weight ratio, lung/body weight ratio and significantly inhibited neurohormonal activation. Taken together, this study indicated that Corydalis yanhusuo exerted salutary effects on heart failure induced by myocardial infarction in rats.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cardiotonic Agents; Coronary Vessels; Corydalis; Dilatation, Pathologic; Dose-Response Relationship, Drug; Heart; Heart Function Tests; Ligation; Lung; Male; Myocardial Infarction; Organ Size; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Rhizome

Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients, and following an infarction, diabetes is associated with an increased risk for the development of left ventricular (LV) dysfunction and heart failure. The goal of this study was to determine if the progression of heart failure following myocardial infarction in type 2 diabetic (T2D) rats is accelerated compared with nondiabetic rats. Male nondiabetic Wistar-Kyoto (WKY) and T2D Goto-Kakizaki (GK) rats underwent coronary artery ligation or sham surgery to induce heart failure. Postligation (8 and 20 wk), two-dimensional echocardiography and LV pressure measurements were made. Heart failure progression, as assessed by enhanced LV remodeling and contractile dysfunction, was accelerated 8 wk postligation in the T2D animals. LV remodeling was evident from increased end-diastolic and end-systolic diameters and areas in the GK compared with the WKY infarcted group. Furthermore, enhanced LV contractile dysfunction was evident from a greater deterioration in fractional shortening and enhanced myocardial performance index (an index of global LV dysfunction) in the GK infarcted group. This accelerated progression was accompanied by greater increases in atrial natriuretic factor and skeletal alpha-actin (gene markers of heart failure and hypertrophy) mRNA levels in GK infarcted hearts. Despite similar decreases in metabolic gene expression (i.e., peroxisome proliferator-activated receptor-alpha-regulated genes associated with fatty acid oxidation) between infarcted WKY and GK rat hearts, myocardial triglyceride levels were elevated in the GK hearts only. These results, demonstrating enhanced remodeling and LV dysfunction 8 wk postligation provide evidence of an accelerated progression of heart failure in T2D rats.

Topics: Actins; Animals; Atrial Natriuretic Factor; Blood Glucose; Cardiac Output, Low; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Fatty Acids, Nonesterified; Heart Rate; Male; Myocardial Infarction; Rats; Rats, Inbred Strains; Rats, Inbred WKY; RNA, Messenger; Ventricular Dysfunction, Left; Ventricular Remodeling

It has been reported that high intramyocardial peroxisome proliferator-activated receptor alpha (PPARalpha) stimulation or overexpression altered cardiac contractile function in mouse models of cardiac hypertrophy and heart failure. Nevertheless, it has never been demonstrated that clinically relevant doses of drugs stimulating PPARalpha activity such as fenofibrate increase the risk to develop heart failure in humans. To determine if fenofibrate accelerates the development of heart failure in large mammals, we have tested its effects on the progression of left ventricular dysfunction in pacing-induced heart failure in pigs. Fenofibrate treatment blunted reduction in left ventricular ejection fraction, reduced cardiac hypertrophy, and attenuated clinical signs of heart failure. Fenofibrate impeded the increase in atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 plasma levels. The expression of PPARalpha, fatty acyl-CoA-oxidase, and carnitine palmitoyltransferase-Ibeta was reduced at mRNA levels in the left ventricle from untreated heart failure pigs but maintained near normal values with fenofibrate. Fenofibrate prevented heart failure-induced overexpression of TNFalpha mRNA and enhanced catalase activity in left ventricle compared to placebo. These data suggest that a clinically relevant dose of fenofibrate does not accelerate but slows down heart failure development in the model of pacing-induced heart failure in large mammals.

Topics: Acyl-CoA Oxidase; Animals; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Cardiomyopathies; Carnitine O-Palmitoyltransferase; Endothelin-1; Female; Fenofibrate; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; PPAR alpha; RNA, Messenger; Swine; Tachycardia; Thiobarbituric Acid Reactive Substances; Ventricular Dysfunction, Left

The activation of the renin-angiotensin system (RAS) contributes to the progression of left ventricular dysfunction. A novel human homologue of the angiotensin-converting enzyme (ACE), named ACE2, has been described but its role in human heart failure (HF) has not been elucidated. Besides, there is controversy as to whether the major angiotensin II-forming-activity in heart is ACE or chymase released from mast cells. Furthermore, long-term blockade of nitric oxide (NO) synthesis has been shown to increase ACE activity. To assess the locally activated vasoactive mediators that may contribute to the ventricular deterioration process, we sought to simultaneously analyze their expression in failing hearts.. We analyzed left ventricular biopsies from 30 patients with heart failure undergoing heart transplantation and 12 organ donors. The mRNA levels of ACE, ACE2, chymase and endothelial nitric oxide synthase (eNOS), were quantified by real-time polymerase chain reaction and mast cell density was assessed by immunohistochemistry. The mRNA levels of the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) were also quantified as controls.. There was higher ACE and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in ACE2 expression were detected. eNOS mRNA levels were lower in failing hearts. Both ANP and BNP expression were higher in pathological than in control samples.. These data document a decompensation of vasoactive systems that may contribute to the progressive impairment of the myocardial function in HF. On the other hand, ACE2 mRNA expression is not altered in human end-stage HF.

Topics: Adult; Aged; Angiotensin-Converting Enzyme 2; Atrial Natriuretic Factor; Biopsy; Cardiac Output, Low; Cell Count; Chymases; Disease Progression; Female; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Humans; Male; Mast Cells; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Renin-Angiotensin System; RNA, Messenger; Serine Endopeptidases; Ventricular Dysfunction, Left

We and other investigators have reported that short- and long-term treatment with adrenomedullin has beneficial effects in heart failure. This study examined the effects of long-term treatment with a vasopeptidase inhibitor plus adrenomedullin in a model of heart failure in rats and assessed potential mechanisms of action.. Dahl salt-sensitive rats aged 11 weeks were randomly divided into three groups: an omapatrilat group, an omapatrilat plus adrenomedullin group, and an untreated group. The effects of these treatments were evaluated after 7 weeks of treatment.. Omapatrilat monotherapy significantly improved left ventricular weight (LVW), blood pressure (BP), and central hemodynamics as compared with the untreated group. Omapatrilat decreased the gene expression levels of adrenomedullin and atrial natriuretic peptide (ANP) in the left ventricle. In addition, omapatrilat decreased mRNA levels of transforming growth factor-beta (TGF-beta), collagen I, collagen III, plasminogen activator inhibitor-1 (PAI-1), and intercellular adhesion molecule-1 (ICAM-1) in the left ventricle, and omapatrilat decreased perifibrosis score and myocyte area histologically. Omapatrilat plus adrenomedullin further improved LVW, central hemodynamics, and mRNA expression of TGF-beta, collagen I, collagen III, PAI-1, and ICAM-1 without changing BP. Omapatrilat plus adrenomedullin further reduced mRNA levels of ANP and adrenomedullin without altering levels of ANP or adrenomedullin in plasma. Interestingly, omapatrilat slightly decreased mRNA levels of subunits of NADPH oxidase, whereas omapatrilat plus adrenomedullin further decreased these variables.. Our results suggest that combined treatment with adrenomedullin and omapatrilat may be a new strategy for the management of heart failure, acting partly by inhibition of the extracellular matrix gene, adhesion molecule, antifibrinolysis, and oxidative stress production.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Collagen; Disease Progression; Drug Therapy, Combination; Gene Expression Regulation; Heart Ventricles; Intercellular Adhesion Molecule-1; Male; NADPH Oxidases; Plasminogen Activator Inhibitor 1; Pyridines; Rats; Rats, Inbred Dahl; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiomegaly; Collagen; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Fibrosis; Heart; Male; Metalloendopeptidases; Myocardium; Neprilysin; Neurotransmitter Agents; Organophosphonates; Phenylalanine; Rats; Rats, Inbred Dahl; RNA, Messenger; Tetrazoles; Thiazepines

Heart failure is a major and escalating public health problem. Recent studies have demonstrated that statins prevented chronic heart failure (CHF) in animal studies. However, it is unknown whether statins therapy initiated after left ventricular (LV) hypertrophy is evident can still effectively prevent CHF. This study tested the hypothesis that statins can prevent the transition of hypertrophy to heart failure.. The rats were studied at 6, 12, and 20 weeks after aortic stenosis (AS) operation. Some rats were given simvastatin (2.0 mg kg(-1) per day) from 13 weeks after AS operation for 8 weeks. Coarctation of aorta in rats resulted in compensatory LV hypertrophy (LVH), concomitant with an increase of superoxide levels and cardiomyocyte apoptosis in LV tissues at 12 weeks after AS operation. This was followed by CHF with a progressive increase in superoxide levels and cardiomyocyte apoptosis in LV tissues at 20 weeks after AS operation. Simvastatin treatment initiated from 13 weeks after AS operation significantly improved LV function and reduced superoxide levels and cardiomyocyte apoptosis in LV tissues. Pretreatment of simvastatin suppressed the hydrogen peroxide-induced apoptosis of cultured cardiomyocytes from neonatal rats.. These data indicate that long-term administration of simvastatin improved LV function and prevented the transition of hypertrophy to CHF. Inhibition of oxidative stress and cardiomyocyte apoptosis may contribute to the benefits of simvastatin treatment on heart of rats with AS.

Topics: Animals; Aortic Coarctation; Aortic Valve Stenosis; Apoptosis; Atrial Natriuretic Factor; Cardiac Output, Low; Caspase 3; Caspases; Chronic Disease; Heart Ventricles; Hydrogen Peroxide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Male; Myocytes, Cardiac; Oxidative Stress; Rats; RNA, Messenger; Simvastatin; Superoxides

In response to pressure-overload, cardiac function deteriorates and may even progress to fulminant heart failure and death. Here we questioned if genetic enhancement of left ventricular (LV) contractility protects against pressure-overload. Transgenic (TG) mice with cardiac-restricted overexpression (66-fold) of the alpha(1A)-adrenergic receptor (alpha(1A)-AR) and their non-TG (NTG) littermates, were subjected to transverse aorta constriction (TAC)-induced pressure-overload for 12 weeks. TAC-induced hypertrophy was similar in the NTG and TG mice but the TG mice were less likely to die of heart failure compared to the non-TG animals (P <0.05). The hypercontractile phenotype of the TG mice was maintained over the 12-week period following TAC with LV fractional shortening being significantly greater than in the NTG mice (42+/-2 vs 29+/-1%, P <0.01). In the TG animals, 11-week beta-AR-blockade with atenolol neither induced hypertrophy nor suppressed the hypercontractile phenotype. The hypertrophic response to pressure-overload was not altered by cardiac alpha(1A)-AR overexpression. Moreover, the inotropic phenotype of alpha(1A)-AR overexpression was well maintained under conditions of pressure overload. Although the functional decline in contractility with pressure overload was similar in the TG and NTG animals, given that contractility was higher before TAC in the TG mice, their LV function was better preserved and heart failure deaths were fewer after induction of pressure overload.

Topics: Actins; Animals; Antihypertensive Agents; Atenolol; Atrial Natriuretic Factor; Blood Pressure; Cardiac Myosins; Cardiac Output, Low; Constriction; Electrocardiography; Gene Expression; Genetic Enhancement; Hypertrophy, Left Ventricular; Mice; Mice, Transgenic; Myocardial Contraction; Myosin Light Chains; Receptors, Adrenergic, alpha-1; Ventricular Function

Hypovolemia is thought to have an important role in the pathogenesis of dialysis-related hypotension.. We studied the effect of hypovolemia simulated by lower body negative pressure (LBNP) in 11 hypotension-prone (HP) and 11 hypotension-resistant (HR) hemodialysis patients. LBNP was applied stepwise from 0 to -20 to -40 mm Hg. Systolic arterial pressure, heart rate, and central venous pressure (CVP) were recorded continuously after cannulation of the right jugular vein. Stroke volume index was measured at each step echocardiographically. At the end of each level of LBNP, blood samples were obtained to measure norepinephrine (NE), epinephrine (E), and atrial natriuretic peptide (ANP) levels.. At baseline, CVP (12 +/- 5 and 16 +/- 7 mm Hg), heart rate (72 +/- 9 and 70 +/- 13 beats/min), cardiac index (2.3 +/- 0.6 and 2.5 +/- 0.9 L/min), NE (median, 341 pg/mL [range,198 to 789 pg/mL] and 365 pg/mL [range, 177 to 675 pg/mL] or 2.02 nmol/L [range, 1.17 to 4.66 nmol/L] and 2.16 nmol/L [range, 1.05 to 4.00 nmol/L]), E (median, 46 pg/mL [range, 18 to 339 pg/mL] and 58 pg/mL [range, 21 to 122 pg/mL] or 251 pmol/L [range, 98 to 1,951 pmol/L] and 317 pmol/L [range, 115 to 666 pmol/L]) were similar, whereas systolic arterial pressure (141 +/- 26 versus 164 +/- 22 mm Hg) and ANP (median, 441 pg/mL [range, 152 to 1,330 pg/mL] versus 804 pg/mL [range, 517 to 3,560 pg/mL] ng/L) were lower (P < 0.05) in HP patients. In response to LBNP (-40 mm Hg), CVP decreased by 6.5 +/- 4.0 mm Hg in the HP group and 4.9 +/- 4.9 mm Hg in the HR group. In HP patients, this decrease was associated with a greater decrease in SI (37% +/- 16% versus 27% +/- 16%) and systolic arterial pressure (19% +/- 21% versus 4% +/- 14%) than in HR patients. Plasma ANP levels did not change, whereas increases in NE and E levels were similar in HP and HR patients.. Patients who frequently experience episodes of hypotension during dialysis also are prone to develop hypotension during LBNP, which results from reduced myocardial contractile reserve and/or inadequate sympathetic tone.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Catecholamines; Disease Susceptibility; Female; Hemodynamics; Humans; Hypotension; Hypovolemia; Lower Body Negative Pressure; Male; Middle Aged; Myocardial Contraction; Renal Dialysis; Stroke Volume; Sympathetic Nervous System

In order to study the influence of gender on circulating levels of cardiac natriuretic hormones (CNHs) in heart failure, we measured the plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by means of highly sensitive and specific IRMA methods in 239 consecutive patients (age 64.7 +/- 11.6 years, range 21-89 years; 170 men and 69 women) with cardiomyopathy. There was different response of CNH according to gender in patients with heart failure, as indicated by the ratio between the individual CNH values of patients and the gender-specific cut-off values. Indeed, the mean ratio for ANP found in men (3.6 +/- 3.6) was significantly higher (p = 0.0075) than that found in women (2.4 +/- 2.1). The mean ratio for BNP was on average 2.3 fold higher (15.9 +/- 27.1 in men and 6.9 +/- 6.8 in women, p = 0.0084). Moreover, age, ejection fraction, and disease severity independently and significantly contributed to regression with both ANP (R = 0.612, F = 39.969, p < 0.0001) and BNP (R = 0.656, F = 49.957, p < 0.0001) values, while gender did not. In conclusion, our study suggests a different, gender-specific activation of the CNH system in this clinical condition, although age, ejection fraction and disease severity seem to be more powerful predictors than gender of circulating levels of ANP and BNP in patients with heart failure.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiac Output, Low; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Severity of Illness Index; Sex Factors

Electrical conductance is greatly altered in end-stage heart failure, but little is known about the underlying events. We therefore investigated the expression of genes coding for major inward and outward ion channels, calcium binding proteins, ion receptors, ion exchangers, calcium ATPases, and calcium/calmodulin-dependent protein kinases in explanted hearts (n=13) of patients diagnosed with end-stage heart failure. With the exception of Kv11.1 and Kir3.1 and when compared with healthy controls, major sodium, potassium, and calcium ion channels, ion transporters, and exchangers were significantly repressed, but expression of Kv7.1, HCN4, troponin C and I, SERCA1, and phospholamban was elevated. Hierarchical gene cluster analysis provided novel insight into regulated gene networks. Significant induction of the transcriptional repressor m-Bop and the translational repressor NAT1 coincided with repressed cardiac gene expression. The statistically significant negative correlation between repressors and ion channels points to a mechanism of disease. We observed coregulation of ion channels and the androgen receptor and propose a role for this receptor in ion channel regulation. Overall, the reversal of repressed ion channel gene expression in patients with implanted assist devices exemplifies the complex interactions between pressure load/stretch force and heart-specific gene expression.

Topics: Action Potentials; Adenosine Triphosphatases; Adrenergic beta-Antagonists; Antiporters; Atrial Natriuretic Factor; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Cardiac Output, Low; Cardiomegaly; Digitalis Glycosides; Electric Conductivity; Gene Expression Regulation; Heart-Assist Devices; Humans; Ion Channels; Myocytes, Cardiac; Natriuretic Peptide, Brain; Promoter Regions, Genetic; Repressor Proteins

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Electrocardiography; Humans; Practice Guidelines as Topic; Predictive Value of Tests

Since the pathophysiology of natriuretic peptides in chronic heart failure (HF) is not uniform, we hypothesized that atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) may also have differential effects in acute HF. Our aim was to compare the haemodynamic actions of ANP with BNP, using a classical vasodilator as the control, in greyhound dogs with acute pacing-induced HF.. The right ventricles of eight anaesthetized dogs were paced (193 +/- 4 bpm) until pulmonary capillary pressure (PCP) increased to approximately 15 mmHg. In each animal, according to a randomized within-animal design, haemodynamic responses to equimolar (10 pmol/kg per min) infusions of ANP and BNP were compared with those to sodium nitroprusside (SNP).. Acute pacing alone increased PCP from 6.6 +/- 0.7 to 15.7 +/- 0.3 mmHg, right atrial pressure (RAP) from 1.9 +/- 0.5 to 4.0 +/- 0.6 mmHg, and systemic vascular resistance (SVR) from 1706 +/- 110 to 2179 +/- 106 dyne s/cm5, and reduced cardiac output (CO) from 4.1 +/- 0.4 to 2.5 +/- 0.2 l/min and arterial pressure from 86.1 +/- 2.4 to 74.5 +/- 2.1 mmHg (all P < 0.01). BNP and SNP improved haemodynamics similarly (CO +13 +/- 3% and +9 +/- 5%; PCP -12 +/- 2% and -12 +/- 2%; RAP -28 +/- 9% and -34 +/- 6%, SVR -15 +/- 3% and -11 +/- 3%, all P < 0.01, except CO with SNP, not significant), but effects of BNP on preload outlasted those of SNP. By contrast, ANP did not improve the haemodynamics. Haematocrit was significantly higher during BNP infusion than with ANP (P < 0.05) or with SNP (P < 0.001).. The haemodynamic responses to exogenous BNP and ANP in acute heart failure were strikingly different. Whereas ANP actions were blunted, BNP response was preserved. Hypothetically, the presence of a putative BNP receptor may explain this finding.

Topics: Acute Disease; Animals; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Output, Low; Cardiac Pacing, Artificial; Dogs; Female; Hematocrit; Hemodynamics; Male; Natriuretic Peptide, Brain; Nitroprusside; Pulmonary Wedge Pressure; Receptors, Atrial Natriuretic Factor; Vascular Resistance; Vasodilator Agents

The tolerability and effectiveness of amiodarone in patients with advanced heart failure (HF) who are intolerant of beta-blockers was investigated in 22 patients (13 with and 9 without 180+/-26 mg/day of amiodarone). Heart rate (HR), blood pressure (BP), left ventricular diastolic dimension and fractional shortening (FS) using echocardiography, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and norepinephrine concentrations were determined at baseline and after 1 and 3 months of therapy. Although 9 patients tolerated amiodarone without any signs of HF, it was exacerbated in 4 patients. In 10 patients taking amiodarone who could be followed medically for 3 months, HR decreased after 1 month and remained unchanged until after 3 months (81+/-12 vs 65+/-7 vs 65+/-7beats/min), accompanied by decreased concentration of BNP (688+/-485 vs 392+/-203 vs 261+/-192pg/ml). FS increased significantly only after 3 months (0.12+/-0.05 vs 0.14+/-0.05 vs 0.16+/-0.04). Amiodarone may be used in patients with advanced HF who are intolerant of beta-blockers.

Topics: Adrenergic beta-Antagonists; Adult; Amiodarone; Anti-Arrhythmia Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Dose-Response Relationship, Drug; Echocardiography; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Retreatment; Severity of Illness Index

We tested the hypotheses that myocardial infarction in mice would lead to progressively worsening heart failure 12-18 weeks later and that exercise testing would provide a suitable means to evaluate left ventricular function sequentially. C57BL/6 mice (n = 69) underwent left coronary artery ligation (n = 50) or thoracotomy without ligation (n = 19). Sixteen animals (32%) died within 24 h of coronary ligation. Twenty additional animals (40%) died between days 3 and 14, and these mice showed infarct sizes of > 50% of the left ventricle. Fourteen animals (28%) that survived two weeks underwent echocardiography and treadmill testing 12 and 18 weeks after infarction, with no further mortality. Mice were then killed, morphometric assessment made, infarct size evaluated, and myocardial norepinephrine content and expression of BNP and ANF measured. Mice with infarcts >30% of the left ventricle (n = 6; 12% of original cohort) had left ventricular dilation (p < 0.0001) and hypertrophy (p < 0.001), impaired left ventricular systolic function (p < 0.0001) and reduced exercise duration (p = 0.03) and total work (p = 0.03) 12-18 weeks after infarction. Mice with infarcts <30% of the left ventricle (n = 8; 16% of original cohort) had no significant functional changes or left ventricular remodeling. Hearts from mice with infarcts > 30 % had reduced myocardial norepinephrine levels (MI <30%: 177+/-54 pg/mg, n = 6; MI >30%: 66+/-14 pg/mg wet weight, n = 4; p = 0.005) and increased mRNA content of BNP (p < 0.03) and ANF (p = 0.023). Coronary artery occlusion in mice provides a relevant model of clinical heart failure that is progressive and can be assessed by sequential exercise testing, providing a means to study the development of heart failure and its treatment.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Disease Progression; Echocardiography; Male; Mice; Mice, Inbred C57BL; Motor Activity; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Norepinephrine

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Humans; Myocardium; Natriuretic Peptide, Brain; Protein Precursors; Ventricular Dysfunction

B-type natriuretic peptide, a proteohormone secreted by the left ventricle in response to wall-tension, is a promising laboratory parameter for the detection and follow-up of heart failure. In this report analytical validation data of a non-isotopic point-of-care testing system for the quantitative determination of BNP (Triage BNP, Biosite, USA) are given. Despite a very short turn-around time of about 10 minutes the assay proved to be reproducible (interassay coefficient of variation (n=10) of 8.4% and 8.0% at concentrations of 19.3 ng/l and 392 ng/l, respectively), linear (r=0.998, from 5 ng/l to 818 ng/l), and rugged with respect to common interferents; compared to the widely used SHIONORIA BNP assay (CIS, France) higher results were found (Triage-BNP = 1.52 x SHIONORIA BNP - 7.0 ng/l; n=70) with a relatively close correlation of the results (r=0.935). It is concluded that the Triage BNP assay meets the analytical requirements for further clinical validation and may allow a more widespread clinical use of BNP determination in contrast to competing assays with long turn-around times.

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Humans; Linear Models; Natriuretic Peptide, Brain; Point-of-Care Systems; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Time Factors

Activation of the sympathetic nervous system, decreased heart rate variability (HRV), and loss of modulation of muscle sympathetic nerve activity (MSNA) within the low frequency (LF, 0.05-0.15 Hz) range are three adverse features of advanced congestive heart failure (CHF). In healthy men, atrial natriuretic peptide (ANP) infusion attenuates reflex increases in MSNA and reduces LF components of HRV spectral power. Sympathoinhibitory actions have also been documented in CHF, but effects on the variability of MSNA and HRV have not been described.. Heart rate and MSNA were recorded in 10 men (aged 39 +/- 3 years, mean +/- SE) with dilated cardiomyopathy (mean EF 20 +/- 4%) treated with angiotensin converting enzyme (ACE) inhibitors. Subjects received i.v. ANP (50 microg bolus then 50 ng/kg/min) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. Signals at baseline, and 13-20 min into each infusion were submitted to spectral analysis.. ANP had no effect on HRV, but increased MSNA LF (from 7.9 +/- 1.5 to 12.1 +/- 2.6 U2; P< 0.02) and total spectral power (from 47.9 +/- 5.4 to 61.9 +/- 6.8 U2; P < 0.05). NTG had no effect on the variability of MSNA or HRV.. In CHF patients receiving ACE inhibitors, ANP (i) does not suppress HRV and (ii) enhances the modulation of MSNA, particularly within the LF range. This latter action is not observed with NTG. These findings suggest beneficial actions of exogenous ANP on neurogenic circulatory control.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiomyopathy, Dilated; Heart Rate; Humans; Male; Middle Aged; Nitroglycerin; Sympathetic Nervous System; Vasodilator Agents

Topics: Adenosine Triphosphate; Animals; Aortic Valve Insufficiency; Atrial Natriuretic Factor; Blotting, Northern; Cardiac Output, Low; Disease Models, Animal; Humans; Ion Channels; Male; Membrane Transport Proteins; Mitochondria, Heart; Mitochondrial Proteins; Muscle, Skeletal; Myocardium; Phosphocreatine; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha; Uncoupling Agents; Uncoupling Protein 2

Chronic heart failure (CHF) studies investigating the clinical, hemodynamic, and therapeutic importance of endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) are largely based on resting plasma levels, which may vary with prior exertion and postprandial status. This study investigated the importance of peak-exercise plasma levels of ET-1, ANP, and BNP in the assessment of left ventricular (LV) systolic function. Thirty-six male-patients ages 58 +/- 10 (mean +/- SD ) with NYHA class I-IV CHF due to coronary artery disease or idiopathic dilated cardiomyopathy were enrolled. LV systolic function was assessed by echocardiography and radionuclide ventriculography. Resting and peak cardiopulmonary exercise venous blood sampling and treadmill exercise testing were performed in the fasting state. Resting plasma levels of ET-1, ANP, and BNP were elevated compared with reference laboratory normal values. Exercise induced significant (p < 0.0001) increase in plasma levels of ET-1, ANP, and BNP. On univariate analysis peak-exercise plasma levels of ET-1, ANP, and BNP were more closely related to echocardiographically determined LV end-diastolic diameter and end-systolic diameter than their resting values. Multiple step-wise regression models identified resting and peak-exercise plasma levels of ET-1 and ANP but only the resting BNP as independent predictors of LV dimensions and systolic function. Peak exercise plasma levels of ANP and ET-1 are potentially more reliable and important than their resting levels as markers of LV systolic dysfunction and LV dimensions in patients with heart failure.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Echocardiography; Endothelin-1; Exercise; Fasting; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Regression Analysis

Brain natriuretic peptide (BNP) is a strong predictor of left ventricular (LV) hypertrophy (LVH) and dysfunction. However, our recent studies suggested that LVH is not necessarily associated with enhanced production of BNP in hypertension. This study aimed to clarify the relation of the characteristics of hypertrophy with the degree of gene expression of BNP in the developmental process of hypertensive heart failure.. Serial changes in LV geometry, histology and atrial natriuretic peptide (ANP) and BNP mRNA levels, were assessed in a hypertensive heart failure model using Dahl salt-sensitive rats (n = 24). We further studied effects of alpha1-receptor antagonist (doxazosin: 1 mg/kg per day, n = 5) and angiotensin II type 1 receptor (AT1R) antagonist (candesartan cilexetil: 1 mg/kg per day, n = 5).. The BNP mRNA level was not elevated at the compensatory hypertrophic stage when ANP mRNA level was elevated. BNP mRNA level was increased with further progression of hypertrophy and development of fibrosis. AT1R blockade prevented such fibrosis and further progression of hypertrophy with normalization of BNP mRNA levels. Compensatory hypertrophy was not suppressed; therefore, ANP mRNA level, although decreased, was still beyond the normal level. The alpha1-receptor blockade slightly attenuated LV hypertrophy with a slight decrease in ANP mRNA levels. LV fibrosis was not prevented, and the BNP mRNA level was not decreased.. BNP gene expression is not enhanced by initial compensatory hypertrophy, but is enhanced by LV fibrosis and late stage progression of hypertrophy dependent on AT1R-mediated signaling pathway.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Echocardiography; Fibrosis; Heart Ventricles; Hemodynamics; Hypertension; Male; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Rats; Rats, Inbred Dahl; RNA, Messenger; Ventricular Remodeling

The effects on myocardial function and loading conditions of clinically relevant doses of the natriuretic peptides (NP) have not been established. The actions of single doses (100 ng x kg(-1) x min(-1) iv over 30 min) of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) were studied in conscious normal dogs and in dogs with pacing-induced heart failure. All three NP reduced end-diastolic pressure in normal dogs, and ANP and BNP reduced end-diastolic volume. In heart failure ANP and BNP reduced EDP, and ANP reduced EDV. Arterial elastance was unchanged in normal dogs and in dogs with heart failure. ANP increased end-systolic elastance (E(es)) in normal dogs, whereas BNP tended to increase E(es) (P = 0.06). In dogs with heart failure, no inotropic effect was seen. In normal dogs, all NP reduced the time constant of isovolumic relaxation (tau), and ANP and BNP reduced tau in dogs with heart failure. Increases in plasma cGMP in dogs with heart failure were blunted. The NP reduced preload and enhanced systolic and diastolic function in normal dogs. Effects of ANP and BNP on preload and diastolic function were maintained in heart failure. Lack of negative inotropic effects in heart failure supports the validity of the NP as therapeutic agents.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclic GMP; Diastole; Dogs; Heart; Male; Myocardial Contraction; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Reference Values

In failing human hearts (FHH) (NYHA IV) the cardiac output is inadequate to meet the metabolic needs of the peripheral systems. By means of thermo-mechanical analysis we have shown that epicardial strips from FHH (37 degrees C) have a depressed tension independent heat (TIH) and tension independent heat rate (dTIH / dt) liberation that correlates with depression in peak isometric force and the rate of relaxation. Furthermore, in response to a change in frequency of stimulation, FHH shows a severe blunting of the force-frequency relationship resulting in a decrease in myocardial reserve and in the frequency at which optimum force is obtained. We used ventricular ANF as an index of the severity of myocardial disease and demonstrated an inverse relationship between ANF mRNA and the sarcoplasmic reticulum (SR) calcium cycling proteins (SERCA 2, Phospholamban, Ryanodine Receptor) while these latter proteins all had a positive correlation with each other. At the same time there was an increase in sarcolemmal sodium calcium exchange protein. The decrease in SR pump proteins correlates with the decrease in myocardial reserve and optimum frequency of contraction. The latter mechanical changes are explainable in terms of a frequency dependent decrease in calcium concentration (aequorin light) in FHH.

Topics: Atrial Natriuretic Factor; Body Temperature Regulation; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Cardiac Output, Low; Heart; Heart Ventricles; Humans; In Vitro Techniques; Isometric Contraction; Myocardial Contraction; Myocardium; RNA, Messenger; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum

A-type and B-type natriuretic peptides (ANP and BNP) are secreted into the systemic circulation via the coronary sinus. Plasma levels of ANP and BNP at the coronary sinus should directly determine the systemic circulating levels. However, the metabolic clearance of these hormones are dependent on similar systems, natriuretic peptide clearance receptor (NPR-C) and neutral endopeptidase 24.11 (NEP), suggesting a possible interaction between ANP and BNP on metabolic clearance. In this study, we examined the interaction on metabolic clearance in patients with heart failure. We obtained blood samples from the coronary sinus and aortic root in 100 patients with heart failure and 28 control subjects. The difference in ANP and BNP levels between the coronary sinus and the aortic root is reflected partly by the metabolic clearance in the pulmonary circulation. In this study, we examined the possible interaction on metabolic clearance between ANP and BNP using a statistical procedure. The ratio of the level of BNP to ANP (BNP/ANP) was significantly higher in the aortic root than in the coronary sinus at any stage of heart failure. We performed multiple regression analysis using ANP and BNP levels at the coronary sinus as independent variables (X1 and X2, respectively) and the ANP level at the aortic root as a dependent variable (Y). The analysis showed that both X1 and X2 were significant variables in the equation. On the other hand, we performed the same analysis using the BNP level at the aortic root as a dependent variable (Y). The analysis showed that only X2 was a significant variable in the equation. This study suggests that (1) the metabolic clearance in the pulmonary circulation is higher for ANP versus BNP and (2) the amount of ANP cleared in the pulmonary circulation depends on the amount of both ANP and BNP secreted from the heart, whereas the amount of BNP cleared in the pulmonary circulation is dependent solely on the amount of BNP secreted from the heart.

Topics: Aorta; Atrial Natriuretic Factor; Cardiac Catheterization; Cardiac Output, Low; Cardiomyopathy, Dilated; Coronary Vessels; Female; Humans; Linear Models; Male; Metabolic Clearance Rate; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Pulmonary Circulation

Topics: Acute Disease; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiotonic Agents; Dyspnea; Humans; Multicenter Studies as Topic; Natriuretic Peptide, Brain; Pulmonary Wedge Pressure; Recombinant Proteins

Anthracyclines are effective antineoplastic drugs, but they frequently cause dose-related cardiotoxicity. The cardiotoxicity of conventional anthracycline therapy highlights a need to search for methods that are highly sensitive and capable of predicting cardiac dysfunction. We measured the plasma level of brain natriuretic peptide (BNP) to determine whether BNP might serve as a simple diagnostic indicator of anthracycline-induced cardiotoxicity in patients with acute leukemia treated with a daunorubicin (DNR)-containing regimen. Thirteen patients with acute leukemia were treated with a DNR-containing regimen. Cardiac functions were evaluated with radionuclide angiography before chemotherapies. The plasma levels of atrial natriuretic peptide (ANP) and BNP were measured at the time of radionuclide angiography. Three patients developed congestive heart failure after the completion of chemotherapy. Five patients were diagnosed as having subclinical heart failure after the completion of chemotherapy. The plasma levels of BNP in all the patients with clinical and subclinical heart failure increased above the normal limit (40 pg/ml) before the detection of clinical or subclinical heart failure by radionuclide angiography. On the other hand, BNP did not increase in the patients without heart failure given DNR, even at more than 700 mg/m(2). The plasma level of ANP did not always increase in all the patients with clinical and subclinical heart failure. These preliminary results suggest that BNP may be useful as an early and sensitive indicator of anthracycline-induced cardiotoxicity.

Topics: Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Daunorubicin; Female; Heart Diseases; Heart Failure; Heart Function Tests; Humans; Leukemia; Male; Middle Aged; Natriuretic Peptide, Brain; Statistics, Nonparametric

The pharmacologic profiles of nicorandil in the cardiovascular system have been characterized by K-channel opening and nitrate activities. However, the effects of nicorandil on acute heart failure have yet to be elucidated. To investigate the effects of nicorandil under such pathophysiologic conditions, we administered nicorandil intravenously to dogs with acute ischemic heart failure induced by coronary embolization and compared the results with those induced by cromakalim and nitroglycerin. The heart failure in this experiment was demonstrated by a reduction of mean blood pressure (MBP) from 143+/-3 to 129+/-2 mm Hg (p < 0.01); cardiac output (CO) from 2.18+/-0.10 to 1.06+/-0.05 L/min (p < 0.01); stroke volume (SV) from 12.7+/-0.6 to 6.8+/-0.3 ml/min (p < 0.01); Vmax, an index of the contractility of the left ventricle, from 105.5+/-4.4 to 49.9+/-1.8 1/s (p < 0.01), and an increase in right atrial pressure (RAP) from 2.9+/-0.3 to 5.3+/-0.3 mm Hg (p < 0.01); left ventricular end-diastolic pressure (LVEDP) from 2.5+/-0.4 to 26.0+/-1.4 mm Hg (p < 0.01); and T, time constant of left ventricular relaxation, from 38.3+/-0.8 to 62.4+/-2.8 ms (p < 0.01). Furthermore, plasma renin activity (PRA) and plasma atrial natriuretic peptide (ANP) increased (from 1.72+/-0.29 to 5.03+/-0.68 ng AngI/ml/h, p < 0.01; from 103.9+/-5.8 to 411.5+/-29.4 pg/ml, p < 0.01, respectively), whereas brain natriuretic peptide (BNP) remained unchanged (from 23.1+/-2.2 to 26.9+/-1.4 pg/ml). Nicorandil (10-40 microg/kg/min, i.v. infusion for 20 min for each dosing) or cromakalim (0.25-1 microg/kg/min) decreased MBP, systemic vascular resistance (SVR), RAP, and LVEDP, and increased CO, SV, and Vmax. However, the reduction of RAP in cromakalim was significantly smaller than those of nicorandil and nitroglycerin in comparison at similar hypotensive doses. Nitroglycerin (2.5-10 microg/kg/min) decreased MBP, RAP, and LVEDP, and increased Vmax but did not change CO or SV. Increased plasma ANP levels, an index of cardiac filling pressure after induction of acute ischemic heart failure, were decreased significantly by cromakalim and tended to decrease by nicorandil or nitroglycerin. Plasma BNP levels and PRA were not influenced by any of these drugs. These results suggest that nicorandil produces the reduction of both preload and afterload followed by an improvement of cardiac contractility in this model. The increase in CO may be mediated mainly by the drug's K-channel opening activities and the

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cromakalim; Dogs; Embolization, Therapeutic; Female; Hemodynamics; Hormones; Male; Microspheres; Myocardial Ischemia; Natriuretic Peptide, Brain; Nicorandil; Nitroglycerin; Potassium Channels; Renin; Vasodilator Agents

The purpose of this study was to investigate whether atrial and brain natriuretic peptides (ANP and BNP, respectively) represent autocrine/paracrine factors and are accumulated in pericardial fluid.. ANP and BNP, systemic hormones produced by the heart, have elevated circulating levels in patients with heart failure. Recent evidence suggests that the heart itself is one of the target organs for these peptides.. With an immunoreactive radiometric assay, we measured the concentrations of these peptides in plasma and pericardial fluid simultaneously in 28 patients during coronary artery bypass graft surgery.. The pericardial levels of BNP were markedly elevated in patients with impaired left ventricular function. We investigated the correlation of ANP and BNP levels in plasma or pericardial fluid with left ventricular hemodynamic variables. None of the hemodynamic variables correlated with ANP levels in plasma or pericardial fluid. Both plasma and pericardial fluid levels of BNP were significantly related to left ventricular end-diastolic and systolic volume indexes (LVEDVI and LVESVI, respectively). In addition, BNP pericardial fluid levels had closer relations with LVEDVI (r = 0.679, p < 0.0001) and LVESVI (r = 0.686, p < 0.0001) than did BNP plasma levels (LVEDVI: r = 0.567, p = 0.0017; LVESVI: r = 0.607, p = 0.0010). BNP levels in pericardial fluid but not in plasma correlated with left ventricular end-diastolic pressure (r = 0.495, p = 0.0074).. BNP levels in pericardial fluid served as more sensitive and accurate indicators of left ventricular dysfunction than did BNP levels in plasma. Thus, BNP may be secreted from the heart into the pericardial space in response to left ventricular dysfunction, and it may have a pathophysiologic role in heart failure as an autocrine/paracrine factor.

Topics: Aged; Atrial Natriuretic Factor; Autocrine Communication; Biomarkers; Cardiac Output, Low; Cardiac Volume; Coronary Artery Bypass; Coronary Disease; Diastole; Female; Hemodynamics; Humans; Hypertension; Male; Mitral Valve Insufficiency; Myocardial Ischemia; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Paracrine Communication; Pericardial Effusion; Radioimmunoassay; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

The arterial ketone body ratio (AKBR), an established clinical tool that reflects hepatic mitochondrial oxidation-reduction potential, predicts the outcome of patients with shock and multiple organ failure and the postoperative outcome in patients who have undergone major liver or heart surgery. The purpose of this study was to determine the prognostic significance of AKBR in patients with acute heart failure. The subjects of this study were 52 patients with acute heart failure. The following parameters were analyzed after Cox univariate hazard analysis was performed: AKBR, plasma norepinephrine, left ventricular ejection fraction, cardiac index, pulmonary arterial wedge pressure, sex, age, human atrial natriuretic peptide, endothelin-1, and cholesterol. The follow-up period was 30 weeks with cardiac death as the end point. Stepwise multivariate proportional hazard analysis revealed that AKBR was the most significant predictor of death, followed by norepinephrine and human atrial natriuretic peptide. Curve-fitting analysis revealed that the relationship between log (norepinephrine) and AKBR could best be described by two distinct lines, with their intersection at AKBR = 0.7 and norepinephrine = 418. With these results we conducted Kaplan-Meier analysis for AKBR > or = 0.7 and AKBR <0.7. The survival rate in patients with AKBR > or = 0.7 was 100%, whereas that in patients with AKBR <0.7 was 15% (p < 0.0001, log-rank analysis). These results indicate that AKBR is a novel independent predictor of death in heart failure.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiac Output, Low; Female; Follow-Up Studies; Heart Diseases; Humans; Ketone Bodies; Male; Middle Aged; Norepinephrine; Prognosis; Proportional Hazards Models; Survival Analysis

Administration of angiotensin converting enzyme (ACE) inhibitors to patients with congestive heart failure (CHF) is associated to a decrease in the abnormal vasoconstrictor neurohormonal activity. This contributes to the sustained benefits of these drugs on symptoms and survival of patients with CHF. There is little information, however, regarding the effects of ACE inhibition on vasodilator and natriuretic hormones.. To evaluate the chronic effects of enalapril, in addition to digitalis and diuretics in patients with chronic cardiac failure.. Nine patients with an idiopathic dilated cardiomyopathy (8 male, aged 48 to 76 years old) under treatment with digitalis and diuretics, received enalapril 20 mg bid during eight weeks. Before and after this treatment period resting left ventricular ejection fraction, functional class, plasma levels of atrial natriuretic factor and bradykinins (BK) and urinary excretion of kalikreins (BK) and prostaglandin E2 (PGE2) were measured.. After enalapril therapy, there was a significant increase in maximal O2 consumption (14.8 +/- 1.2 to 18.6 +/- 1.5 ml/kg/min, p < 0.05) and radionuclide LV ejection fraction (27.4 +/- 1.1 to 31.4 +/- 0.9% p < 0.05). This was associated with a significant decrease in plasma ANP levels (559 +/- 158 to 178 +/- 54.8 pg/ml) and UK (391 +/- 112 to 243 +/- 92 Cu/24 h).. The decrease in ANP levels, which is a well known marker of prognosis in CHF, could contribute to explain the sustained clinical benefits observed with ACE inhibitors in patients with CHF.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Bradykinin; Cardiac Output, Low; Cardiomyopathy, Dilated; Chronic Disease; Dinoprostone; Enalapril; Female; Humans; Kallikreins; Male; Middle Aged; Oxygen Consumption; Stroke Volume; Vasodilator Agents

To determine whether the attenuation in the growth capacity of myocytes in the overloaded aging heart is associated with an impairment in the activation of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in the stressed cells, large myocardial infarcts were produced in Fischer 344 rats at 4 and 16 months of age, and the animals were killed 6 hours, 3 days, and 7 days later. After the documentation of cardiac failure, the unaffected myocytes were enzymatically dissociated, and the expression of IGF-1 and IGF-1R was measured at these three time points after surgery. The level of expression of IGF-1R mRNA increased at 3 days and remained elevated at 7 days in both age groups. In addition, an increase in IGF-1R protein in these cells was found, with no apparent difference with age. This phenomenon was coupled with an upregulation of IGF-1 mRNA of comparable magnitude in the younger and older animals. In contrast, the increases in the dimensional properties of myocytes were delayed and of smaller magnitude in the older infarcted rats. Moreover, the expression of atrial natriuretic factor, used as a molecular marker of myocyte cellular hypertrophy, was greater at 3 days in 4-month-old rats and at 7 days in 16-month-old rats. Thus, aging may affect the hypertrophic response of myocytes after infarction but has no impact on the ability of the cells to enhance the expression of IGF-1 and IGF-1R, which may sustain only in part the growth reserve mechanisms of the pathological heart.

Topics: Aging; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Hemodynamics; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Myocardial Infarction; Myocardium; Polymerase Chain Reaction; Rats; Rats, Inbred F344; Receptor, IGF Type 1; RNA, Messenger; Transcription, Genetic; Ventricular Dysfunction

The neuroendocrine profile and echocardiographic features of 40 patients (81 +/- 1 years, means +/- standard error) with heart failure and impaired left ventricular systolic function were compared with those of an age-matched group of healthy subjects, 20 younger patients with heart failure (aged 58 +/- 1 years) and 15 younger healthy subjects. Normal elderly subjects had a neuroendocrine profile similar to that of healthy younger subjects apart from elevated plasma norepinephrine (958 +/- 84 vs 302 +/- 118 pg/ml; p< 0.001) and atrial natriuretic peptide ( 40 +/- 6 vs 28 +/- 5 pg/ml; p<0.05). Despite a similar severity of heart failure, elderly patients had smaller ventricular dimensions (left ventricular internal dimension in diastole 51 +/- 2 vs 69 +/- 3 mm;p<0.0001 and greater impairment of ventricular compliance using Doppler indexes. Plasma norepinephrine was higher (1,191 +/- 80 vs 620 +/- 67 ppg/ml; p<0.01), and plasma atrial natriuretic peptide, plasma active renin, and angiotensin II were lower in elderly patients than in the younger patients with heart failure. As functional capacity declines with age, elderly patients may have less severe cardiac dysfunction for any given level of functional impairment, and this may account for most of the differences in neuroendocrine activity with age. Age appears to be an important determinant of plasma norepinephrine and may be a confounding factor in interpreting the prognostic significance of this hormone.

Topics: Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Cardiac Output, Low; Echocardiography; Humans; Middle Aged; Neurosecretory Systems; Norepinephrine; Renin-Angiotensin System; Ventricular Dysfunction, Left

Experiments were performed to test the postulate that neural influences underlie the suppressed excretory response to acute volume expansion (VE) typically observed 3-4 wk after myocardial infarction to induce chronic heart failure (CHF). Responses to VE were assessed in innervated (intact) and denervated (DNX) kidneys of anesthetized CHF rats and sham-operated controls. CHF rats exhibited blunted natriuretic responses to VE in both intact kidneys (35% of sham response) and DNX kidneys (55% of sham DNX response). CHF rats also displayed suppressed excretory responses to atrial natriuretic factor (0.25 microgram.kg-1.min-1 iv) in both intact kidneys (74% of sham response) and DNX kidneys (63% of sham DNX response). Additional experiments confirmed that the compliance of the venoatrial junction did not differ between sham rats (52 +/- 2 mmHg/microliter) and CHF rats (54-2 mmHg/microliter). The observations support the contention that both tonic renal sympathetic renal nerve activity and suppressed renal atrial natriuretic factor responsiveness likely contribute to the blunted excretory response to VE during CHF.

Topics: Animals; Atrial Function; Atrial Natriuretic Factor; Blood Volume; Cardiac Output, Low; Chronic Disease; Hemodynamics; Kidney; Male; Myocardium; Nervous System; Plasma Substitutes; Pressure; Rats; Rats, Sprague-Dawley; Venae Cavae

Left ventricular diastolic dysfunction is common in patients with systolic heart failure and the restrictive type of filling pattern appears to be associated with increased cardiac mortality. Both artrial and brain (or ventricular) natriuretic peptides are also proven markers of the severity of heart failure. The aim of this study was to determine in a large cohort of patients with systolic heart failure whether diastolic abnormalities, and in particular the restrictive filling pattern of transmitral flow velocity, correlate with plasma atrial and brain natriuretic peptide levels.. Sixty-eight consecutive patients with symptomatic systolic heart failure (ejection fraction < 0.5) underwent two-dimensional Doppler echocardiography of left ventricular systolic and diastolic function, together with measurement of atrial and brain natriuretic peptides.. The restrictive filling pattern was present in 62%, the abnormal relaxation pattern in 31% and only 7% were normal. Atrial and brain natriuretic peptide (ANP/BNP) levels were significantly higher in the restrictive compared to the abnormal relaxation group (ANP: 202.2 +/- 31.7 vs 102.5 +/- 22.1 pg.ml-1, P = 0.012; BNP: 277.8 +/- 27.7 vs 162.4 +/- 21.9 pg.ml-1, P = 0.002). In addition, a restrictive filling pattern was associated with lower ejection fractions (P = 0.026), higher pulmonary artery systolic pressure (P < 0.001), larger left atrial size (P = 0.044), and were more likely to be in New York Heart Association class III or IV than those with an abnormal relaxation pattern (P = 0.007). Both atrial and brain natriuretic peptides correlated inversely with ejection fraction (P < 0.001), fractional shortening (P < 0.001), and positively with pulmonary artery pressure (P = 0.004 and 0.001 respectively). There were no significant correlations between single diastolic parameters and atrial or brain natriuretic peptide levels for the total patient group except between mitral peak A wave velocity and brain natriuretic peptides (r = -0.3, P = 0.01). For those with abnormal relaxation pattern mitral, valve E-wave deceleration time correlated significantly with both atrial and brain natriuretic peptide levels (P < 0.01).. This study confirms that the restrictive filling pattern of transmitral flow velocity is a marker of more severe heart failure, as indicated by its association with higher atrial and brain natriuretic peptide levels, lower ejection fraction and higher pulmonary artery pressure. Thus, this easily obtained Doppler-derived marker of diastolic dysfunction is useful for identifying those patients with more severe heart failure.

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Diastole; Echocardiography, Doppler; Female; Humans; Male; Middle Aged; Mitral Valve; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Prognosis; Stroke Volume; Ventricular Dysfunction, Left

The purpose of this study was to determine whether high plasma levels of atrial natriuretic peptide (ANP) in compensated heart failure are important in the maintenance of sodium balance. This was achieved by subjecting eight dogs to bilateral atrial appendectomy (APX) to blunt the ANP response to pacing-induced heart failure. Five intact dogs served as controls. In controls, 14 days of left ventricular pacing at 240 beats/min produced a sustained fall in cardiac output and mean arterial pressure of approximately 40 and 20%, respectively; compared with cardiac output, reductions in renal blood flow (up to approximately 25%) were less pronounced and even smaller decrements in GFR occurred (up to 9%). Despite these changes and a threefold elevation in plasma norepinephrine concentration, plasma renin activity (PRA) did not increase and sodium balance was achieved during the second week of pacing in association with a six- to eightfold rise in plasma levels of ANP. Similar responses occurred in four dogs in which APX was relatively ineffective in blunting the ANP response to pacing. In marked contrast, there were substantial increments in PRA and in plasma norepinephrine concentration, and marked sodium and water retention during the last week of pacing in four dogs with APX and severely deficient ANP. These results indicate that ANP plays a critical role in promoting sodium excretion in the early stages of cardiac dysfunction.

Topics: Adaptation, Physiological; Animals; Atrial Function, Right; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiac Pacing, Artificial; Diuresis; Dogs; Heart Atria; Hematocrit; Hemodynamics; Homeostasis; Kidney; Male; Natriuresis; Norepinephrine; Potassium; Pressure; Renin; Sodium

Atrial natriuretic peptide (ANP) exerts hemodynamic effects by direct venodilation in the chick embryo. We hypothesized that ANP-induced venodilation affects ventricular diastolic filling resulting in reduced ventricular preload. Chick ANP (0.1 microgram in 10 microL of normal saline) was suffused onto the vitelline vascular bed in stage 21 (3 1/2 d) chick embryos. Equivalent aliquots of normal saline were suffused as sham controls, and normal embryos received no suffusion. We measured simultaneously dorsal aortic blood velocity and atrioventricular blood velocity with a 20-MHz pulsed-Doppler velocity meter. Analog wave forms were digitally sampled at 500 Hz, and the dorsal aortic cross-sectional area was used to calculate dorsal aortic blood flow. Passive ventricular filling volume equaled dorsal aortic stroke volume multiplied by the fraction of passive area; active filling volume equaled dorsal aortic stroke volume multiplied by the fraction of active area. Data were summarized as mean +/- SEM (n > or = 7 per group) and analyzed by analysis of variance. Cycle lengths were similar in ANP-suffused, sham control, and normal embryos. Dorsal aortic blood flow decreased from 0.49 +/- 0.04 mm3/S at baseline to 0.27 +/- 0.05 mm3/S at 4 min post-ANP suffusion (p < 0.05) and was unchanged in sham control and normal embryos (p > 0.05). Passive ventricular filling was reduced by ANP suffusion, whereas active filling was unaffected, resulting in a decreased passive/active filling ratio from 0.64 +/- 0.07 at baseline to 0.32 +/- 0.08 at 4 min in ANP-suffused embryos (p < 0.05). Passive/active ratio was unchanged in sham control and normal embryos. Thus, ANP-mediated vasodilation reduces cardiac output via decreased passive ventricular filling in the embryonic heart.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Flow Velocity; Cardiac Output, Low; Chick Embryo; Gestational Age; Stroke Volume; Vasodilator Agents

Atrial natriuretic peptide (ANP) has been extensively studied in cardiovascular disorders in recent years. Particular attention has been paid to the role of ANP in the pathogenesis of hypertension and congestive heart failure and in the neurohormonal response to myocardial infarction. However, no published data are available on the significance of ANP in hypertensive patients with acute myocardial infarction.. We studied the relationship between plasma ANP concentration and systolic blood pressure, diastolic blood pressure, left atrial dimension, left ventricular diastolic dimension and left ventricular mass index in patients with essential hypertension in the acute phase of myocardial infarction. Plasma ANP concentrations were determined at 0, 4, 8, 16, 24, 48 and 72 h after admission in 40 patients with a first myocardial infarction (18 hypertensive patients, group 1; 22 normotensive patients, group 2). Left atrial dimension and left ventricular diastolic dimension were assessed echocardiographically within the first 48 h of acute myocardial infarction.. Maximum and mean plasma ANP values at 0, 4, 8, 16, 24, 48, and 72 h as well as mean ANP concentrations within the 72 h period were higher in group 1 than in group 2 (P < 0.001). Plasma ANP concentration, left atrial dimension (r = 0.59) and left ventricular diastolic dimension (r = 0.56) were positively correlated in both groups.. Acute myocardial infarction is characterized by a more pronounced rise in plasma ANP concentration in hypertensive patients than in those without a history of hypertension. Plasma ANP concentration correlates with left heart chamber sizes.

Topics: Acebutolol; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Creatine Kinase; Creatinine; Echocardiography; Female; Furosemide; Heart Atria; Heart Ventricles; Humans; Hypertension; Isoenzymes; Male; Metoprolol; Middle Aged; Myocardial Infarction; Nifedipine; Potassium; Sodium

We examined the hemodynamic and neurohumoral effects of carperitide in dogs with low-output heart failure (LHF) produced by volume expansion, ligation of the left anterior descending coronary artery and methoxamine infusion. Carperitide (0.1 approximately 1 micrograms/kg/min, i.v. infusion for 30 min) decreased pulmonary arterial pressure, right atrial pressure and systemic vascular resistance and increased cardiac output. These pharmacological activities were equivalent to those of nitroglycerin (NG, 3 micrograms/kg/min). Although most of the animals did not excrete urine after induction of LHF, carperitide, unlike NG, increased urine volume. The plasma level of cyclic GMP was elevated about three times by induction of LHF and further increased after treatment with carperitide (1 microgram/kg/min). Carperitide had no effects on plasma renin activity, plasma aldosterone concentration and plasma noradrenaline. These results taken together indicate that carperitide reduces both preload and afterload in association with an increase in cyclic GMP production and improves the untoward hemodynamic alterations in LHF dogs.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cyclic GMP; Diuresis; Dogs; Female; Hemodynamics; Male; Methoxamine; Nitroglycerin; Peptide Fragments; Renin-Angiotensin System

The present study examines in detail the short-term cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 micrograms/h for 60 min restored cardiac output to prepacing values and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Cardiac Output, Low; Electrophysiology; Heart Failure; Hemodynamics; Norepinephrine; Renin; Sheep

Death in chronic heart failure (CHF) can be from progression of disease or sudden and unexpected. We have attempted to identify factors that predict sudden death in CHF. We followed up 44 patients with CHF for 12-50 (mean 36) months. 4 patients died of non-cardiovascular causes and were excluded from analysis. There were 7 sudden deaths (symptoms for less than 1 h in a previously stable patient) and 12 from progressive CHF. Patients who died of progressive CHF had lower left-ventricular ejection fractions and higher concentrations of atrial natriuretic factor than the 21 survivors, but there were no differences in these variables between survivors and those who died suddenly. However, the sudden death group had significantly (p < 0.05) greater inter-lead variability in the QT interval on the electrocardiogram (QT dispersion; 98.6 [95% CI 79.1-118] ms1/2) than survivors (53.1 [41.9-64.3] ms1/2) or the group who died from progressive CHF (66.7 [51.8-81.6] ms1/2). QT dispersion is a marker of myocardial electrical instability. The association of increased QT dispersion with sudden death suggests that patients at high risk of such death could be identified by means of this simple, reproducible test. This group might benefit from more intensive treatment.

Topics: Aged; Aged, 80 and over; Aldosterone; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Chronic Disease; Death, Sudden, Cardiac; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Norepinephrine; Retrospective Studies

The effects of natriuretic peptides in kidney are blunted in congestive heart failure (CHF). The aim of this study is to examine the changes of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) second messenger productions in CHF. Experiments were conducted on 300-day-old normal and cardiomyopathic hamsters. Blood was collected for ANF measurement. cGMP accumulation studies were done in glomeruli upon ANF and BNP stimulation, and in inner medullary collecting duct (IMCD) cells upon ANF stimulation. Higher plasma ANF levels were found in cardiomyopathic hamsters (811.3 +/- 124.6 vs. 166.6 +/- 13 pg/ml, p < 0.01). ANF-stimulated cGMP accumulations in glomeruli and IMCD cells were higher in cardiomyopathic hamsters. Increased BNP-stimulated cGMP accumulations were also observed in cardiomyopathic hamster glomeruli. These results suggest that the renal hyporesponsiveness to natriuretic peptides in CHF in not due to attenuated ANF and BNP second messenger productions.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cells, Cultured; Cricetinae; Cyclic GMP; Heart Failure; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Mesocricetus; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Second Messenger Systems

The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. Our purpose was to determine whether the functional impairment of the failing heart is associated with changes in levels of mRNA encoding proteins that modulate parameters of contraction and relaxation and whether the increased fibrosis observed in the failing heart is related to elevated expression of genes encoding extracellular matrix components. We studied hearts of 18- to 24-month-old spontaneously hypertensive rats with signs and symptoms of heart failure (SHR-F) or without evidence of failure (SHR-NF) and of age-matched normotensive Wistar-Kyoto (WKY) rats. Compared with WKY rats, SHR-NF exhibited left ventricular (LV) hypertrophy (2.2-fold) and right ventricular (RV) hypertrophy (1.5-fold), whereas SHR-F were characterized by comparable LV hypertrophy (2.1-fold) and augmented RV hypertrophy (2.4-fold; all P < .01). Total RNA was isolated from ventricles and subjected to Northern blot analysis. In SHR-F hearts, the level of alpha-myosin heavy chain mRNA was decreased in both ventricles to 1/3 and 1/5 of the SHR-NF and WKY values, respectively (both P < .01). Levels of beta-myosin heavy chain, alpha-cardiac actin, and myosin light chain-2 mRNAs were not significantly altered in hearts of SHR-NF or SHR-F. Levels of alpha-skeletal actin were twofold greater in SHR-NF hearts compared with WKY hearts and were intermediate in SHR-F hearts. Levels of atrial natriuretic factor (ANF) mRNA were elevated threefold in the LV of SHR-NF (P < .05) but were not significantly increased in the RV of SHR-NF compared with WKY rats. During the transition to failure (SHR-F versus SHR-NF), ANF mRNA levels increased an additional 1.6-fold in the LV and were elevated 4.7-fold in the RV (both P < .05). Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SRCA) mRNA were maintained in the LV of hypertensive and failing hearts at levels not significantly different from WKY values. In contrast, the level of RV SRCA mRNA was 24% less in SHR-NF compared with WKY rats, and during the transition to failure, this difference was not significantly exacerbated (29% less than the WKY value). The levels of fibronectin and pro-alpha 1(I) and pro-alpha 1(III) collagen mRNAs were not significantly elevated in either ventricle of the SHR-NF group but were fourfold to fivefold higher in both ventricles of SHR-F (all P < .05).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiac Output, Low; Cardiomegaly; Contractile Proteins; Extracellular Matrix Proteins; Gene Expression; Genes; Heart; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sarcoplasmic Reticulum

To investigate the role of endogenous atrial natriuretic peptide (ANP) in rats with heart failure (HF), we administered HS-142-1 (HS; 3 mg/kg body wt iv), a novel nonpeptide ANP-receptor antagonist, to rats with surgically induced myocardial infarction and sham-operated rats. HF was characterized by a higher left ventricular end-diastolic pressure and higher plasma ANP concentration vs. controls. HS administration significantly reduced the plasma and urinary levels of guanosine 3',5'-cyclic monophosphate in rats with HF [plasma concentration 10.6 +/- 2.6 vs. 2.7 +/- 0.4 nM (P < 0.05); urinary excretion 48 +/- 8 vs. 12 +/- 2 pmol/min (P < 0.05)]. Systemic and renal hemodynamics were unaffected by HS administration. Urine flow (-35%) and urinary sodium excretion (-50%) were significantly decreased after HS only in those rats with HF that had no changes in systemic and renal hemodynamics. These results suggest that the elevated ANP levels in HF do not contribute directly to the maintenance of systemic hemodynamics but rather compensate for the HF mainly via diuresis and natriuresis, achieved by the inhibition of renal tubular reabsorption rather than by renal vasodilatation.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cyclic GMP; Diuresis; Hemodynamics; Male; Polysaccharides; Rats; Rats, Wistar; Renal Circulation; Renin

Neurohumoral parameters in 45 asymptomatic patients with acute myocardial infarction were measured. In patients with mild left ventricular dysfunction (ejection fraction < or = 45% and/or left ventricular end-diastolic pressure > or = 15 mm Hg), atrial natriuretic peptide levels differed significantly from those in patients with normal left ventricular function (127 +/- 74 pg/ml vs. 79 +/- 71 pg/ml; p < 0.001). After stimulus an increase in atrial natriuretic peptide levels (79 +/- 71 to 118 +/- 86 pg/ml; p < 0.001) was found only in patients with normal hemodynamic parameters. These data show that in patients with left ventricular dysfunction, the atrial natriuretic system is activated; however, atrial natriuretic peptide response to stimulus is present only in patients with normal hemodynamics.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Radioimmunoassay; Renin; Ventricular Function, Left

High levels of endogenous atrial natriuretic peptide (ANP) are thought to compensate the condition of patients with heart failure by reducing preload and afterload. However, recent reports have indicated that a high plasma ANP level is a prognostic predictor in patients with heart failure. Therefore, the role of endogenous ANP has not been clearly established in patients with heart failure.. The plasma ANP and cGMP levels were determined in the femoral artery and the femoral vein of 97 patients with chronic congestive heart failure (CHF). The plasma ANP level decreased significantly, whereas the plasma cGMP levels increased significantly from the femoral artery to the femoral vein. Among patients with mild CHF (n = 52), the plasma cGMP level correlated with the ANP level, and the calculated ANP extraction level also correlated with the calculated cGMP production in the peripheral circulation (r = 0.70, p < 0.001). In contrast, these correlations were not found in patients with severe CHF (n = 45). Among these patients, the plasma cGMP levels seemed to reach a plateau despite high levels of plasma ANP, and the molar ratio of cGMP production to ANP extraction in the peripheral circulation was significantly lower than in patients with mild CHF (36.7 +/- 9.5 versus 183 +/- 17, p < 0.001). In patients with acute severe CHF (n = 9) and those with mild CHF, patients who were administered exogenous ANP, plasma cGMP levels increased in proportion to those of plasma ANP without saturation.. These results indicate that downregulation of ANP receptors coupled to guanylate cyclase may occur in the peripheral vascular beds of patients with chronic severe CHF.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Chronic Disease; Down-Regulation; Extremities; Female; Femoral Artery; Femoral Vein; Guanylate Cyclase; Humans; Male; Middle Aged; Osmolar Concentration; Receptors, Atrial Natriuretic Factor

The acute and chronic interactions of the renal nerves, atrial natriuretic factor (ANF), and mineralocorticoids for the regulation of sodium balance were examined in dogs with an arteriovenous (AV) fistula and the syndrome of high-output heart failure (HOHF) (n = 6). After the AV fistula and bilateral renal denervation, the animals avidly retained sodium for 5-7 days and then regained sodium balance for the subsequent 3 wk. This compensation was associated with the sustained elevations of plasma ANF and the normalization of plasma renin. Subsequent administration of deoxycorticosterone acetate (DOCA) for 10 days produced consistent sodium retention despite additional elevations in plasma ANF. All of these responses were similar to previous studies in AV fistula dogs with intact renal nerves. In a separate part of the study, the renal actions of acute synthetic ANF infusions were examined in these renal-denervated AV fistula dogs before and after DOCA. In the pre-DOCA experiments, ANF infusions at 15, 30, and 100 ng.kg-1.min-1 produced dose-related increases in urinary sodium excretion and significant elevations in creatinine clearance. In the presence of DOCA, urinary sodium excretion was markedly attenuated during identical ANF infusions. The composite results suggest that mineralocorticoids have an important modulatory role for the regulation of sodium balance in experimental HOHF. However, compared with earlier studies in compensated AV fistula dogs with intact renal nerves, the present studies demonstrate that blockade of efferent renal sympathetic nerve activity can restore the natriuretic expression of acute elevations in circulating ANF.

Topics: Animals; Arteriovenous Fistula; Atrial Natriuretic Factor; Cardiac Output, Low; Creatinine; Denervation; Desoxycorticosterone; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Kidney; Mineralocorticoids; Neurotransmitter Agents; Sodium

Atrial natriuretic factor (ANF) is produced by myocardial tissue, and the plasma ANF concentration is known to be elevated in congestive heart failure (CHF). Data from animal models indicate that myocardial concentrations of ANF are depleted in CHF, and this has given rise to the hypothesis that CHF is characterized by depletion of stored ANF. To date, the molecular forms of ANF and their concentrations in atrial and ventricular myocardium remain poorly characterized in the normal and the failing human heart.. We measured ANF concentrations in fresh tissue from failing human hearts explanted at the time of cardiac transplantation and from organ donors whose normal hearts could not be used for transplantation. We determined total ANF and alpha, beta, and gamma ANF concentrations in the right and left atrial appendages, atrial free walls, and ventricles. In normal hearts, ANF concentration in the atrial appendages was 40-fold higher than ANF in the rest of the atrial free wall and in the ventricles. In the failing hearts, atrial appendage ANF concentrations increased 5- to 10-fold, and atrial free wall ANF concentrations increased 200-fold. Analysis of molecular forms of ANF demonstrated significant increases in the gamma and beta forms in the left atrial appendage of failing hearts. alpha, beta, and gamma ANF forms were also significantly increased in right and left atrial free wall tissue from failing hearts. In addition, failing hearts were characterized by absolute and relative increases in the precursor form gamma ANF.. These data from fresh tissues suggest that cardiac ANF stores are not decreased in severe CHF in humans; rather, chronic CHF is characterized by marked increases in atrial ANF tissue concentrations, particularly the beta and gamma ANF forms. These findings are consistent with intracellular accumulation of precursor ANF forms in severe chronic human CHF.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Cardiac Output, Low; Child; Child, Preschool; Humans; Middle Aged; Myocardium; Osmolar Concentration; Reference Values; Tissue Distribution

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

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

1. The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99-126), (b) an endopeptidase-24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats. 2. Infusion of low-dose-ANP (100 ng kg-1 min-1) produced a gradual increase in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure. 3. Infusion of high-dose ANP (300 ng kg-1 min-1) produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure. 4. Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low-dose ANP infusion (100 ng kg-1 min-1) to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-1 min-1). However, unlike high-dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low-dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi.5. Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high-dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542.6. Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A-V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7. These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E-24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C-ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.

Topics: Animals; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuretics; Glomerular Filtration Rate; Lithium; Male; Natriuresis; Neprilysin; Peptide Fragments; Rats; Rats, Wistar

We have investigated whether binding parameters and subtypes of glomerular, papillary, and vascular atrial natriuretic factor (ANF) receptors differ in rats with moderate high-output heart failure [aortocaval (AC) shunt] from their sham-operated controls. Body weight was lower and relative heart weight was higher in the AC shunt group than in the control group. Plasma renin activity (PRA) was also greater in AC shunt rats. Plasma COOH- and NH2-terminal ANF levels were higher in AC shunt animals than in their control counterparts. Total atrial ANF content was elevated in both the right and left atria of the AC shunt group. Glomerular and papillary ANF receptor density (Bmax) and ANF receptor affinity (Kd) were similar in both AC shunt and control rats. Vascular ANF receptor density and affinity were lower in AC shunt (Bmax = 65 +/- 13 fmol.mg protein; Kd = 467 +/- 52 pM) than in control rats (Bmax = 188 +/- 34 fmol.mg protein; Kd = 278 +/- 11 pM). Irreversible cross-linking of 125I-labeled ANF followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions and radioautography demonstrated that both high- and low-molecular weight receptors were unchanged in glomerular membranes and downregulated in vascular membranes from AC shunt animals. However, guanosine 3',5'-cyclic monophosphate (cGMP) production by the isolated glomeruli of AC shunt rats was lower than that of controls. We conclude that in the presence of elevated plasma ANF levels, glomerular, papillary, and vascular ANF receptors may be regulated differently.

Topics: Animals; Atrial Natriuretic Factor; Autoradiography; Blood Vessels; Cardiac Output, Low; Cyclic GMP; Electrophoresis, Polyacrylamide Gel; Heart Ventricles; Kidney Glomerulus; Male; Molecular Weight; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

To define the renal effects of atrial natriuretic peptide (ANP) in heart failure, we studied rats with heart failure after coronary artery ligation. The rats received either captopril (2 milligrams drinking water) or placebo for 4 weeks. Glomerular filtration rate, renal plasma flow, filtration fraction, urine volume, urinary sodium excretion and the percent fractional excretion of sodium were measured before and after an infusion of ANP (0.3 microgram/kg/min). To determine whether changes in ANP receptor binding and responsiveness occur in heart failure and after captopril treatment, we performed radioreceptor binding studies and measured guanylate cyclase activity. Atrial natriuretic peptide in sham-operated rats decreased mean arterial pressure from 118 +/- 5 to 95 +/- 5 mm Hg (P less than .001), increased urine volume from 0.06 +/- 0.02 to 0.16 +/- 0.05 ml/min/kg (P less than .05), urinary sodium excretion, 14.2 +/- 3.1 to 41.4 +/- 8.9 mu eq/min/kg (P less than .02), filtration fraction from 0.30 +/- 0.03 to 0.40 +/- 0.4 (P less than .05), and the percent fractional excretion of sodium from 0.84 +/- 0.19 to 2.85 +/- 0.61 (P less than .02). Atrial natriuretic peptide in untreated rats with heart failure produced no significant systemic or renal hemodynamic effects. In rats with heart failure treated with captopril, ANP decreased mean arterial pressure from 93 +/- 4 to 86 +/- 4 mm Hg (P less than .05) and increased hematocrit from 50 +/- 2 to 52 +/- 1 (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Captopril; Cardiac Output, Low; Disease Models, Animal; Down-Regulation; Guanylate Cyclase; Hemodynamics; Kidney; Kidney Glomerulus; Kinetics; Male; Myocardial Infarction; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Renal Circulation; Renin-Angiotensin System

Treatment of male rabbits with adriamycin at a cardiotoxic dose (1 mg/kg intravenously, i.v., twice a week for 9 weeks) caused cardiovascular disturbances characteristic of chronic heart failure. The severity of symptoms varied, indicating differences in the individual sensitivity of the animals to adriamycin. Thus, cardiac output (CO) was decreased by greater than 40% in only 4 of the 7 animals in which it was measurable at 9 weeks. Elevated levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA), as well as pulmonary congestion, hydrothorax, and ascites were also evident. The baroreflex response to sodium nitroprusside (NPS) was blunted. The response to the inotropic drug dobutamine was depressed by 50% as compared with the control animals. Right ventricular beta-adrenoceptor density was significantly reduced in these animals (22.9 +/- 3.1 as compared with 31.8 +/- 1.0 fmol/mg protein in control animals) owing to a selective downregulation of the beta 1-adrenoceptor population. The loss of beta-adrenoceptors was highly correlated with severity of heart failure symptoms: i.e., baroreflex dysfunction as indicated by the NPS slope (r = 0.91), decrease in CO during the previous weeks (r = 0.88), and plasma norepinephrine (NE) levels (r = 0.96). However, when all adriamycin-treated animals were compared collectively regardless of the severity of heart failure, with the controls, no difference in the beta-adrenoceptor density was detectable, a finding in agreement with previous observations in this model. Chronic treatment of rabbits with adriamycin thus causes low-output failure, reflecting some of the findings reported for the human disease; however, individual sensitivity to adriamycin varies considerably between rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Output, Low; Dobutamine; Down-Regulation; Doxorubicin; Heart; Heart Rate; In Vitro Techniques; Injections, Intravenous; Male; Nitroprusside; Organ Size; Pressoreceptors; Rabbits; Receptors, Adrenergic, beta; Renin

We tested the hypothesis that the atrial natriuretic peptide (ANP) mediated decrease in baroreceptor sensitivity that is seen in normal rats is more pronounced in a state of depressed cardiac performance. Holtzman rats (n = 15) were injected with Adriamycin (1 mg/kg i.p. 3 times/week for 8-10 weeks). Control rats (n = 17) were injected with 0.9% saline. Experiments were done in conscious animals that had been catheterized for i.v. infusions and for measurement of arterial blood pressure (ABP) and heart rate (HR). ANP (250 ng.kg-1.min-1) or saline vehicle was infused i.v. Graded periodic bolus injections of phenylephrine or sodium nitroprusside were given to assess baroreceptor sensitivity (beats.min-1.mmHg-1) up to 60 mmHg (1 mmHg = 133.3 Pa) above and below resting ABP. The following day the experiment was repeated with the ANP-vehicle regimen reversed. Finally, the rats were anesthetized and the rate of left ventricular pressure increase (dP/dt) was measured. Data evaluation included calculation of least squares linear regression slopes of peak delta HR vs. peak delta ABP, applying corrections for experimental errors in both the dependent and independent variables. Adriamycin rats (A) did not differ significantly from control rats (C) with respect to either initial ABP (A = 105 +/- 5; C = 100 +/- 3; mean mmHg +/- SEM) or initial HR (335 +/- 9 vs. 312 +/- 13 beats.min-1). However, their indices of cardiac performance were significantly depressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Doxorubicin; Heart Rate; Male; Pressoreceptors; Rats; Reflex; Regression Analysis

Brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are novel natriuretic peptides, originally isolated from porcine brain. Similar to atrial natriuretic peptide (ANP), BNP is also synthesized in and secreted from cardiocytes, but CNP is not expressed at significant levels in normal adult myocardium. Previous studies have indicated that the serum level and ventricular expression of the ANP gene were augmented in patients with heart failure. Recently, the serum level of BNP was also reported to increase in human heart failure. To examine whether or not the expression of these natriuretic peptides is regulated in ventricular myocardium in a concordant manner, we performed Northern blot analysis using total cellular RNA isolated from the diseased left ventricles of 30 cardiac transplant recipients with end-stage heart failure, seven ventricles from organ donors (control group), and two ventricles of artificially aborted 17- and 19-week-old fetuses. The levels of mRNAs encoding both BNP and ANP increased significantly (p less than 0.01) in the left ventricular myocardium from the patients with end-stage heart failure as compared with the control group. The levels of BNP mRNA correlated positively with those of ANP mRNA (r = 0.73, p less than 0.01) and negatively with those of sarcoplasmic reticulum Ca(2+)-ATPase mRNA (r = -0.66, p less than 0.01) in the left ventricular myocardium from the patients with heart failure. There was also a negative correlation between the levels of ANP and the sarcoplasmic reticulum Ca(2+)-ATPase mRNAs (r = -0.65, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiac Output, Low; Female; Fetus; Gene Expression; Heart; Heart Ventricles; Humans; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; RNA, Messenger

Atrial natriuretic peptide alters left ventricular performance in patients with heart failure. To assess the direct effects of this hormone on myocardial function, its actions were compared with those of the pure vasodilator nitroprusside in 10 patients with heart failure. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained during a baseline period, during nitroprusside infusion, during a second baseline period and during atrial natriuretic peptide infusion. The baseline end-systolic pressure-volume relation was generated in nine patients from pressure-volume loops obtained during the two baseline periods and during afterload reduction with nitroprusside. Mean arterial pressure decreased with atrial natriuretic peptide (89 +/- 3 to 80 +/- 2 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (90 +/- 4 to 73 +/- 3 mm Hg, p less than 0.05). Left ventricular end-diastolic pressure also decreased with atrial natriuretic peptide (24 +/- 2 to 16 +/- 3 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (24 +/- 2 to 13 +/- 3 mm Hg, p less than 0.05). Cardiac index increased during infusion of each agent from 2.0 +/- 0.2 to 2.4 +/- 0.2 liters/min per m2 (p less than 0.01). Heart rate increased slightly with nitroprusside but did not change with atrial natriuretic peptide. Peak positive first derivative of left ventricular pressure (dP/dt), ejection fraction and stroke work index were unchanged by either agent. The relation between end-systolic pressure and volume during atrial natriuretic peptide infusion was shifted slightly leftward from the baseline value in four patients, slightly rightward in four and not at all in one patient, indicating no consistent inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Diastole; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Nitroprusside

Renal plasma flow (RPF), glomerular filtration rate (GFR), renal proximal tubular delivery of sodium and water evaluated by lithium clearance, and hormonal parameters were measured in 12 patients with congestive heart failure NYHA class II-IV before and after captopril treatment for 4 wk and in 13 healthy control subjects. RPF and GFR were significantly decreased in heart failure, whereas the filtration fraction (FF) was increased. Treatment with captopril increased RPF and decreased FF, whereas GFR was unchanged. Total and fractional urinary excretion of sodium were reduced in the patients compared with the controls, but increased after captopril. Fractional excretion of lithium was normal in heart failure and was increased by captopril. Atrial natriuretic peptide, guanosine 3',5'-cyclic monophosphate, and aldosterone in plasma were significantly elevated in heart failure and were reduced by treatment with captopril. Plasma renin activity was increased in patients, correlated inversely with RPF, and increased further after captopril treatment. It is concluded that the reduced sodium excretion in heart failure was caused by a combination of diminished glomerular filtration and enhanced tubular reabsorption beyond the proximal tubule and that treatment with captopril increased urinary sodium excretion partly due to an attenuated sodium reabsorption in the proximal tubule. The present data in patients with congestive heart failure are consistent with an increased intrarenal angiotensin II generation and an elevated plasma level of aldosterone being involved in the pathogenesis of the glomerular hemodynamic changes and the enhanced distal tubular reabsorption, respectively.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Circadian Rhythm; Cyclic GMP; Dinoprostone; Female; Glomerular Filtration Rate; Heart Rate; Humans; Male; Middle Aged; Myocardium; Potassium; Renal Circulation; Renin; Renin-Angiotensin System; Sodium; Urinary Retention

A canine model of chronic heart failure was produced by multiple sequential intracoronary embolizations with microspheres. Twenty closed-chest dogs underwent three to nine intracoronary embolizations performed 1-3 wk apart. Embolizations were discontinued when left ventricular (LV) ejection fraction was less than 35%. LV ejection fraction was 64 +/- 2% at baseline and decreased to 21 +/- 1% at 3 mo after the last embolization (P less than 0.001). During the same period, LV end-diastolic pressure increased from 6 +/- 1 to 22 +/- 3 mmHg (P less than 0.001); LV end-diastolic volume increased from 64 +/- 3 to 101 +/- 6 6 ml (P less than 0.001), and cardiac output decreased from 2.9 +/- 0.2 to 2.3 +/- 0.1 l/min (P less than 0.01). These changes were accompanied by significant increases of pulmonary artery wedge pressure and systemic vascular resistance. Plasma norepinephrine increased from 332 +/- 17 pg/ml at baseline to 791 +/- 131 pg/ml at 3 mo after the last embolization (P less than 0.01); plasma levels of atrial natriuretic factor increased from 12.7 +/- 10.0 to 28.8 +/- 8.6 pmol/l (P less than 0.01), whereas plasma renin activity remained unchanged. Gross and microscopic postmortem examination showed patchy myocardial fibrosis and LV hypertrophy. We conclude that multiple intracoronary embolizations with microspheres, separated in time, can lead to chronic heart failure in dogs. The preparation is stable and reproducible and manifests many of the sequelae of heart failure that result from loss of contractile myocardium.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Cardiac Output, Low; Chronic Disease; Coronary Disease; Disease Models, Animal; Dogs; Embolism; Heart Ventricles; Microspheres; Norepinephrine; Pulmonary Wedge Pressure; Renin; Stroke Volume; Vascular Resistance; Ventricular Function, Left

This study evaluated the role of changes in heart rate, atrial pressure, volume, and cardiac tissue atrial natriuretic factor (ANF) concentration in the modulation of plasma ANF concentration in a model of pacing-induced heart failure.. The effects of acute right ventricular pacing (250 beats/min), acute volume expansion (35 ml/min), and volume expansion after 1 week of right ventricular pacing on plasma ANF concentration were compared in eight dogs (group 1). As shown during right ventricular pacing previously, volume expansion produced significant increases in cardiac filling pressures and left atrial volume. Right ventricular pacing and volume expansion produced similar increments in plasma ANF concentration: from 32 +/- 12 to 168 +/- 153 pg/ml (p less than 0.05) and from 32 +/- 9 to 137 +/- 113 pg/ml (p less than 0.05), respectively. When pacing was initiated after volume expansion, plasma ANF concentration increased further to 462 +/- 295 pg/ml (p less than 0.05) despite little change in filling pressures and left atrial volume. With repeated volume expansion after 1 week of pacing, there were no significant further increases in left atrial volume and plasma ANF concentrations (from 332 +/- 121 to 407 +/- 113 pg/ml) despite significant increases in filling pressures. Atrial and ventricular tissue samples were also obtained from 21 dogs paced to severe heart failure (group 2) and from 14 normal dogs (controls). In all groups, atrial ANF was higher than ventricular ANF concentration. At 1 week (group 1), left atrial appendage ANF concentration (6.2 +/- 2.5 versus 16.1 +/- 10.3 ng/mg) was reduced, whereas left ventricular free wall ANF concentration (0.62 +/- 0.31 versus 0.24 +/- 0.16 pg/mg) was increased compared with that of controls (both p less than 0.001). At severe heart failure (group 2), atrial ANF remained low, whereas ventricular ANF concentration was similar to that of the controls.. These data indicate that in pacing-induced heart failure, changes in heart rate, atrial pressure, and volume all contribute to the increased plasma ANF concentration. However, by 1 week (early heart failure), ANF release is attenuated, perhaps because of the inability of the atria to be stretched further and because of reduced atrial ANF concentration. In addition, the ventricle may be an additional source of ANF.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cardiac Output, Low; Cardiac Pacing, Artificial; Dogs; Heart; Heart Atria; Heart Rate; Myocardium; Osmolar Concentration; Plasma Substitutes; Time Factors

The relationship between plasma levels of immunoreactive atrial natriuretic peptide (ir-ANP), arginine vasopressin (AVP), cardiac rhythm and different haemodynamic variables were studied at rest and during exercise in 16 patients with heart failure undergoing heart catheterization for clinically indicated reasons. Even though there was no significant relationship between pulmonary capillary wedge pressure (PCW) and ir-ANP at rest (r = 0.39; P = 0.14) changes in these variables with exercise correlated well (r = 0.71; P = 0.002). Change in right atrial mean pressure, heart rate, mean arterial blood pressure or cardiac index did not significantly influence change in plasma levels of ir-ANP. The correlation between PCW and AVP at rest (r = 0.92; P less than 0.001) disappeared during exercise. Calculated ir-ANP/PCW ratios decreased slightly during exercise, but were not influenced by initial atrial pressures or atrial fibrillation. These observations provide evidence for a similar responsiveness of ANP in patients with sinus rhythm and atrial fibrillation. The ability of rapid change in ANP plasma levels during exercise was preserved and proportional to changes in PCW over a wide pressure range in the studied patient group. This finding indicates that left atrium distension rather than right atrium distension is the major determinant for the release of ANP in patients with congestive heart failure. The observed rapid responsiveness of ANP to change in left atrial pressure may allow the hormone to modulate haemodynamic response during short periods of exercise.

Topics: Adult; Aged; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Exercise; Female; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Wedge Pressure; Radioimmunoassay; Rest

Topics: Atrial Natriuretic Factor; Cardiac Output, Low; Humans; Male; Middle Aged; Myocardium; Renal Dialysis; Water-Electrolyte Imbalance

Atrial natriuretic factor 95-126 [ANF (95-126)] is a novel 32 amino acid peptide which is thought to originate from the kidney. The systemic hemodynamic and renal effects of equimolar doses of intravenous synthetic ANF (95-126) and synthetic alpha ANF (99-126) were examined in normal dogs (n = 6) and in dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure (n = 5). ANF (95-126) and alpha ANF (99-126) were infused at 5 and 10 pmol/kg/min for 75-min periods each. In the normal and AV fistula dogs the two peptides similarly decreased mean arterial pressures and right atrial pressures (P less than .05). Creatinine clearance and urinary volume excretion increased (P less than .05) in the normal dogs with both peptides, but only ANF (95-126) produced significant elevations (P less than .05) of these two parameters in the AV fistula animals. With the highest infusion dose, ANF (95-126) increased urinary sodium excretion to at least twice the levels observed with alpha ANF (99-126) in both groups of dogs (P less than .05). The decreases in plasma renin and aldosterone were comparable for the two peptides in both groups of animals. These results indicate that ANF (95-126) is more potent than alpha ANF (99-126) for the promotion of a natriuresis, particularly in AV fistula dogs with compensated high-output heart failure, in which the sodium excretory actions of alpha ANF (99-126) were attenuated markedly.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Creatine; Diuretics; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Kidney; Peptide Fragments

Sixteen patients presenting for abdominal aortic surgery were divided into two groups according to whether or not there was a history and clinical evidence of chronic heart failure (CHF). Atrial natriuretic peptide (ANP) and catecholamines were measured during a preoperative exercise test and then with induction of anaesthesia and surgery. Patients in the CHF group (n = 8) had a much-reduced cardiac output (CO) rise in response to exercise compared to the control group (13% vs. 75%, P less than 0.05). This difference was due to the absence of a stroke volume increase in the CHF group. Induction of anaesthesia resulted in a greater fall in mean arterial pressure in the CHF group prior to the start of surgery, due to a greater fall in CO. Plasma ANP levels were higher in the CHF group at rest and at each exercise stage (P less than 0.05). ANP levels were not altered by induction of anaesthesia or intubation, but increased with the start of surgery in the CHF group (P less than 0.05). Increases in plasma catecholamine levels in response to exercise and to surgery were similar in the two groups. Changes in endogenous ANP may be important in counteracting the undesirable effects of vasoconstrictor hormones during physical exercise or surgical stress.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia, Intravenous; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Output, Low; Electrocardiography; Epinephrine; Exercise Test; Heart Rate; Humans; Intraoperative Care; Intubation, Intratracheal; Middle Aged; Norepinephrine; Preoperative Care; Pulmonary Wedge Pressure; Time Factors; Vascular Resistance

The therapeutic potential of atrial natriuretic peptide (ANP) was assessed in an ovine model of heart failure induced by rapid left ventricular (LV) pacing and compared with the effects of angiotensin converting enzyme (ACE) inhibition. Hemodynamic, hormonal, and metabolic measurements were studied during three 5-day periods of LV pacing. No treatment (control) or a continuous ANP infusion (25 ng/kg/min) was given in random order during the first two periods, while ACE inhibitor was always given during the third period. Baseline measurements immediately prior to the start of each pacing phase showed no significant variation. Significant neurohumoral activation and hemodynamic responses were observed in each pacing phase. During ANP infusion, plasma ANP levels were 3-5-fold higher than those observed in the control or ACE inhibition treatment phases. Compared with control, a natriuresis was observed on the first day, whereas glomerular filtration rate (GFR) tended to be maintained during ANP infusion. The rise in left atrial pressure and plasma aldosterone tended to be blunted. When the two treatment phases were compared, the rise in left atrial pressure during LV pacing was less with ACE inhibition, whereas there was a similar reduction in sodium retention after the initial natriuresis with ANP. By contrast, GFR tended to be maintained better during ANP infusion compared to ACE inhibition. These results suggest that ANP, or a similar "enhancing" analogue, may be useful in the treatment of heart failure, especially if administered early in the development of the disorder.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiac Pacing, Artificial; Female; Glomerular Filtration Rate; Hemodynamics; Infusions, Intra-Arterial; Sheep

The changes in plasma immunoreactive atrial natriuretic factor (iANF) and urinary Na excretion that occur in response to an oral load of Na and to infusion of synthetic atrial natriuretic factor (ANF) were examined in conscious dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure. After ingestion of a meal containing 125 meq Na, plasma iANF and right atrial pressure increased from high basal levels of 506 +/- 46 pg/ml and 96 +/- 5 mmH2O to peak responses of 728 +/- 43 pg/ml (P less than 0.05) and 104 +/- 6 mmH2O (P less than 0.05). These increases were associated with a brisk postprandial natriuresis and diuresis of a magnitude previously observed in normal dogs. Synthetic ANF infusions that achieved plasma iANF levels of similar and higher magnitude to those observed during the feeding experiments did not produce a significant natriuresis in these AV fistula dogs. In separate series of experiments, chronic effects of normal and low-Na diets on daily Na excretion and postabsorptive plasma iANF, renin, and aldosterone were studied in normal and AV fistula dogs. During the normal Na diet of 40 meq/day, both groups had normal levels of renin and aldosterone, but Na balance was achieved in AV fistula animals in the presence of a fourfold elevation in plasma iANF compared with normal dogs (P less than 0.05). During 2 wk of Na restriction, cumulative negative Na balance and marked stimulation of renin and aldosterone were similar in normal and AV fistula animals, but plasma iANF did not change significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Absorption; Aldosterone; Animals; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Cardiac Output, Low; Chronic Disease; Diet, Sodium-Restricted; Dogs; Eating; Female; Kidney; Renin; Sodium

Elucidation of the role of (elevated) endogenous atrial natriuretic factor (ANF) in chronic heart failure has been hampered by a lack of specific inhibitors. We used a newly developed monoclonal antibody that has been shown to specifically block both exogenously and endogenously released ANF in vivo. For assessment of the vasodilatory action of ANF in chronic heart failure, either this antibody against ANF or ascites (control serum) was injected in rats with myocardial infarction and failure and in sham animals. Ascites did not alter central hemodynamics in either the sham or infarcted group. Antibody significantly increased right atrial pressure, left ventricular end-diastolic pressure, and systemic vascular resistance (SVR) in the infarction group but did not affect these variables in the sham group. Because renal blood flow, as measured by radioactive microspheres, decreased significantly in all four groups, probably due to nonspecific renal vasoconstrictor effects of the ascites, a separate group of infarcted animals was treated with purified ANF antibody (devoid of nonspecific effects) or mouse IgG as a control injection. In these animals, right atrial pressure increased from 1.1 +/- 0.7 to 2.6 +/- 0.7 mm Hg (p less than 0.001). Although SVR, renal blood flow velocity (measured by Doppler probe), and renal vascular resistance did not change in the infarcted animals after administration of purified ANF antibody, a significant correlation was found between baseline plasma ANF values and the change in SVR exerted by purified ANF antibody (r = 0.758, p less than 0.02, n = 9); that is, SVR increased in rats with high baseline plasma ANF (greater than 350 pg/ml), but decreased in animals with plasma ANF less than 200 pg/ml. These results suggest that moderately elevated endogenous plasma ANF levels in chronic heart failure do affect central hemodynamics, primarily by reducing venous pressure (e.g., by decreasing intravascular volume or by venous dilation). Arterial vasodilation, however, appears to emerge when plasma ANF is greatly increased.

Topics: Animals; Antibodies, Monoclonal; Atrial Natriuretic Factor; Cardiac Output, Low; Chronic Disease; Hemodynamics; Male; Myocardial Infarction; Rats; Rats, Inbred Strains; Vasodilator Agents

Plasma atrial natriuretic factor, aldosterone, renin activity, and antidiuretic hormone were studied in low output heart failure syndromes: cardiogenic shock in ten patients with acute myocardial infarction of the anterior wall (first group), hypovolemic shock after melena from peptic ulcer in ten subjects (second group), and hypotension with bradycardia syndrome in ten patients with acute myocardial infarction of the inferior wall (third group). Circulating atrial natriuretic factor in patients with cardiogenic shock (102.4 +/- 7.4 pg/ml) was significantly higher than in healthy volunteers matched for sex and age (8.4 +/- 0.3 pg/ml). In these patients there was a positive correlation between atrial natriuretic factor and central venous pressure values. Atrial natriuretic factor and central venous pressure values in the second and third groups were within normal range. Plasma aldosterone was high in all groups, plasma renin activity was elevated in the first and third groups, and high antidiuretic hormone was observed in the first and second groups. These findings indicate that in low output heart failure syndromes only hemodynamic changes affecting the atria stimulate atrial natriuretic factor release. No correlations were found between plasma atrial natriuretic factor and other hormones. In particular, high atrial natriuretic factor levels in the patients with cardiogenic shock did not inhibit release of aldosterone, renin, or antidiuretic hormone. It may be surmised that in these patients the hemodynamic effects override the inhibitory effects of atrial natriuretic factor.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Bradycardia; Cardiac Output, Low; Female; Heart Failure; Humans; Male; Melena; Middle Aged; Myocardial Contraction; Myocardial Infarction; Peptic Ulcer Hemorrhage; Renin; Shock, Cardiogenic; Vascular Resistance; Vasopressins; Venous Pressure

The aim of the study was to investigate plasma concentrations of atrial natriuretic peptide, aldosterone, and renin during experimentally induced acute central venous congestion.. Two experimental calf models were used: (1) right heart failure due to pulmonary artery obstruction; (2) inferior vena cava syndrome produced by inferior vena caval obstruction. Hormonal responses and haemodynamic variables were measured over 6 h.. Experiments were performed on three female "Schwarzbund" calves, age 3 months, weight 92 +/- 8 kg.. In the pulmonary artery obstructed group there was an increase of plasma aldosterone from 6.5(SEM 1.6) to 22.1(3.2) ng.dl-1 (p less than 0.05), of renin from 0.7(0.1) to 2.5(0.3) Goldblatt units x 10(-4).ml-1 (p less than 0.05), and of atrial natriuretic peptide from 22.1(4.5) to 141.4(27.8) pmol.litre-1 (p less than 0.05). During inferior vena caval obstruction, aldosterone increased from 2.4(0.4) to 20.9(2.0) ng.dl-1 (p less than 0.05), and renin increased from 0.4(0.05) to 2.0(0.20) Goldblatt units x 10(-4).ml-1 (p less than 0.05). In this experiment, atrial natriuretic peptide remained unchanged. Cardiac output decreased in both groups. There was significant fluid and electrolyte retention during both experiments, with urine volume decreasing from 87.7(11.6) to 35.0(1.2) ml-h-1 in experiment (1), and from 185(14) to 95.7(8.6) ml.h-1 in experiment (2).. The study suggests (1) that in an experimental acute state of reduced cardiac output due to pulmonary artery stenosis with constantly increased right heart pressures, raised endogenous atrial natriuretic peptide failed to induce diuresis and natriuresis; (2) that in acute right heart failure, renin and aldosterone secretion could not be suppressed by raised atrial natriuretic peptide concentrations; and (3) atrial natriuretic peptide secretion seemed to be exhausted after 6 h continuous atrial distension.

Topics: Acute Disease; Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Output, Low; Cattle; Central Venous Pressure; Constriction, Pathologic; Diuresis; Electrolytes; Female; Heart Atria; Pulmonary Artery; Renin; Syndrome; Vena Cava, Inferior

Increased activity of the renin-angiotensin system is thought to play a major role in the pathogenesis of salt retention and edema formation in congestive heart failure. The present study evaluates the effects of chronic inhibition of angiotensin-converting enzyme on the response to infusion of exogenous atrial natriuretic factor (ANF) in salt-retaining rats with chronic arteriovenous (a-v) fistula, an experimental model of high-output congestive heart failure. Administration of ANF in incremental doses (5-50 micrograms.kg-1.h-1) to Inactin-anesthetized, sham-operated control rats resulted in dose-dependent increases in urine flow, sodium excretion, and glomerular filtration rate, and significant decreases in mean arterial blood pressure. These effects of atrial peptide were markedly attenuated in salt-retaining rats with a-v fistula. However, chronic oral treatment with the angiotensin-converting-enzyme inhibitor enalapril restored the natriuretic response of sodium-retaining rats with a-v fistula to high doses of ANF. At a dose of 50 micrograms.kg-1.h-1, fractional excretion of Na (FENa) in a-v fistula rats given enalapril was 4.0 +/- 0.5%, which was significantly greater than that in a-v fistula rats without enalapril (0.5 +/- 0.4%, P less than 0.05) and not different from the response in sham-control rats (4.9 +/- 0.7%). The improvement in the natriuretic response after enalapril was not associated with a significant increase in GFR and occurred despite a decrease in mean arterial pressure. Moreover, chronic enalapril treatment did not significantly alter the plasma levels of immunoreactive ANF in either the sham controls or in the rats with a-v fistula.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Disease Models, Animal; Enalapril; Kidney; Rats; Rats, Inbred Strains; Renin-Angiotensin System

In response to a meat meal containing 125 mEq of sodium, conscious dogs (n = 5) with an arteriovenous (AV) fistula and chronic compensated heart failure exhibited temporally related increases in postprandial plasma immunoreactive atrial natriuretic factor (iANF), right atrial pressure, and sodium excretion. In separate experiments, two weeks of dietary sodium restriction produced similar marked stimulation of renin and aldosterone both in normal dogs (n = 5), and in AV fistula dogs (n = 5) with chronic high circulating levels of ANF. Plasma iANF did not change (P greater than .05) in either group. These results suggest that the ANF system is involved in the postprandial regulation of sodium excretion in the AV fistula dogs with compensated heart failure. In the postabsorptive state, however, the activity of the renin-aldosterone axis is closely related to dietary sodium intake and appears to function independently of the ANF system for the prevention of sodium loss.

Topics: Aldosterone; Animals; Arteriovenous Fistula; Atrial Natriuretic Factor; Cardiac Output; Cardiac Output, Low; Dogs; Female; Renin; Renin-Angiotensin System; Sodium; Sodium, Dietary

We investigated whether rats with high-output heart failure [aortocaval (AC) shunts] release atrial natriuretic factor (ANF) and excrete sodium after moderate volume expansion (VE) as do sham-operated controls. Mean arterial blood pressure was lower (92.5 +/- 4.4 vs. 114.0 +/- 1.3 mmHg) and relative heart weight was higher (545.6 +/- 35.1 vs. 253.8 +/- 9.8 mg/100 g body wt) in animals with AC shunts than in their controls. Central venous pressure (CVP) was elevated (3.61 +/- 0.36 vs. 0.37 +/- 0.94 mmHg) and heart rate decreased (332.5 +/- 8 vs. 370.0 +/- 9.9 beats/min) in AC rats. This group also presented lower basal urinary sodium excretion (UNaV), urinary volume, and hematocrit than their sham-operated controls. Basal plasma COOH- and NH2-terminal ANF levels were greatly elevated in AC shunt animals (165.43 +/- 55.73 and 1,692.98 +/- 305.63 fmol/ml, respectively) when compared with the controls (14.27 +/- 1.49 and 331.67 +/- 29.84 fmol/ml, respectively). VE was performed in conscious rats 3 times at 15-min intervals with human plasma protein fraction. The effect of VE on CVP, left-ventricular end-diastolic pressure, the increases in plasma COOH- and NH2-terminal ANF, and the diuretic and natriuretic responses were similar in both experimental groups. U(NA)V was positively correlated with plasma COOH- (r = 0.50, P less than 0.01) and NH2- (r = 0.60, P less than 0.001) terminal ANF only in the controls. One main peak of immunoreactive ANF corresponding to the elution time of a small peptide such as ANF-(99-126) was detected in the plasma of AC animals after VE. We conclude that ANF release and natriuresis are conserved after moderate VE in a rat model of moderate high-output experimental heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Chronic Disease; Diastole; Diuresis; Male; Natriuresis; Plasma Substitutes; Rats; Rats, Inbred Strains

It has been shown that renal responses to atrial natriuretic peptide (ANP) are markedly attenuated in patients with heart failure. This study aimed to determine if vasodilative response to ANP is altered in patients with heart failure. In patients with heart failure (n = 7) and age-matched normal subjects (n = 7), forearm blood flow was measured using a strain-gauge plethysmograph during intra-arterial infusion of alpha-human ANP (50, 100, 200, and 400 ng/min) or nitroglycerin (100, 200, 400, and 600 ng/min). Forearm vasodilatation evoked with intra-arterial alpha-human ANP in patients with heart failure was considerably less (p less than 0.01) than that in normal subjects. In contrast, nitroglycerin produced comparable forearm vasodilatation in the two groups. Plasma ANP and cyclic guanosine monophosphate (GMP) levels at rest were higher in patients with heart failure than in normal subjects (p less than 0.05 for both), but the increases in plasma ANP and cyclic GMP in the venous effluents during intra-arterial ANP infusion did not differ between the two groups. These results indicate that the direct vasodilative effect of ANP on forearm vessels was attenuated in patients with heart failure as compared with that in normal subjects. The mechanisms responsible for this alteration are not clear but might involve mechanisms other than down-regulation of the ANP receptors because the increases in venous plasma cyclic GMP caused by intra-arterial ANP were comparable between patients with heart failure and normal subjects.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Cyclic GMP; Female; Forearm; Heart Rate; Humans; Injections, Intra-Arterial; Male; Middle Aged; Nitroglycerin; Regional Blood Flow; Vasodilation; Veins

In conscious dogs with and without congestive heart failure, we investigated hemodynamic, hormonal, and renal effects of a new natriuretic peptide [ANP-(95-126)]. Unlike ANP-(99-126), which is secreted in the heart and rapidly inactivated in the kidney, ANP-(95-126) most likely originates from the kidney and is not destroyed by proteolysis in membrane preparations of kidney cortex. In healthy animals intravenous ANP-(95-126) significantly decreased mean arterial pressure, cardiac output, stroke volume, and right atrial pressure and increased heart rate without changing mean pulmonary arterial pressure and total peripheral vascular resistance. In dogs with congestive heart failure, ANP-(95-126) showed no effects on mean arterial pressure, cardiac output, stroke volume, and peripheral vascular resistance but reduced right atrial pressure and pulmonary arterial pressure. Both, in dogs before and after the induction of heart failure, the new peptide led to a significant increase of urine flow and sodium and chloride excretion. In healthy dogs there were indirect indications for a small inhibitory effect on renin and aldosterone secretion. Thus, in contrast to the considerable attenuation of renal effects of ANP-(99-126) in heart failure, the efficacy of ANP-(95-126) on renal excretory function is well preserved, which may be because of the lack of proteolytic degradation in the kidney. These results suggest that ANP-(95-126) may have clinical implications for the treatment of patients with congestive heart failure.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Female; Hormones; Osmolar Concentration; Peptide Fragments

Changes of neurohumoral factors including vasodilatory prostaglandins (PGs) were investigated in an experimental model of moderate low-cardiac-output status induced by rapid right ventricular pacing (240 beats/min). After 7 days of pacing, we studied the response of renal, hormonal, and hemodynamic parameters to cyclooxygenase inhibition by indomethacin and the effects of the renin system by converting-enzyme blockade in addition to the inhibition of PG synthesis. Lowering cardiac output increased plasma levels of norepinephrine and atrial natriuretic peptide. Plasma renin concentration was suppressed, despite a fall in cardiac output and blood pressure and a stimulation of sympathetic nerve activity. Urinary excretion of PGE2 was increased (P less than 0.04); plasma levels of PGE2 and 6-keto-PGF1 alpha were unchanged as measured in blood from the renal vein, pulmonary artery, and aorta. During low cardiac output, we found a significant decrease of glomerular filtration rate, whereas renal blood flow and renal and peripheral vascular resistances were unchanged. Administration of indomethacin decreased plasma and urinary PGs significantly, markedly reduced renal blood flow, and increased renal vascular resistance without affecting peripheral vascular resistance. The additional blockade of the renin-angiotensin system by captopril showed mainly a vasodilator effect on peripheral arterial resistance vessels, resulting in an increase of cardiac output. Our results suggest that, in moderate low-cardiac-output status, renal blood flow is maintained by renal vasodilator PGs, which counterbalance vasoconstrictor mechanisms like the activated sympathetic nerve activity. We indirectly showed the importance of angiotensin II in preserving glomerular filtration rate, which declines when renin secretion is suppressed, as it may be the case in moderate heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Dogs; Female; Indomethacin; Kidney; Norepinephrine; Prostaglandins; Renal Circulation; Renin-Angiotensin System

The renal response to atrial natriuretic factor (ANF) has been shown to be blunted in several experimental models of acute and chronic congestive heart failure. The mechanism responsible for this blunted response has been postulated to be activation of the renin-angiotensin system with associated potent antinatriuretic effects and/or the reduction in renal perfusion pressure (RPP) characteristic of heart failure. The present study was designed to examine the relative role of these two factors in mediating the blunted response to ANF in a model of acute low output heart failure produced by thoracic inferior vena cava constriction (TIVCC) in the anesthetized dog. TIVCC was produced in five groups of dogs. In group 1, ANF was infused after TIVCC to document the blunted natriuretic response. In group 2, ANF was infused after TIVCC in the presence of blockade of intrarenal angiotensin II (ANG II) by the intrarenal infusion of saralasin (Sar) at a dose without systemic effects. In group 3, ANF was infused after TIVCC in the presence of restoration of RPP by infusion of ANG II at a dose titrated to restore RPP to the level present before TIVCC. In group 4, ANF was infused in the presence of restoration of RPP with ANG II and blockade of intrarenal ANG II with Sar. Group 5 served as an additional control group where the effect of ANG II and Sar in TIVCC was examined in the absence of ANF. Restoration of RPP but not blockade of intrarenal ANG II resulted in a restoration of the response of sodium excretion and glomerular filtration rate to ANF. ANG II plus Sar in the absence of ANF did not produce a natriuresis. We conclude that RPP, more than intrarenal ANG II, modulates the blunted renal response to ANF observed in this model of acute low-output heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiac Output, Low; Dogs; Glomerular Filtration Rate; Hemodynamics; Kidney; Renal Circulation; Renin; Saralasin; Vascular Resistance; Vena Cava, Inferior

We have established an easily reversible acute heart failure model in beagle canines by reversible aortic or mitral regurgitation (AR or MR). To cause reversible AR, a basket catheter was inserted into the left ventricle from the apex and fixed at the aortic valve in 10 canines. To cause MR, a basket catheter was inserted into the left atrium via the pulmonary vein and fixed at the mitral valve in 10 canines. The regurgitation by AR or MR was caused by extending the tip basket wire, and the recovery from the regurgitation was immediately possible by closing it. Left atrial pressure (LAP), right atrial pressure (RAP) and pulmonary artery pressure (PAP) were increased significantly during AR or MR, and decreased to the normal level after the release of AR or MR. Using these reversible acute heart failure models, the effects of both advancing and restoring acute heart failure by the secretion of ANP were examined by observing the changes of ANP concentration and its molecular forms in the plasma and left atrial tissue in the same canine. Plasma ANP concentration showed a reversible change. In group analysis, plasma ANP concentration did not correlate with LAP or RAP, but in each canine it showed high correlations with LAP (r = 0.70 approximately 0.94, 0.82 +/- 0.07) and RAP (r = 0.60 approximately 0.93, 0.79 +/- 0.08), having a different slope in each regression line. The ANP concentration in the atrial tissue was decreased during AR or MR, but the low level was maintained after AR or MR. The main molecular form of ANP in the plasma was alpha-ANP and that in the tissue was gamma-ANP. In summary, the tissue storage of ANP was decreased because the ANP secretion caused by stimulation of acute heart failure exceeded its production. The ANP secretion was decreased by the subsequent elimination of heart failure, but the production was not stimulated rapidly, because the tissue content remained unchanged.

Topics: Acute Disease; Animals; Aortic Valve Insufficiency; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Chromatography, High Pressure Liquid; Disease Models, Animal; Dogs; Heart Atria; Hemodynamics; Mitral Valve Insufficiency; Myocardium; Radioimmunoassay

The aim of this paper was to study plasma atrial natriuretic factor, renin activity, aldosterone and antidiuretic hormone in low-output heart failure syndromes such as cardiogenic shock, hypovolemic shock and hypotension with bradycardia syndrome. A total of 30 patients were investigated: 10 with cardiogenic shock due to acute myocardial infarction of the anterior wall (systolic and diastolic blood pressure 56.0 +/- 3.7/40.5 +/- 2.0 mmHg; heart rate 119.7 +/- 1.2 beats/min; central venous pressure 16.2 +/- 0.6 cmH2O) (I group), 10 with hypovolemic shock induced by melena in peptic ulcer (systolic and diastolic blood pressure 74.5 +/- 1.5/57.5 +/- 1.7 mmHg; heart rate 111.0 +/- 1.4; central venous pressure 6.3 +/- 0.5 cmH2O) (II group), 10 with hypotension with bradycardia syndrome which occurred in patients during acute myocardial infarction of the inferior wall (systolic and diastolic blood pressure 71.9 +/- 2.0/58.0 +/- 2.6 mmHg; heart rate 52.0 +/- 2.2 beats/min; central venous pressure 4.6 +/- 0.4 cmH2O) (III group). Plasma atrial natriuretic factor values were measured using radioimmunoassay after chromatographic pre-extraction; plasma renin activity, aldosterone and antidiuretic hormone values were calculated using radioimmunoassay. Circulating atrial natriuretic factor was significantly (p less than 0.01) higher in patients with cardiogenic shock (102.4 +/- 7.4 pg/ml) than in healthy volunteers (8.4 +/- 0.3 pg/ml). In the former there was a positive correlation between atrial natriuretic factor and central venous pressure values. Atrial natriuretic factor and central venous pressure values in the IInd and IIIrd groups of patients were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Bradycardia; Cardiac Output, Low; Female; Hemodynamics; Humans; Hypotension; Male; Middle Aged; Myocardial Infarction; Renin; Shock; Shock, Cardiogenic; Vasopressins

The influence of positive end-expiratory pressure (PEEP) ventilation on plasma concentrations of atrial natriuretic factor (ANF) was studied in dogs anesthetized with sodium pentobarbital during normal cardiac function and during acutely impaired left ventricular function. Left ventricular impairment was induced by injecting repeated doses of polystyrene microspheres with a diameter of 50 microns into the main left coronary artery, causing a severe depression of left ventricular performance. This was accompanied by doubling of ANF concentrations measured in blood sampled from aorta. Application of PEEP (10 cmH2O (0.98 kPa] reduced plasma ANF in dogs both with normal and impaired left ventricular function. The decrease was significantly greater during left ventricular impairment compared to control, 31 and 19%, respectively. A positive correlation was observed between plasma ANF and transmural left ventricular end-diastolic pressure when all data were pooled, but not between ANF and transmural right atrial pressure. This implies that transmural left ventricular end-diastolic and hence transmural left atrial pressure probably is the principal determinant of acute ANF release in this model. Reduced plasma ANF in response to PEEP even during acute left ventricular impairment when ANF release was augmented, was probably due to diminished atrial distension during PEEP ventilation.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Coronary Vessels; Disease Models, Animal; Dogs; Female; Hemodynamics; Male; Microspheres; Positive-Pressure Respiration

The feedback control of neuroendocrine activity by cardiopulmonary blood volume is disturbed in congestive heart failure. By analyzing plasma catecholamine kinetics, we tested in 11 chronically instrumented conscious dogs whether attenuations in the sympathoadrenal inhibition induced by atrial natriuretic peptide (ANP) contributed to this disturbance. Low-output failure was brought about by continuous ventricular pacing at 265 beats/min for 2 weeks. This resulted in a decline in aortic flow by 37 +/- 5% (SEM), an increase in peripheral vascular resistance by 48 +/- 4%, a 13 +/- 3-fold elevation in plasma ANP, a 9 +/- 3-fold elevation in plasma renin activity, and an augmentation of the norepinephrine-release rate into plasma by 132 +/- 17%. During ANP infusion, the epinephrine-release rate declined by 26 +/- 5% per 10-fold elevation in plasma ANP before pacing and by 31 +/- 7% (not significantly different) after 2 weeks of pacing. Before pacing, ANP attenuated plasma renin activity and caused hypotension without a rise in norepinephrine-release rate. After 2 weeks of pacing, ANP lowered norepinephrine release (by 16 +/- 6%) without affecting blood pressure or plasma renin activity, and vascular nonresponsiveness to ANP was verified under autonomic blockade. These data indicate that, during the development of heart failure, an inhibitory action of ANP on norepinephrine release is unmasked by an ANP-specific vascular desensitization, whereas the inhibition of epinephrine release is observed throughout. It is concluded that ANP-induced sympathoadrenal inhibition is not attenuated and, therefore, does not contribute to the disturbed regulation observed early in the development of failure.

Topics: Adrenal Medulla; Animals; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiac Pacing, Artificial; Dogs; Epinephrine; Feedback; Female; Heart Failure; Male; Norepinephrine; Sympathetic Nervous System

Alterations in the vasopressor system found in cardiac failure are part of compensatory measures that may modify pharmacologic-therapeutic response. Therefore, in 64 patients with dilated cardiomyopathy, we investigated its enhanced activity in different clinical stages of the disease as compared to normal controls. Patients in NYHA class II (n = 20) demonstrated increased activity of the sympathico-adrenal, renin-angiotensin-aldosterone, vasopressin, and atrial natriuretic factor systems, while maximum values were found in patients of NYHA class IV (n = 24). In these patients, noradrenaline was enhanced by a factor of 7, adrenaline by a factor of 2, plasma-renin-activity by a factor of 7, angiotensin II by a factor of 2.5, aldosterone by a factor of 5, vasopressin by a factor of 1.5, and ANF by a factor of 4 as compared to normal controls. Clinical NYHA classes correlated to a certain degree with the various plasma hormones. Patients treated with an aldosterone inhibitor in addition to digitalis and diuretics revealed significantly higher values for aldosterone, vasopressin, and angiotensin II as compared to those who received digitalis and diuretics alone. The addition of ACE-inhibitor therapy resulted in a decrease of angiotensin II, aldosterone, and vasopressin. Plasma catecholamines and ANF, however, did not change under the influence of cardiac medication. Diuretic treatment in NYHA class II patients reduced plasma volumes (p less than 0.01). Plasma volume in NYHA class IV patients only was found to be higher than in normal controls. Thus, analysis of the neurohumoral system can aid both in the identification of the clinical degree of dilated cardiomyopathy and in its optimal therapy.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiac Output, Low; Cardiomyopathy, Dilated; Catecholamines; Female; Humans; Male; Middle Aged; Plasma Volume; Renin-Angiotensin System; Vasoconstrictor Agents