European Heart Journal Advance Access published online on April 8, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi227
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Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand
* To whom correspondence should be addressed. Aims To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2). Methods and Results Eight sheep were administered the CRF-R2 antagonist CRF(9-41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9-41) in HF significantly increased mean arterial pressure (MAP) (71±2 vs. 75±2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3±5.2 vs. 39.4±5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87±1 vs. 89±2 mmHg, P=0.0689; CTPR 21.9±2.0 vs. 24.4±2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9-41) increased plasma urocortin-I (Normal 10.3±0.8 vs. 19.8±1.3 pmol/L, P<0.001; HF 14.4±0.9 vs. 25.3±0.8 pmol/L, P<0.001), renin (Normal 0.34±0.06 vs. 0.41±0.02 nmol/L/hr, P=0.013; HF 1.14±0.29 vs. 1.57±0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370±62 vs. 563±99 pmol/L, P=0.0813; HF 662±141 vs. 1024±209 pmol/L, P=0.095), and endothelin-1 (HF 3.18±0.18 vs. 4.74±1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively). Conclusion These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin-angiotensin-aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.
Received November 11, 2004
Revised February 13, 2005
Accepted February 17, 2005
Preclinical research
Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure
Miriam T. Rademaker, E-mail: miriam.rademaker{at}chmeds.ac.nz
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