Urocortin 1 (Ucn) may be involved in the pathophysiology of heart failure (HF), but the impact of Ucn1 administration on progression of the disease is unknown. The aim of this study was to investigate the effects of Ucn1 in sheep from the onset of cardiac overload and during the subsequent development of HF. Eight sheep underwent two four-day periods of HF-induction by rapid left ventricular pacing (225bpm) in conjunction with continuous intravenous infusions of Ucn1 (0.1ug/kg/hr) and a vehicle control (0.9% saline). Compared to control, Ucn1 treatment attenuated the pacing-induced decline in cardiac output (Day 4: 2.43±0.46 vs 3.70±0.89L/min, p<0.01) and rises in left atrial pressure (24.9±1.0 vs 11.9±1.1mmHg, p<0.001) and peripheral resistance (38.7±9.4 vs 25.2±6.1mmHg/L/min, p<0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02±1.17 vs 0.87±0.1nmol/L/hr, p<0.001), aldosterone (1313±324 vs 413±174pmol/L, p<0.001), endothelin-1 (3.8±0.5 vs 2.0±0.1pmol/L, p<0.001) and vasopressin (10.8±4.1 vs 1.8±0.2pmol/L, p<0.05) seen during pacing alone, and blunted the progressive rises in plasma epinephrine (2132±697 vs 1250±264pmol/L, p<0.05), norepinephrine (3.61+0.73 vs 2.07±0.52nmol/L, p<0.05), and atrial (p<0.05) and brain (p<0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (Day 4: 0.75±0.34 vs 1.59±0.50mmol/hr, p<0.05) and suppressed pacing-induced falls in creatinine clearance (p<0.05). These findings indicate that Ucn1 treatment from the onset of cardiac overload has the ability to repress the ensuing hemodynamic and renal deterioration and concomitant adverse neurohumoral activation, thereby delaying the development of overt HF. These data strongly support a use for Ucn1 as a therapeutic option early in the course of the disease.