Effects of the Endothelin ETA-Receptor Antagonist FR139317 on Development of Hypertension and Cardiovascular Hypertrophy in Deoxycorticosterone Acetate-Salt Hypertensive Rats

Abstract

We investigated the role of endothelin-1 (ET-1) in the development of hypertension and cardiovascular hypertrophy in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Two weeks after the start of DOCA-salt treatment, the rats were divided into two groups and were given FR139317 [(R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]- carbonyl]amino-4-methyl-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)] propionyl]amino-3-(2-pyridyl) propionic acid], a specific ETA-receptor antagonist, or its vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Vehicle-treated DOCA-salt rats developed marked hypertension after 4 weeks. FR139317 significantly suppressed the increase in systolic blood pressure with values averaging 163 +/- 8 mmHg (P < 0.05 vs DOCA-salt rats receiving vehicle, 195 +/- 9 mmHg). Morphological studies in the rats given the vehicle showed vascular medial hypertrophy, with a significant increase in the wall area and wall-to-lumen ratio. A marked decrease in vascular wall hypertrophy was observed in the FR139317-treated DOCA-salt rats. The cardiac hypertrophy in DOCA-salt hypertensive rats was also significantly reduced by FR139317. Therefore, these results suggest that ET-1 plays an important role in the development of DOCA-salt hypertension presumably by stimulating the ETA receptor. In addition, we found that an ETA-receptor antagonist effectively reduced cardiovascular hypertrophy in the rats, so the cardiovascular hypertrophy noted in DOCA-salt hypertensive rats may be related to ET-1.