Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure

Abstract

Worsening renal function in the setting of human acute heart failure (AHF) predicts poor outcomes, such as rehospitalization and increased mortality. Understanding potential renoprotective mechanisms is warranted. The guanylate cyclase (GC) enzymes and their second messenger cGMP are the target of two important circulating neurohumoral systems with renoprotective properties. Specifically, natriuretic peptides (NP) released from the heart with AHF target particulate GC in the kidney, while the nitric oxide (NO) system is an activator of renal soluble GC. We hypothesized that both systems are essential to preserve renal excretory and hemodynamic function in AHF but with distinct roles. We investigated these roles in three groups of anesthetized dogs (6 each) with AHF induced by rapid ventricular pacing. After a baseline AHF clearance, each group received intrarenal vehicle (control), N(G)-monomethyl-l-arginine (l-NMMA), a competitive NO inhibitor (50 microg.kg(-1).min(-1)) or a specific NP receptor antagonist, HS-142-1 (0.5 mg/kg). We observed that intrarenal l-NMMA decreased renal blood flow (RBF) without significant decreases in glomerular filtration rate (GFR), urinary sodium excretion (UNaV), or urinary cGMP. In contrast, HS-142-1 resulted in a decrease in UNaV and cGMP excretion together with a reduction in GFR and an increase in distal fractional tubular sodium reabsorption. We conclude that in AHF, the NP system plays a role in maintaining sodium excretion and GFR, while the function of NO is in the maintenance of RBF. These studies have both physiological and therapeutic implications warranting further research into cardiorenal interactions in this syndrome of AHF.