Abstract 2494: Beneficial Actions of Co-Targeting Particulate and Soluble Guanylate Cyclase Dependent cGMP Pools in Experimental Heart Failure

Abstract

Background: B-type natriuretic peptide (BNP) signals via particulate guanylyl cyclase (pGC) and cyclic guanosine monophosphate (cGMP). In heart failure (HF), BNP reduces cardiac filling pressures and in selected patients augments sodium excretion and glomerular filtration rate (GFR). Studies have established that pGC and soluble guanylyl cyclase (sGC), the main target of nitric oxide (NO), can be compartmentalized with both enzymes affecting distinct intracellular cGMP pools, resulting in different biological actions. Importantly, sGC may be oxidized in disease states like HF making it unresponsive to NO and nitrovasodilators. BAY 58 –2667 (BAY) is a novel NO and heme independent sGC activator that preferentially stimulates oxidized sGC. We hypothesized that adding direct sGC stimulation with BAY to pGC activation with BNP in HF would enhance vasodilation and cardiac unloading without attenuating the distinct renal actions of BNP. Methods: Severe HF was induced by tachypacing in 13 dogs. On day 11, cardiorenal function was assessed in an acute study under anesthesia at baseline and with intravenous BNP (50 ng/kg/min) alone or in combination with BAY (0.3 ug/kg/min). Results: BNP significantly increased urine flow (UV), urinary sodium excretion (UNaV), GFR, renal blood flow (RBF) and systemic vascular resistance (SVR) and decreased cardiac output (CO), mean arterial pressure (MAP), right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP). Despite a greater decrease in MAP compared to BNP, BAY+BNP resulted in similar increases in UNaV, UV and GFR. Dual pGC and sGC stimulation resulted in greater decreases in SVR, RAP and PCWP together with an augmentation of CO compared to BNP alone. Conclusion: Particulate GC activation with BNP in experimental HF enhances renal function and leads to renal but not systemic vasodilation. Addition of the sGC stimulator BAY provides systemic vasodilation, greater cardiac unloading, and augmented CO. Despite a larger decrease in MAP, additional sGC stimulation does not impair the renal actions observed with pGC stimulation alone. These findings support coactivation of sGC with BAY and pGC with BNP as a novel and beneficial therapeutic strategy in HF to optimize activation of distinct GC enzymes and cGMP.