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: Miriam T Rademaker, Christopher J Charles, Leigh J Ellmers, Lynley K Lewis, M Gary Nicholls, A Mark Richards
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 57 Issue 6 Pg. 1136-44 (Jun 2011) ISSN: 1524-4563 [Electronic] United States
• PMID: 21536988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Oligopeptides
• Urocortins
• Vasopressins
• Aldosterone
• antiarrhythmic peptide
• Sodium
• Creatinine
• Renin

Topics

• Aldosterone (blood)
• Animals
• Blood Pressure (drug effects)
• Cardiac Output (drug effects)
• Creatinine (urine)
• Endocrine System (drug effects, physiopathology)
• Endothelin-1 (blood)
• Female
• Heart (drug effects, physiopathology)
• Heart Failure (blood, physiopathology, urine)
• Hemodynamics (drug effects)
• Infusions, Intravenous
• Kidney (drug effects, physiopathology)
• Mice
• Oligopeptides (blood)
• Renin (blood)
• Sheep
• Sodium (urine)
• Time Factors
• Urocortins (administration & dosage, pharmacology)
• Vascular Resistance (drug effects)
• Vasopressins (blood)