Effect of chronic treatment with two different ET(A) selective endothelin receptor antagonists on blood pressure and small artery structure of deoxycorticosterone acetate (DOCA)-salt hypertensive rats.
Chronic treatment with a combined ET(A) and ET(B) endothelin receptor antagonist blunts hypertension development and small artery hypertrophy in deoxycorticosterone acetate (DOCA)-salt treated rats, in which endothelin-1 is overexpressed in endothelial cells of blood vessels. To determine whether ET(A) receptor antagonism played a predominant role in these findings, in this study the effects of two orally active ET(A) selective endothelin receptor antagonists, A-127722.5 and LU 135252, were evaluated on blood pressure and small artery structure in DOCA-salt hypertensive rats. Rats received A-127722.5 (30 mg/kg/day) or LU 135252 (50 mg/kg/day) in their drinking water since induction of hypertension. Whereas three of 10 untreated DOCA-salt hypertensive rats died, in the two treated groups none died and all appeared healthier. Systolic blood pressure of treated DOCA-salt hypertensive rats, measured with the tail cuff method, was lower than that of untreated DOCA-salt hypertensive rats by a mean of 20 mm Hg (P < .01) after 4 weeks of treatment with A-127722.5 and by 14 mm Hg (P < .01) with LU 135252. Cardiac and aortic relative weights were unaffected by treatment with either agent. Small arteries of the mesenteric, coronary, renal, and femoral vasculature, examined under standardized conditions after mounting on a wire myograph, were found to exhibit significant inward hypertrophic remodeling in DOCA-salt hypertensive rats. DOCA-salt hypertensive rats treated with A-127722.5 had a significantly smaller media width and media-to-lumen ratio in the four vascular beds examined, and rats treated with LU 135252 showed these findings in mesenteric and renal small arteries. These results demonstrate that chronic ET(A) selective antagonism induces similar effects to those of combined ET(A)/ET(B) receptor antagonists in DOCA-salt hypertensive rats; namely, mild reduction in development of hypertension and blunting of small artery morphological changes, and also appears to improve survival. These results suggest a role of ET(A) receptors in the endothelin dependent component of blood pressure elevation in DOCA-salt hypertensive rats, and in the small artery morphological changes present in this model of experimental hypertension.
Li
J S
JS
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montréal, University of Montréal, Québec, Canada.
Turgeon
A
A
Schiffrin
E L
EL
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000473:pathology*; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012965:Sodium Chloride; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; C107831:darusentan; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D000077868:Atrasentan