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(Circulation. 2005;112:3624-3632.)
© 2005 American Heart Association, Inc.

Heart Failure

Integrated Hemodynamic, Hormonal, and Renal Actions of Urocortin 2 in Normal and Paced Sheep

Beneficial Effects in Heart Failure

Miriam T. Rademaker, PhD; Vicky A. Cameron, PhD; Christopher J. Charles, PhD; A. Mark Richards, MD, PhD, FRACP

From Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch, New Zealand.

Correspondence to Dr Miriam Rademaker, Department of Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. E-mail miriam.rademaker{at}chmeds.ac.nz

Received May 10, 2005; revision received June 23, 2005; accepted August 11, 2005.

Background— Urocortin 2 (Ucn2) has potent cardiovascular actions and may participate in the pathophysiology of heart failure (HF). The integrated hemodynamic, endocrine, and renal effects of Ucn2 are unknown.

Methods and Results— Eight sheep received incremental intravenous boluses of murine Ucn2 (10, 50, and 100 µg at 2-hour intervals) before (normal) and during pacing-induced HF. Compared with control data, Ucn2 induced rapid and dose-dependent increases in cardiac output (peak effects: normal 4.3±0.2 versus 6.1±0.2 L/min, P<0.001; HF 2.3±0.1 versus 4.5±0.2 L/min, P<0.001) and reductions in peripheral resistance (normal 20.2±1.0 versus 15.2±0.8 mm Hg/L per minute, P<0.01; HF 32.2±1.7 versus 13.6±0.5 mm Hg/L per minute, P<0.001) and left atrial pressure (normal 4.3±0.3 versus 0.5±0.2 mm Hg, P<0.01; HF 22.9±0.6 versus 5.1±1.8 mm Hg, P<0.001). Mean arterial pressure was minimally elevated in normals and decreased in HF (both P<0.01). In both states, Ucn2 reduced plasma atrial natriuretic peptide levels (normal 13±2 versus 10±2 pmol/L; HF 200±20 versus 72±10 pmol/L) and similarly increased corticotropin, cortisol, and Ucn1 (all P<0.001). In HF only, Ucn2 dose dependently decreased plasma vasopressin (3.09±0.36 versus 1.62±0.12 pmol/L, P<0.01), renin (2.98±1.17 versus 0.69±0.10 nmol/L per hour, P<0.001), aldosterone (1186±303 versus 364±122 pmol/L, P<0.001), endothelin-1 (3.39±0.23 versus 2.56±0.18 pmol/L, P<0.01), epinephrine (1633±260 versus 657±142 pmol/L, P<0.01), and brain natriuretic peptide (36±3 versus 18±4 pmol/L, P<0.001) concentrations. Renal effects, including increased urine volume (1.7-fold, P<0.05), sodium excretion (>12-fold, P<0.01), and creatinine excretion (1.3-fold, P<0.001), also occurred only in HF.

Conclusions— Ucn2 has marked and beneficial hemodynamic, hormonal, and renal effects in experimental HF. These results support a role for Ucn2 in pressure/volume homeostasis in HF and suggest that the peptide may have therapeutic potential in this disease.

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CLINICAL PERSPECTIVE

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Urocortin: Advancing the Neurohumoral Hypothesis of Heart Failure

John C. Burnett, Jr
Circulation 2005 112: 3544-3546. [Full Text]

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