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

BACKGROUND: The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. METHODS AND RESULTS: Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, 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 HF 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 HF and identifies the receptor as a potential therapeutic target in this disease.