Therapeutic Actions of a New Synthetic Vasoactive and Natriuretic Peptide, Dendroaspis Natriuretic Peptide, in Experimental Severe Congestive Heart Failure

Abstract

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 Ϫ1 · min Ϫ1 in dogs (nϭ7) with severe CHF induced by rapid ventricular pacing for 10 days at 245 bpm. In addition, we determined endogenous DNP in normal (nϭ4) and failing (nϭ4) 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. Key Words: heart failure Ⅲ natriuretic peptides Ⅲ cyclic guanosine monophosphate Ⅲ renin Ⅲ endopeptidase A s the prevalence of congestive heart failure (CHF) has increased during the past decade, so has hospitalization for acutely decompensated CHF. 1 This has resulted in a continued search for new therapeutic agents to treat CHF, including intravenous agents for acutely decompensated CHF, which is characterized by markedly elevated cardiac filling pressure with pulmonary congestion, impaired glomerular filtration rate (GFR) with sodium retention, and activation of the renin-angiotensin-aldosterone system.Recently, a new member of the natriuretic peptide family, Dendroaspis natriuretic peptide (DNP), has been reported. 2 DNP, originally isolated from the venom of the Dendroaspis angusticeps (green mamba snake), is a 38-amino-acid peptide that contains a 17-amino-acid disulfide ring structure with 15-residue C-terminal extension. This peptide, which shares structural similarity to atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), potently vasorelaxes isolated precontracted rodent aorta and canine coronary arteries and augments the formation of 3Ј,5Ј cyclic guanosine monophosphate (cGMP) in aortic endothelial and smooth muscle cells. 2,3 We have reported that DNP immunoreactivity is present...

Targeting Heme-Oxidized Soluble Guanylate Cyclase in Experimental Heart Failure

“…7 On day 11 of pacing, cardiorenal parameters were assessed in an acute study under anesthesia with pentobarbital and fentanyl. The day before the experiment, animals were fed 300 mg of lithium carbonate for the assessment of renal tubular function and were fasted with ad libitum access to water.…”

“…Proximal and distal fractional sodium reabsorption were assessed with the lithium clearance technique. 7 Left ventricular external work in joules per minute was estimated as follows: (mean arterial pressureϪpulmo-nary capillary wedge pressure)ϫcardiac outputϫ0.13.…”

Cardiorenal and Humoral Properties of a Novel Direct Soluble Guanylate Cyclase Stimulator BAY 41-2272 in Experimental Congestive Heart Failure

“…4 After 10 days of pacing, dogs were anesthetized with pentobarbital, intubated, and ventilated with 5 L/min supplemental oxygen. A flow-directed balloon-tipped thermodilution catheter was inserted via the right external jugular vein for hemodynamic measurements.…”

“…Plasma renin activity, angiotensin II, and aldosterone were determined by commercially available radioimmunoassays as described previously. 4 …”

“…1 Furthermore, oral administration of BAY 41-2272 lowered mean arterial pressure in spontaneously hypertensive rats, showed antiplatelet activity, and enhanced survival in a low-NO rat model of hypertension. 1 This study was designed to characterize for the first time the acute cardiorenal actions of the innovative molecule BAY 41-2272 in a large animal model of severe CHF 4 and to compare it with nitroglycerin, a commonly used vasodilator.…”