Sustained Hemodynamic, Endocrine, and Renal Effects

Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n 6) or urocortin 2 (0.75 g/kg per hour; n 6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905 73 versus urocortin 2 1424 158 mm Hg/s; P 0.001) and output (2.6 0.1 versus 3.8 0.3 L/min; P 0.001), together with reductions in left atrial pressure (28 1 versus 12 1 mm Hg; P 0.001) and peripheral resistance (30 2 versus 20 2 mm Hg/L per min; P 0.001). In contrast, urocortin 2–induced falls in mean arterial pressure were not established until the second day (day 4: 74 2 versus 72 2 mm Hg; P 0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33 0.27 versus 0.73 0.20 nmol/L per hour; P 0.001), aldosterone (970 383 versus 396 96 pmol/L; P 0.05), vasopressin (2.4 0.8 versus 1.3 0.1 pmol/L; P 0.05), endothelin 1 (7.2 0.7 versus 4.5 0.4 pmol/L; P 0.01), and atrial (269 27 versus 150 19 pmol/L; P 0.001) and B-type (65 9 versus 29 6 pmol/L; P 0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P 0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P 0.001) and creatinine (1.4-fold; P 0.001) excretion and creatinine clearance (1.5-fold; P 0.01) compared with control. Food consumption was temporarily suppressed (P 0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure. (Hypertension. 2011;57:1136-1144.)