RENAL AND VASCULAR EFFECTS OF CHRONIC ENDOTHELIN RECEPTOR ANTAGONISM IN MALIGNANT HYPERTENSIVE RATS

The effect of the combined ET(A)/ET(B) endothelin receptor antagonist bosentan on blood pressure, vascular hypertrophy, and pathologic renal changes was investigated in a model of malignant hypertension, severe vascular hypertrophy, and enhanced vascular expression of endothelin- 1, the deoxycorticosterone acetate (DOCA), and salt-treated spontaneou sly hypertensive rat (SHR). DOCA-salt treated SHR received 100 mg bose ntan per kilogram weight per day mixed with their food. Systolic blood pressure of untreated DOCA-salt SHR rose to 241 +/- 1.5 mm Hg, wherea s that of bosentan-treated rats rose to 221 +/- 5.1 mm Hg (P < .01). C ardiac and conduit artery mass were not affected by treatment. Small a rteries from the coronary, renal, and mesenteric circulations showed a smaller media width and cross-sectional area of the media in rats tre ated with bosentan than in untreated rats. The kidneys showed the pres ence of fibrinoid necrosis in a high percentage of afferent arterioles and glomeruli of untreated DOCA-SHR. Some kidneys of treated rats exh ibited less severe vascular hypertrophy and lesser extent of vascular or glomerular fibrinoid necrosis, but the renal injury score of bosent an-treated DOCA-SHR was only at the limit of significance from that of untreated rats (P = .06). These results suggest a role for endothelin -l in blood pressure elevation and the severe vascular hypertrophy of small arteries of the coronary, renal, and mesenteric vasculature, but not of the heart or larger conduit vessels in the malignant hypertens ion that SHR develop after treatment with DOCA and salt. Although some bosentan-treated rats showed fewer renal lesions, a significant effec t on renal pathology could not be unambiguously demonstrated. Further studies will be necessary to determine whether endothelin antagonists may indeed offer some degree of renal protection and have therapeutic potential in severe or malignant hypertension.