Renal Response to Acute Neutral Endopeptidase Inhibition in Mild and Severe Experimental Heart Failure

Abstract

Background-Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. Methods and Results-We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in 4 groups of anesthetized dogs (normal, nϭ8; mild CHF, nϭ6; severe CHF, nϭ5; and severe CHF with chronic AT 1 receptor antagonism, nϭ5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT 1 receptor antagonism. Conclusions-The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

Targeting Heme-Oxidized Soluble Guanylate Cyclase in Experimental Heart Failure

“…9,10 In this model of CHF, BAY 58-2667 potently reduced cardiac preload and afterload as indicated by the decreases in right atrial pressure, pulmonary capillary wedge pressure, and mean systemic and pulmonary arterial pressure. Concomitantly, cardiac output was increased.…”

Beneficial Renal and Hemodynamic Effects of Omapatrilat in Mild and Severe Heart Failure

“…This effect, of preserved ANP and BNP levels despite significant falls in left atrial pressure and MAP, is similar to that seen in other studies with combined ACE and neutral endopeptidase inhibition 15 and differs from isolated ACE inhibition, which usually causes distinct, statistically significant falls in plasma levels of the cardiac peptides, 15,30 or isolated neutral endopeptidase inhibition, in which ANP and BNP may be augmented 15 or remain stable. 31 Baseline levels of the cardiac peptides and cGMP were lower on day 2 with omapatrilat, probably reflecting hemodynamic changes leading to reduced atrial and ventricular distending pressure (the major stimulus to cardiac peptide secretion). 32 However, within several days treatment levels increased both before and after dosing.…”

“…We examined the effects of the vasopeptidase inhibitor omapatrilat in an established pacing model 26 of both mild HF, in which there is sodium balance and activation of the cardiac peptides but not the RAA system, and severe HF, in which there is activation of both cardiac peptides and the RAA system and also marked sodium retention and volume overload. 31 Omapatrilat induced substantial, well-tolerated, beneficial hemodynamic effects. The absolute changes in MAP, left atrial pressure, and cardiac output with omapatrilat were similar in both phases, and therefore the relative changes were greater in severe HF, likely reflecting greater activation of both the RAA system and the cardiac peptides in this state.…”

Maximizing the Renal Cyclic 3′-5′-Guanosine Monophosphate System with Type V Phosphodiesterase Inhibition and Exogenous Natriuretic Peptide

“…Recent evidence suggests that both the NP/cGMP and NO/cGMP signaling pathways are impaired in overt CHF and that such impairment may contribute to the progression of cardiorenal dysfunction in CHF (2,5). With regard to the kidney, we previously reported, as have others, that the glomerular, natriuretic, and urinary cGMP excretory responses to both atrial natriuretic peptide and brain NP (BNP) are attenuated in overt experimental and human CHF (6,7). In addition, Nesiritide, the recombinant human BNP (Scios, Inc., Fremont, CA) that is approved for the management of acute decompensated CHF, in some clinical studies failed to demonstrate a renal-enhancing property (8,9).…”