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

Cyclosporine, a potent immunosuppressant, is associated with the devel opment of hypertension and nephrotoxicity. We have previously shown th at endothelin release from the arteries is increased in rats with cycl osporine-induced hypertension. We conducted the present study to deter mine whether the specific endothelin type A (ET(A)) receptor antagonis t FR 139317 prevents cyclosporine-induced hypertension and whether cyc losporine 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 re sponses to norepinephrine and angiotensin II in isolated mesenteric ar teries. FR 139317 normalized the vasoconstrictor responses to angioten sin II and norepinephrine. Cyclosporine (25 mg/kg per day) given for 4 weeks increased ET(A) receptor mRNA expression in the rat aorta and m esenteric artery (170% and 176%, respectively). Little change was obse rved in ET(B) receptor mRNA. These results indicate that cyclosporine may increase blood pressure by increasing not only endothelin producti on but also ET(A) receptor in the vasculature. The specific ET(A) rece ptor antagonist FR 139317 may prevent the hypertension induced by cycl osporine.