Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure

Abstract

Background - BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results - CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg-1 · min-1; n=8) or NTG (1 and 5 μg · kg-1 · min-1; n=6). Administration of 10 μg · kg-1 · min-1 BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg; P<0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg; P<0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg; P<0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min; P<0.05) and renal blood flow (131±17 to 162±18 mL/min; P<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance. Conclusion - The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.