Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep.
OBJECTIVE
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.
Rademaker
Miriam T
MT
Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch, New Zealand. miriam.rademaker@chmeds.ac.nz
Charles
Christopher J
CJ
Espiner
Eric A
EA
Fisher
Steve
S
Frampton
Christopher M
CM
Kirkpatrick
Carl M J
CM
Lainchbury
John G
JG
Nicholls
M Gary
MG
Richards
A Mark
AM
Vale
Wylie W
WW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012756:Sheep; D054832:Urocortins; D014655:Vascular Resistance / Q000187:drug effects
D018696:Neuroprotective Agents; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone