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

Abstract

. Distinct roles for renal particulate and soluble guanylyl cyclases in preserving renal function in experimental acute heart failure. Am J Physiol Regul Integr Comp Physiol 293: R1580-R1585, 2007. First published August 1, 2007; doi:10.1152/ajpregu.00284.2007.-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),) 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.ACUTE HEART FAILURE (AHF) represents an important clinical challenge and poses a major healthcare problem as hospitalization for AHF continues to increase and outcomes remain poor (31, 41). Specially, the worsening of renal function in the setting of human AHF strongly predicts poor outcomes, such as rehospitalization and increased mortality (2,19,20,35,46). To preserve and/or enhance renal function in AHF, an understanding of intrarenal factors that may protect the kidney in this syndrome may provide a direction on optimal use of current therapies and also lead to newer therapeutic strategies (14).From an integrated cardiorenal physiological perspective, AHF involves acute cardiac overload with release of the natriuretic peptides (NP) atrial and brain NP (ANP and BNP, respectively), which activate the particulate guanylyl cyclase (pGC) NP receptor-A (NPR-A), resulting in the generation of the second messenger cGMP and the effector PKG. Of note, the NPR-A is also the target of the intrarenal NP urodilatin that, like ANP and BNP, is being developed for the treatment of AHF (33). Infusion of these three NPs in animals and humans results in natriuresis and diuresis and, at certa...

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure

“…40 These two signalling systems are organized differently in terms of subcellular localization and mediate distinct physiological functions despite sharing the same second messenger. 41 In this regard, some studies [42][43][44] At any rate, RGZ treatment did not significantly increase excretory response to ACh infusion in CHF rats, while some improvement was observed in control rats. This aligns with a previous work from our laboratory showing blunted ACh-mediated renal vasodilatory response in rats with ACF, 25 suggesting that RGZ selectively improves signalling transduced by particulate GC rather than soluble GC.…”

Origins of Cardiorenal Syndrome and the Cardiorenal Connection

“…65,67 Different models of nephrectomy exist in mice, but these are not as robust as those in rats, with variable changes in renal function and cardiac abnormalities. [68][69][70][71][72] The renal hemodynamic response to heart failure (HF) induced by pacing in dogs has also been investigated, [73][74][75] but whether there is histological damage is unknown. Furthermore, there is no proven model of CKD in dogs.…”

B-Type Natriuretic Peptide: Beyond a Diagnostic

“…We hypothesized that each pathway would play specific roles in the control of kidney function in ADHF consistent with distinct GC enzymes for each system. (16) These studies revealed distinct roles for these two endogenous cGMP activating systems in ADHF whereby the endogenous NPs play a greater role in the preservation of GFR and sodium excretion while the endogenous NO system was more important in the control of renal blood flow. These studies suggest that the preservation of renal function in experimental ADHF is mediated by dual cGMP systems which activate both pGC and sGC enzymes.…”