EFFECTS OF AN ENDOTHELIN RECEPTOR ANTAGONIST IN RATS WITH CYCLOSPORINE-INDUCED HYPERTENSION

Cyclosporine, a potent immunosuppressant, is associated with the development of hypertension and nephrotoxicity. We have previously shown that endothelin release from the arteries is increased in rats with cyclosporine-induced hypertension. We conducted the present study to determine whether the specific endothelin type A (ET(A)) receptor antagonist FR 139317 prevents cyclosporine-induced hypertension and whether cyclosporine increases ET(A) receptor mRNA in blood vessels. Cyclosporine (25 mg/kg per day) given for 4 weeks increased blood pressure from 98+/-12 to 156+/-14 mm Hg; this increase was blunted by coadministration of 10 mg/kg per day FR 139317 (ie, blood pressure was 138+/-14 mm Hg) in Wistar-Kyoto rats. Cyclosporine induced greater vasoconstrictor responses to norepinephrine and angiotensin II in isolated mesenteric arteries. FR 139317 normalized the vasoconstrictor responses to angiotensin II and norepinephrine. Cyclosporine (25 mg/kg per day) given for 4 weeks increased ET(A) receptor mRNA expression in the rat aorta and mesenteric artery (170% and 176%, respectively). Little change was observed in ET(B) receptor mRNA. These results indicate that cyclosporine may increase blood pressure by increasing not only endothelin production but also ET(A) receptor in the vasculature. The specific ET(A) receptor antagonist FR 139317 may prevent the hypertension induced by cyclosporine.