cyclic-gmp and Cardiac-Output--Low

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

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

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

We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts.. 8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O(2) consumption (VO(2)) (coronary blood flow*O(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay.. 8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL.. In controls, cyclic AMP attenuated cyclic GMPs negative functional and metabolic effects. The effects and the interaction were blunted in the HYP and HYP-FAIL groups.

Topics: Animals; Cardiac Output, Low; Cardiotonic Agents; Coronary Circulation; Coronary Vessels; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dogs; Hypertrophy, Left Ventricular; Isoproterenol; Myocardial Contraction; Myocardium; Oxygen Consumption

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Blood Pressure; Cardiac Output, Low; Colforsin; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dobutamine; Dogs; Female; Heart; Hemodynamics; Immunohistochemistry; Male; Myocardial Contraction; Myocardium; Phosphodiesterase Inhibitors; Piperazines; Purines; Purinones; Pyrazoles; Receptors, Adrenergic, beta; Signal Transduction; Sildenafil Citrate; Sulfones

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

We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure.. Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F(max)) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus 0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0. 56 micromol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts.. We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.

Topics: Actin Cytoskeleton; Cadaver; Calcium; Cardiac Output, Low; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Heart Ventricles; Humans; Hydrogen-Ion Concentration; Myocardial Contraction; Myocardium; Osmolar Concentration; Phosphates

We tested the hypothesis that pacing-induced cardiac failure of hypertrophic hearts would reduce the functional and metabolic responses of these hearts to guanylate cyclase inhibition and this was associated with alterations in cyclic GMP.. Methylene blue (MB, 2 mg/kg/min, guanylate cyclase inhibitor) was infused into the left anterior descending coronary artery in 5 control, 5 left ventricular hypertrophy (LVH), and 5 LVH pacing-induced failure dogs. Regional myocardial work was calculated as the integrated product of force and segment shortening and regional myocardial O(2) consumption (VO(2)) from coronary blood flow and O(2) extraction measurements. Cyclic GMP was determined by radioimmunoassay.. MB increased regional work (635 +/- 169 vs 1649 +/- 500, 781 +/- 184 vs 1569 +/- 203 g * mm/min) and VO(2) (8.3 +/- 1.4 vs 10.9 +/- 1.4, 7.3 +/- 0.7 vs 9.1 +/- 0.7 ml O(2)/min/100 g) in both control and LVH dogs but not in failure dogs (536 +/- 234 vs 623 +/- 193, 3.6 +/- 1.1 vs 4.7 +/- 1.9). MB also decreased cyclic GMP in control dogs (1170 +/- 142 vs 812 +/- 105 pmol/g). LVH dogs had elevated baseline cyclic GMP (5875 +/- 949) compared to control dogs but also demonstrated decreased cyclic GMP in response to MB (2820 +/- 372). In failure dogs, basal cyclic GMP was also elevated (4650 +/- 613) compared to control dogs but there was a lack of response to MB (3670 +/- 640).. We conclude that the myocardial function, VO(2) and cyclic GMP responses to methylene blue are diminished in the transition from hypertrophy to cardiac failure.

Topics: Animals; Cardiac Output, Low; Cardiac Pacing, Artificial; Cyclic GMP; Dogs; Hypertrophy, Left Ventricular; Methylene Blue; Myocardial Contraction; Myocardium; Reference Values

1 Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation. 2 Cardiac output indices of coronary artery-ligated and sham-operated rats were 125+/-8 and 189+/-10 ml min(-1) kg(-1), respectively (P<0.05), indicating the development of CHF at this period. 3 The maximal relaxant response of aortic segments to 10 microM acetylcholine in rats with CHF and sham-operated rats was 64.0+/-5.7 and 86.9+/-1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats. 4 In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 microM isoprenaline (44.5+/-6.7%) was lower that sham-operated rats (81.3+/-2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by NG-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 microM dibutyryl cyclic AMP in rats with CHF (26.8+/-2.7%) was lower than that in sham-operated rats (63.4+/-11.8%, P<0.05). 5 Trandolapril (3 mg kg(-1) day(-1)) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5+/-3.6 ml min(-1)) was lower than that of sham-operated rats (55.0+/-3.0 ml min(-1)), and this reduction was reversed (54.1+/-3.4 ml min(-1)) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7+/-1.0%; that to isoprenaline, 80.5+/-2.8%; that to dibutyryl cyclic AMP, 54.7+/-6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged. 6 The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment

Topics: Acetylcholine; Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Cardiac Output, Low; Colforsin; Cyclic AMP; Cyclic GMP; Hemodynamics; Indoles; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Wistar; Vasodilator Agents

To elucidate pathophysiological alterations in vascular relaxation in rats with chronic heart failure (CHF), guanosine 3',5'-cyclic monophosphate (cGMP)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated vasorelaxations in pulmonary artery (PA) and thoracic aorta (TA) of rats were examined 12 wk after coronary artery ligation. Acetylcholine (ACh)-induced relaxation was attenuated in endothelium-intact segments of both arteries, whereas sodium nitroprusside-induced relaxation was attenuated only in endothelium-intact TA segments of rats with CHF. Vasorelaxations elicited by isoproterenol and NKH-477, a water-soluble forskolin analogue, were diminished mainly in PA segments of the CHF rat. NG-nitro-L-arginine methyl ester (L-NAME)-induced decrease in cGMP level was less in endothelium-intact TA segments of the rat with CHF (0.20 +/- 0.06 vs. 0.99 +/- 0.26 pmol/mg protein in control), suggesting that basal nitric oxide (NO) production is reduced in CHF. Treatment with L-NAME attenuated the isoproterenol-induced relaxation only in endothelium-intact TA segments in control rats but not in CHF rats. The results suggest that both cGMP- and cAMP-mediated relaxations are impaired in CHF, and a reduction of NO synthesis, presumably in endothelial cells, plays a significant role in pathophysiological alterations in vessels of rats with CHF.

Topics: Animals; Aorta, Thoracic; Cardiac Output, Low; Chronic Disease; Cyclic AMP; Cyclic GMP; Enzyme Inhibitors; Heart; Isoproterenol; Male; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Norepinephrine; Pulmonary Artery; Rats; Rats, Wistar; Vasoconstrictor Agents; Vasodilation

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 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

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

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.

Topics: Absorption; Animals; Cardiac Output, Low; Cardiovascular System; Constriction; Cyclic GMP; Dogs; Glomerular Filtration Rate; Heart Failure; Kidney Tubules; Male; Natriuresis; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Renal Circulation; Sodium; Thorax; Vena Cava, Inferior

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

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

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