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