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Urocortin 2 sustains haemodynamic and renal function during introduction of beta-blockade in experimental heart failure

Rademaker, Miriam T.; Charles, Christopher J.; Nicholls, Gary; Richards, Mark

doi: 10.1097/HJH.0b013e3283493776
Original papers: Kidney

Objectives: The challenge in management of acute decompensated heart failure (ADHF) is relieving congestion and improving symptoms while preserving renal and systemic perfusion at a level that can tolerate introduction of drugs such as beta-blockers which may have adverse effects acutely yet have proven benefit in the longer term. Urocortin 2 (Ucn2) is a novel peptide with therapeutic potential in heart failure. The present study investigated the effects of combined Ucn2 and beta-blockade in heart failure.

Methods: Ucn2 and metoprolol were administered for 3 h, separately and together, in eight sheep with pacing-induced congestive heart failure.

Results: Compared with time-matched controls, metoprolol significantly reduced heart rate (HR), left ventricular contractility, cardiac output (CO) and mean arterial pressure (MAP), together with increases in peripheral resistance and left atrial pressure (LAP). In contrast, Ucn2 elevated HR, contractility, CO and MAP, and decreased peripheral resistance and LAP. Combined Ucn2 + metoprolol produced intermediate haemodynamic effects closer to those observed with Ucn2 than with beta-blockade. All three active treatment regimes decreased plasma renin activity, whereas only Ucn2 and Ucn2 + metoprolol significantly reduced plasma aldosterone. Compared with metoprolol alone (which tended to reduce urine output and creatinine excretion/clearance), Ucn2 + metoprolol increased urine volume, sodium and creatinine excretion and clearance.

Conclusion: Ucn2 coupled with beta-blockade in experimental heart failure improves CO and MAP, sustains HR, reduces peripheral resistance, LAP and aldosterone and augments renal function. These results suggest a role for Ucn2 as a short-term parenteral therapy in the initial stages of managing ADHF that improves tolerance to introduction of beta-blockers.

Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago, Christchurch, New Zealand

Correspondence to Associate Professor Miriam Rademaker, Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago, Christchurch, P.O. Box 4345, Christchurch, New Zealand Tel: +64 3 3640 544; fax: +64 3 3640 525; e-mail: miriam.rademaker@otago.ac.nz

Abbreviations: ADHF, acute decompensated heart failure; CO, cardiac output; CRF, corticotrophin-releasing factor; CTPR, calculated total peripheral resistance; dP/dt(max), maximum derivative of pressure over time; HR, heart rate; LAP, left atrial pressure; MAP, mean arterial pressure; RAS, renin–angiotensin system; Ucn2, urocortin 2

Received 24 January, 2011

Revised 2 May, 2011

Accepted 26 May, 2011

© 2011 Lippincott Williams & Wilkins, Inc.