title: Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep.
abstract: 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.
authors.affiliation: Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch, New Zealand. miriam.rademaker@chmeds.ac.nz
authors.forename: Miriam T
authors.initials: MT
authors.lastname: Rademaker
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Charles
authors.forename: Eric A
authors.initials: EA
authors.lastname: Espiner
authors.forename: Steve
authors.initials: S
authors.lastname: Fisher
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Frampton
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
authors.forename: John G
authors.initials: JG
authors.lastname: Lainchbury
authors.forename: M Gary
authors.initials: MG
authors.lastname: Nicholls
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.forename: Wylie W
authors.initials: WW
authors.lastname: Vale
mesh_terms: 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
chemical_list: D018696:Neuroprotective Agents; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone