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J Am Coll Cardiol, 2002; 40:1495-1505
© 2002 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure

Comparison with normal sheep

Miriam T. Rademaker, PhD*,*, Christopher J. Charles, PhD*, Eric A. Espiner, MD, FRACP*, Steve Fisher, NZCS, DipMLT*, Christopher M. Frampton, PhD*, Carl M. J. Kirkpatrick, Bpharm*, John G. Lainchbury, MD, FRACP*, M. Gary Nicholls, MD, FRACP, FACC*, A. Mark Richards, MD, PhD, FRACP* and Wylie W. Vale, PhD{dagger}

* Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch, New Zealand
{dagger} Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, USA

Manuscript received March 10, 2002; revised manuscript received April 30, 2002, accepted May 31, 2002.

* Reprint requests and correspondence: Dr. Miriam T. Rademaker, Department of Medicine, The Christchurch School of Medicine, P.O. Box 4345, Christchurch, New Zealand.
miriam.rademaker{at}chmeds.ac.nz

OBJECTIVES: The goal of this study was to determine the bioactivity of urocortin (Ucn) in experimental heart failure (HF).

BACKGROUND: Urocortin may participate in cardiovascular function and pressure/volume homeostasis. Its effects in HF are unknown.

METHODS: Eight normal sheep and eight sheep with pacing-induced HF received ovine Ucn (10, 50, and 100 mg intravenous boluses at 2-h intervals) in vehicle-controlled studies.

RESULTS: Urocortin boluses dose-dependently increased plasma Ucn (p < 0.001). Pharmacokinetics were similar in normal and HF sheep with half-lives approximating 1.3 and 19.5 h for the first and second phases, respectively. In HF, cardiac output increased (twofold), while peripheral resistance, left atrial pressure (both 50% falls: p < 0.001), and mean arterial pressure (p < 0.05) fell. In normal sheep, changes in peripheral resistance and atrial pressure were blunted and in arterial pressure were directionally opposite. Urocortin induced persistent, dose-dependent falls (30% to 50%) in plasma vasopressin, renin activity, aldosterone, natriuretic peptides (all p < 0.001), and endothelin-1 (p < 0.05) in HF sheep, while adrenocorticotrophic hormone and cortisol levels rose acutely (both p < 0.001). In comparison, Ucn in normal sheep resulted in a similar rise in cortisol and fall in aldosterone, no significant effects on plasma renin activity and natriuretic peptides, and a rise in vasopressin. Urocortin produced dose-dependent, sustained increases in urine volume (twofold, p < 0.01), sodium excretion (>9-fold rise, p < 0.001), and creatinine clearance (p < 0.001) in HF sheep. No significant renal effects were observed in normal sheep.

CONCLUSIONS: Urocortin has profound and sustained hemodynamic, hormonal, and renal effects in experimental HF. Urocortin may have a role in pressure/volume homeostasis in HF and may provide a novel therapeutic approach to this disease.

Abbreviations and Acronyms
  ACTH
  adrenocorticotrophic hormone
  AngII
  angiotensin II
  ANP
  atrial natriuretic peptide
  AVP
  arginine vasopressin
  BNP
  brain natriuretic peptide
  cAMP
  cyclic adenosine monophosphate
  CO
  cardiac output
  CRF
  corticotropin-releasing hormone
  CTPR
  calculated total peripheral resistance
  CV
  coefficients of variation
  HF
  heart failure
  HR
  heart rate
  LAP
  left atrial pressure
  LV
  left ventricle/ventricular
  MAP
  mean arterial pressure
  PRA
  plasma renin activity
  RAP
  right atrial pressure
  Ucn
  urocortin




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