Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure.
OBJECTIVE
To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2).


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).


CONCLUSIONS
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.
Rademaker
Miriam T
MT
Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. miriam.rademaker@chmeds.ac.nz
Charles
Chris J
CJ
Espiner
Eric A
EA
Frampton
Chris M
CM
Lainchbury
John G
JG
Richards
A Mark
AM
D000818:Animals; D002303:Cardiac Output, Low / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D016232:Endothelins / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D011897:Random Allocation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012084:Renin-Angiotensin System / Q000502:physiology*; D012756:Sheep; D054832:Urocortins
C101531:CRF receptor type 2; D016232:Endothelins; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone