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Interactions of Enhanced Urocortin 2 and Mineralocorticoid Receptor Antagonism in Experimental Heart Failure

Background—Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. Methods and Results—Ucn2 and an MRA (canrenoic acid [CA]) were infused for 4 hours, both singly and together, in 8 sheeps with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance but without eliciting a supplementary reduction in arterial pressure. Ucn2 cotreatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II, and vasopressin concentrations. Although both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2- to 3-fold greater than that elicited by separate CA. Ucn2 cotherapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 cotreatment reduced potassium concentrations. Conclusions—Ucn2 cotreatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, while also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF.