Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure

• Published in: Journal of the American College of Cardiology Vol. 40; no. 8; pp. 1495 - 1505
• Main Authors: Rademaker, Miriam T, Charles, Christopher J, Espiner, Eric A, Fisher, Steve, Frampton, Christopher M, Kirkpatrick, Carl M.J, Lainchbury, John G, Nicholls, M.Gary, Richards, A.Mark, Vale, Wylie W
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2002
• Subjects: RAP; Ucn; ANP; BNP; ACTH; HR; LV; cAMP; CO; CTPR; CV; CRF; LAP; AVP; AngII; MAP; HF; PRA
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(02)02170-8

The goal of this study was to determine the bioactivity of urocortin (Ucn) in experimental heart failure (HF). Urocortin may participate in cardiovascular function and pressure/volume homeostasis. Its effects in HF are unknown. Eight normal sheep and eight sheep with pacing-induced HF received ovine Ucn (10, 50, and 100 mg intravenous boluses at 2-h intervals) in vehicle-controlled studies. Urocortin boluses dose-dependently increased plasma Ucn (p < 0.001). Pharmacokinetics were similar in normal and HF sheep with half-lives approximating 1.3 and 19.5 h for the first and second phases, respectively. In HF, cardiac output increased (twofold), while peripheral resistance, left atrial pressure (both 50% falls: p < 0.001), and mean arterial pressure (p < 0.05) fell. In normal sheep, changes in peripheral resistance and atrial pressure were blunted and in arterial pressure were directionally opposite. Urocortin induced persistent, dose-dependent falls (30% to 50%) in plasma vasopressin, renin activity, aldosterone, natriuretic peptides (all p < 0.001), and endothelin-1 (p < 0.05) in HF sheep, while adrenocorticotrophic hormone and cortisol levels rose acutely (both p < 0.001). In comparison, Ucn in normal sheep resulted in a similar rise in cortisol and fall in aldosterone, no significant effects on plasma renin activity and natriuretic peptides, and a rise in vasopressin. Urocortin produced dose-dependent, sustained increases in urine volume (twofold, p < 0.01), sodium excretion (>9-fold rise, p < 0.001), and creatinine clearance (p < 0.001) in HF sheep. No significant renal effects were observed in normal sheep. Urocortin has profound and sustained hemodynamic, hormonal, and renal effects in experimental HF. Urocortin may have a role in pressure/volume homeostasis in HF and may provide a novel therapeutic approach to this disease.