title: Prolonged urocortin 2 administration in experimental heart failure: sustained hemodynamic, endocrine, and renal effects.
abstract: Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P<0.001) and output (2.6±0.1 versus 3.8±0.3 L/min; P<0.001), together with reductions in left atrial pressure (28±1 versus 12±1 mm Hg; P<0.001) and peripheral resistance (30±2 versus 20±2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74±2 versus 72±2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33±0.27 versus 0.73±0.20 nmol/L per hour; P<0.001), aldosterone (970±383 versus 396±96 pmol/L; P<0.05), vasopressin (2.4±0.8 versus 1.3±0.1 pmol/L; P<0.05), endothelin 1 (7.2±0.7 versus 4.5±0.4 pmol/L; P<0.01), and atrial (269±27 versus 150±19 pmol/L; P<0.001) and B-type (65±9 versus 29±6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure.
authors.affiliation: Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. miriam.rademaker@otago.ac.nz
authors.forename: Miriam T
authors.initials: MT
authors.lastname: Rademaker
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Charles
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Ellmers
authors.forename: Lynley K
authors.initials: LK
authors.lastname: Lewis
authors.forename: M Gary
authors.initials: MG
authors.lastname: Nicholls
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D004703:Endocrine System / Q000187:drug effects / Q000503:physiopathology; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D009842:Oligopeptides / Q000097:blood; D012083:Renin / Q000097:blood; D012756:Sheep; D012964:Sodium / Q000652:urine; D013997:Time Factors; D054832:Urocortins / Q000008:administration & dosage / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*; D014667:Vasopressins / Q000097:blood
chemical_list: D019332:Endothelin-1; D009842:Oligopeptides; D054832:Urocortins; D014667:Vasopressins; D000450:Aldosterone; C029579:antiarrhythmic peptide; D012964:Sodium; D003404:Creatinine; D012083:Renin