Hemodynamic, Hormonal and Renal Effects of (Pro)Renin Receptor Blockade in Experimental Heart Failure Rademaker et al: (Pro)Renin Receptor Blockade in Heart Failure

Background—The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure. The effects of (P)RR blockade in heart failure have not previously been investigated. Methods and Results—Eight sheep received on two separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP)(1, 5 and 25mg at 90min intervals), both before (Normal) and after induction of heart failure by rapid left ventricular pacing. In Normal sheep, HRP reduced heart rate (p<0.001) and hematocrit (p=0.019) compared to time-matched control data, without significantly affecting any other hemodynamic, hormonal or renal variables. In sheep with heart failure, HRP treatment induced progressive falls in mean arterial pressure (p<0.001) in association with decreases in left atrial pressure (p<0.001), peripheral resistance (p=0.014) and hematocrit (p<0.001). Cardiac contractility tended to decline (p=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (p=0.004), with similar trends observed for plasma angiotensin II and aldosterone (p=0.093 and p=0.088, respectively). Circulating natriuretic peptides, endothelin-1 and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (p=0.024), a natriuresis (p=0.046) and a tendency for creatinine excretion and clearance to improve. Conclusions— (P)RR antagonism in experimental heart failure resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in heart failure, and identifies the receptor as a potential therapeutic target in this disease.