Citations

Mild heart failure is characterized by increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11, which degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, urinary ANP excretion, and glomerular filtration rate ( P <0.05 for OMA versus ACE inhibition). Plasma renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.

Abstract—Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca2+-dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO byl-NG-monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca2+-dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis.

Abstract —Dendroaspis natriuretic peptide (DNP), a recently discovered peptide, shares structural similarity to the other known natriuretic peptides, ANP, BNP, and CNP. Studies have reported that DNP is present in human and canine plasma and atrial myocardium and increased in plasma of humans with congestive heart failure (CHF). In addition, synthetic DNP is markedly natriuretic and diuretic and is a potent activator of cGMP in normal animals. To date, the ability of synthetic DNP to improve cardiorenal function in experimental CHF is unknown. Synthetic DNP was administered intravenously at 10 and 50 ng · kg −1 · min −1 in dogs (n=7) with severe CHF induced by rapid ventricular pacing for 10 days at 245 bpm. In addition, we determined endogenous DNP in normal (n=4) and failing (n=4) canine atrial and ventricular myocardium. We report that administration of synthetic DNP in experimental severe CHF has beneficial cardiovascular, renal, and humoral properties. First, DNP in CHF decreased cardiac filling pressures, specifically right atrial pressure and pulmonary capillary wedge pressure. Second, DNP increased glomerular filtration rate in association with natriuresis and diuresis despite a reduction in mean arterial pressure. Third, DNP increased plasma and urinary cGMP and suppressed plasma renin activity. Fourth and finally, we report that DNP immunoreactivity is present in canine atrial and ventricular myocardium and increased in CHF. These studies report the acute intravenous actions of synthetic DNP in experimental severe CHF and suggest that on the basis of its beneficial properties, DNP may have potential as a new intravenous agent for the treatment of decompensated CHF.

Abstract —To determine whether natriuretic peptides in addition to the renin-angiotensin system are involved in functional and structural vascular changes in salt-sensitive hypertension, we compared equipotent hypotensive treatment with the dual neutral endopeptidase/ACE inhibitor omapatrilat (35 mg · kg −1 · d −1 ) or the ACE inhibitor captopril (100 mg · kg −1 · d −1 ). The reactivity and geometry of mesenteric resistance arteries from Dahl salt-sensitive rats were studied in vitro under perfused and pressurized conditions. Chronic salt administration increased systolic blood pressure by 57±4 mm Hg, whereas concentrations of atrial natriuretic peptide were reduced in heart and in plasma ( P <0.05). In addition, the medial cross-sectional area of small mesenteric arteries was increased and endothelium-dependent relaxation in response to acetylcholine and contraction in response to endothelin-1 were impaired in the mesenteric arteries of salt-sensitive rats on a high-salt diet ( P <0.05). Concomitant treatment with either omapatrilat or captopril reduced the increase in systolic blood pressure and hypertrophic remodeling to a similar degree ( P <0.05) but affected plasma and cardiac atrial natriuretic peptide levels differently ( P <0.05). In addition, omapatrilat normalized endothelium-dependent relaxations to a greater extent than captopril ( P <0.05). Furthermore, vasopeptidase inhibition increased cGMP levels compared with captopril ( P <0.05). Contractions to endothelin-1 were normalized by either antihypertensive drug. These results suggest that in the Dahl rat, with similar reductions in systolic blood pressure, omapatrilat is superior to captopril in preventing impaired endothelial function in small resistance arteries. Thus, vasopeptidase inhibition may have therapeutic advantages of the prevention of changes in vascular function and structure in salt-sensitive forms of hypertension.

The present study determined circulating concentrations of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) and also investigated the vasorelaxing action of ANP and CNP on isolated contracted aorta. We also defined the vasorelaxing action of a novel and newly synthesized 27-amino acid chimera of ANP and CNP termed vasonatrin peptide (VNP), which we compared with ANP and CNP in WKY rats and SHR. Plasma and urinary cyclic GMP and sodium excretion were also investigated. Plasma ANP was increased in SHR in contrast to no change in circulating CNP. Plasma and urinary cyclic GMP and sodium excretion were no different between WKY rats and SHR. In WKY rats maximal relaxations to VNP in aortic rings without endothelium were greater than those to ANP and CNP. In SHR aortic rings the potency of VNP relaxation was preserved, the actions of ANP were enhanced, and the actions of CNP were markedly impaired. In association with these vasorelaxing actions, these data suggest that (1) circulating CNP is not different in SHR and WKY rats, but the aortic relaxing action of CNP is markedly impaired in SHR; (2) endogenous plasma ANP is significantly increased in SHR without associated increases in plasma or urinary cyclic GMP; (3) there is an increase in aortic relaxation to exogenous ANP in SHR; and (4) VNP has a potent endothelium-independent aortic relaxing action in both WKY rats and SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

BACKGROUND Hypercholesterolemia is characterized by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. This abnormality may be due to reduced synthesis of endothelium-derived relaxing factor and/or enhanced synthesis and release of an endothelium-derived contracting factor. Endothelin is an endothelium-derived vasoconstrictor and mitogenic peptide that is present in normal plasma, and its circulating concentrations are elevated in disease states that are characterized by abnormal endothelium-dependent relaxation to acetylcholine. The current studies were designed to test the hypotheses that experimental hypercholesterolemia results in elevation of plasma and tissue endothelin immunoreactivity and that the abnormal acetylcholine-evoked coronary vasoconstriction in the hypercholesterolemic animals is associated with further elevation of plasma endothelin. METHODS AND RESULTS Plasma concentrations and molecular forms of endothelin immunoreactivity were determined following 2% cholesterol diet for 4 months in pigs and during intracoronary acetylcholine administration. Second, we assessed the presence of endothelin in the coronary vascular wall by using immunohistochemistry. Hypercholesterolemia elevated plasma endothelin concentration and enhanced coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increases plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction. The predominant molecular form of endothelin in hypercholesterolemia is the biological active endothelin-1. CONCLUSIONS This study suggests a role for endothelin as an early participant and a marker for the endothelial dysfunction in hypercholesterolemia as well as a participant in the atherogenic process.

BACKGROUND beta-Atrial natriuretic factor (beta-ANF) is an antiparallel dimer of alpha-ANF (alpha-ANF) with diminished cyclic GMP generation in vitro. To date, the presence of beta-ANF in the circulation of humans with severe congestive heart failure (CHF) remains controversial. The current study was designed to determine the presence and magnitude of circulating beta-ANF in severe CHF, to correlate plasma beta-ANF with the degree of ventricular dysfunction, and to investigate the role of human plasma and atrial tissue in the degradation of beta-ANF. METHODS AND RESULTS Venous plasma samples were obtained from patients (n = 12) with severe CHF and normal volunteers (n = 8). Total plasma ANF was measured by radioimmunoassay. alpha-ANF and beta-ANF in nonextracted plasma were separated by gel filtration chromatography using a P-6 column. Right atrial tissue samples (n = 5) were collected from a different group of patients at the time of open-heart surgery. 125I beta-ANF and I125 ANF were incubated with atrial tissue or plasma. The corresponding peak areas of beta-ANF were determined by Tamaya Digital Planimeter. beta-ANF represented 61% of total plasma ANF in CHF patients and was not detected in normal human plasma. The elevation of beta-ANF correlated with the severity of ventricular dysfunction. Thirty percent of beta-ANF and 100% alpha-ANF were converted to smaller peptide fragments in atrial tissue no conversion in plasma. CONCLUSIONS beta-ANF is the principal form of circulating ANF in patients with severe CHF and correlates with the degree of left ventricular dysfunction. beta-ANF is not generated from alpha-ANF and may be degraded rapidly in atrial tissue to smaller peptide fragments that do not occur in plasma. As beta-ANF is reported to have reduced biological action, the current studies may support the conclusion that the ANF system in CHF has reduced functional activity despite increases in circulation concentrations.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.