Four-day urocortin-I administration has sustained beneficial haemodynamic, hormonal, and renal effects in experimental heart failure

Abstract

Aims: To investigate the subacute effects of a sustained intravenous infusion of urocortin-I (Ucn-I) in experimental heart failure (HF).

Methods and results: In eight sheep with pacing-induced HF, a 4-day infusion of Ucn-I (0.3 microg/kg/h) induced prompt (30 min) and sustained (4-day) increases in cardiac output (CO, Day 4: 1.8+/-0.2 vs. 2.3+/-0.2 L/min, P<0.001) and stroke volume (7.8+/-0.8 vs. 10.2+/-1.0 mL/beat, P=0.0011), and reductions in mean arterial pressure (MAP, 72+/-3 vs. 70+/-3 mmHg, P=0.0305), left atrial pressure (26+/-1 vs. 11+/-2 mmHg, P<0.001), and total calculated peripheral resistance (43+/-6 vs. 32+/-4 mmHg/L/min, P<0.001). Ucn-I also induced persistent falls in plasma renin (1.34+/-0.23 vs. 0.77+/-0.10 nmol/L/min, P=0.048), aldosterone (3273+/-1172 vs. 382+/-44 pmol/L, P=0.0098), endothelin-1 (4.6+/-0.3 vs. 2.7+/-0.3 pmol/L, P<0.001), vasopressin (24+/-4 vs. 14+/-2 pmol/L, P=0.0028) and atrial (184+/-14 vs. 154+/-29 pmol/L, P=0.0226) and brain (43+/-5 vs. 32+/-6 pmol/L, P=0.0016) natriuretic peptides. Plasma adrenocorticotrophic hormone and cortisol rose transiently on Day 0. Ucn-I enhanced urinary sodium excretion (5.3-fold, P=0.0001) and creatinine clearance (1.3-fold, P=0.0055) long-term, and tended to increase urine output (P=0.0748). Food intake was attenuated over the first 2 days of treatment (P=0.0283).

Conclusion: Four-day administration of Ucn-I induces sustained reductions in cardiac preload and MAP, improvements in CO and renal function, and inhibition of a range of vasoconstrictor/volume-retaining factors. These findings support Ucn-I's therapeutic potential in HF.