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European Heart Journal Advance Access originally published online on June 16, 2005
European Heart Journal 2005 26(19):2055-2062; doi:10.1093/eurheartj/ehi351
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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

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

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

Received 7 October 2004; revised 30 March 2005; accepted 12 May 2005; online publish-ahead-of-print 16 June 2005.

* Corresponding author. Tel: +64 3 3640544; fax: +64 3 3640525. E-mail address: miriam.rademaker{at}chmeds.ac.nz

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.

Key Words: Urocortin-I • Heart failure • Pharmacology • Blood pressure • Cardiac output • Hormones


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