Integrated hemodynamic, hormonal, and renal actions of urocortin 2 in normal and paced sheep: Beneficial effects in heart failure

Abstract

Background - Urocortin 2 (Ucn2) has potent cardiovascular actions and may participate in the pathophysiology of heart failure (HF). The integrated hemodynamic, endocrine, and renal effects of Ucn2 are unknown. Methods and Results - Eight sheep received incremental intravenous boluses of murine Ucn2 (10, 50, and 100 μg at 2-hour intervals) before (normal) and during pacing-induced HF. Compared with control data, Ucn2 induced rapid and dose-dependent increases in cardiac output (peak effects: normal 4.3±0.2 versus 6.1±0.2 L/min, P<0.001; HF 2.3±0.1 versus 4.5±0.2 L/min, P<0.001) and reductions in peripheral resistance (normal 20.2±1.0 versus 15.2±0.8 mm Hg/L per minute, P<0.01; HF 32.2±1.7 versus 13.6±0.5 mm Hg/L per minute, P<0.001) and left atrial pressure (normal 4.3±0.3 versus 0.5±0.2 mm Hg, P<0.01; HF 22.9±0.6 versus 5.1±1.8 mm Hg, P<0.001). Mean arterial pressure was minimally elevated in normals and decreased in HF (both P<0.01). In both states, Ucn2 reduced plasma atrial natriuretic peptide levels (normal 13±2 versus 10±2 pmol/L; HF 200±20 versus 72±10 pmol/L) and similarly increased corticotropin, cortisol, and Ucn1 (all P<0.001). In HF only, Ucn2 dose dependently decreased plasma vasopressin (3.09±0.36 versus 1.62±0.12 pmol/L, P<0.01), renin (2.98±1.17 versus 0.69±0.10 nmol/L per hour, P<0.001), aldosterone (1186±303 versus 364±122 pmol/L, P<0.001), endothelin-1 (3.39±0.23 versus 2.56±0.18 pmol/L, P<0.01), epinephrine (1633±260 versus 657±142 pmol/L, P<0.01), and brain natriuretic peptide (36±3 versus 18±4 pmol/L, P<0.001) concentrations. Renal effects, including increased urine volume (1.7-fold, P<0.05), sodium excretion (>12-fold, P<0.01), and creatinine excretion (1.3-fold, P<0.001), also occurred only in HF. Conclusions - Ucn2 has marked and beneficial hemodynamic, hormonal, and renal effects in experimental HF. These results support a role for Ucn2 in pressure/volume homeostasis in HF and suggest that the peptide may have therapeutic potential in this disease. © 2005 American Heart Association, Inc.