Urocortin 3: haemodynamic, hormonal, and renal effects in experimental heart failure

Aims To investigate the haemodynamic, hormonal, and renal effects of peripheral urocortin 3 (Ucn3) administration for the first time in either normal health or heart failure (HF). Methods and results Eight sheep received incremental intravenous boli of Ucn3 (10, 50, and 100 mu g at 2-h intervals) before (normal) and during pacing-induced HF. Compared with controls, Ucn3 induced immediate, dose-dependent increases in cardiac output (normal 4.21 +/- 0.23 vs. 5.65 +/- 0.32 L/min, P < 0.001; HF 2.20 +/- 0.14 vs. 4.43 +/- 0.31 L/min, P < 0.001) and decreases in peripheral resistance (normal 20.8 +/- 1.0 vs. 16.2 +/- 0.8 mmHg/L/min, P < 0.01; HF 34.4 +/- 1.7 vs. 16.2 +/- 0.5 mmHg/L/min, P < 0.001) and left atrial pressure (normal 4.5 +/- 0.3 vs. 0.6 +/- 0.2 mmHg, P < 0.001; HF 23.0 +/- 0.6 vs. 5.8 +/- 1.9 mmHg/L/min, P < 0.001). Arterial pressure was minimally elevated in normals (P < 0.001) and reduced in HF (P < 0.05). In HF only, Ucn3 decreased plasma vasopressin (3.33 +/- 0.36 vs. 1.73 +/- 0.21 pmol/L, P < 0.05), endothelin-1 (3.56 +/- 0.28 vs. 2.64 +/- 0.24 pmol/L, P < 0.001), renin (2.74 +/- 1.17 vs. 1.04 +/- 0.22 nmol/L/h, P < 0.001), aldosterone (1494 +/- 400 vs. 726 +/- 168 pmol/L, P < 0.05), and epinephrine (1608 +/- 278 vs. 1039 +/- 75 pmol/L, P < 0.05), and increased urine output (P < 0.05), sodium excretion (P < 0.01), and creatinine clearance (P < 0.05). Conclusion Ucn3 has significant cardiovascular effects in normal and HF sheep, supporting a role for this peptide in circulatory regulation. In HF, more prominent haemodynamic changes were associated with beneficial endocrine and renal effects, suggesting Ucn3 has therapeutic potential in this disease.