Endothelin-1 expression in blood vessels of DOCA-salt hypertensive rats treated with the combined ETA/ETB endothelin receptor antagonist bosentan

Abstract

In previous studies it has been shown that blood vessels of deoxycorticosterone acetate (DOCA) salt hypertensive rats present significantly higher immunoreactive ET-1 (ir-ET-1) content and increased ET-1 gene expression. DOCA-salt hypertensive rats respond to treatment with the combined ET_A/ET_B endotheiin receptor antagonist bosentan with lowering of blood pressure. In the present study, we investigated the ir-ET-1 levels and the expression of the ET-1 gene in blood vessels of DOCA-salt hypertensive rats treated or not treated with bosentan. Blood pressure was significantly lower in bosentan-treated rats (185 ± 6 mmHg; 1 mmHg = 133.3 Pa) compared with DOCA-salt hypertensive rats (203 ± 4 mmHg; p < 0.01). Plasma ir-ET-1 concentration was slightly but significantly elevated (p < 0.01) in DOCA-salt hypertensive rats compared with uninephrectomized control rats, and was further increased (p < 0.01) in bosentan-treated rats. The tissue wet weight and ir-ET-1 content of segments of thoracic aorta were significantly increased (p < 0.01) in DOCA-salt hypertensive rats in comparison with control rats, but were similar in bosentan-treated DOCA-salt rats. The abundance of ET-1 mRNA measured by Northern blot analysis in thoracic aorta and the ir-ET-1 content were attenuated by bosentan treatment. Tissue wet weight and ir-ET-1 content in the mesenteric vascular bed were similar in bosentan-treated and -untreated DOCA-salt rats, and were significantly higher in both groups than in control rats (p < 0.01). ET-1 mRNA levels were increased in mesenteric arteries of DOCA-salt hypertensive rats and were further enhanced by bosentan treatment. These data suggest that inhibition of ET_A and ET_B receptor mediated ET-1 responses by bosentan has a slight but beneficial effect on blood pressure of DOCA-salt hypertensive rats. Chronic blockade of both ET receptors results in increased circulating levels of ET-1 and attenuated ET-1 expression and vascular hypertrophy in aorta but not in the mesenteric vasculature. ET-1 may be involved in the maintenance of elevated blood pressure in DOCA-salt hypertension and perhaps other experimental models of hypertension in the rat in part through a vascular hypertrophic effect.Key words: endothelin-1, endothelin receptor antagonist, aorta, mesenteric arteries, immunoreactive ET-1, preproET-1 mRNA, gene expression.