Effects of an Endothelin Receptor Antagonist in Rats With Cyclosporine-Induced Hypertension

Publisher Website
Google Scholar
Abstract
Abstract 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.