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European Heart Journal Advance Access published online on June 16, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi351
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European Heart Journal © The European Society of Cardiology 2005; All rights reserved
Received October 7, 2004
Revised March 30, 2005
Accepted May 12, 2005

Preclinical research

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

Miriam T. Rademaker 1*, Chris J. Charles 1, Eric A. Espiner 1, Chris M. Frampton 1, John G. Lainchbury 1, and A. Mark Richards 1

1 Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand

* To whom correspondence should be addressed.
Miriam T. Rademaker, E-mail: miriam.rademaker{at}chmeds.ac.nz


  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 µg/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.

Keywords: Urocortin-I; Heart failure; Pharmacology; Blood pressure; Cardiac output; Hormones.
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