Effects of Chronic AVP V2R Blockade in Congestive Heart Failure in Sheep

Abstract

The chronic effects of AVP V2 receptor (V2R) antagonism or ACE inhibition in conscious sheep with congestive heart failure (CHF) using the non-peptide V2R antagonist, OPC-31260 (1), and the ACE inhibitor, ramipril, were examined. Fifteen ovarectomised ewes equipped with epicardial right ventricular pacing leads and transonic cardiac output (CO) flow probe, had rapid ventricular pacing until the animal developed CHF. Then animals received oral OPC-31260 (10mg/kg twice daily, n=5), ramipril (1mg/kg daily, n=5) or vehicle (n=5) for 8 days. Throughout the experiment, animals were allowed free tap water. Oral OPC-31260 produced significant water diuresis, significant increase in CO (△CO; +0.92 L/min) and decrease in right atrial pressure (RAP) with significant increase in plasma osmolality and sodium concentration from 2 hours after first dosing; these hemodynamic effects were maintained throughout the treatment period without significant changes in systemic vascular resistance (SVR), although plasma osmolality and sodium concentration returned towards pre-treatment value on the last treatment day. Oral ramipril caused no significant changes with acute dosing but significant increases in CO (△CO; +0.88 L/min), urine volume and sodium excretion and decrease in SVR (ΔSVR; -22.8%) were observed after second treatment day. In vehicle-treated sheep, cardiac function, urine volume and sodium excretion remained lower. These results suggest V2R antagonism using OPC-31260 may be a novel therapeutic maneuver in CHF.