Mechanisms of FK 506-induced hypertension in the rat

Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clini cal utility of FK 506 is complicated by substantial hypertension and nephro toxicity. To clarify the mechanisms of FK 506-induced hypertension, we stud ied the chronic effects of FK 506 on the synthesis of endothelin-l (ET-1), the expression of mRNA of ET-I and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression o f mRNA of eNOS and C-type natriuretic peptide (CNP) in rat brood vessels. I n addition, the effect of the specific endothelin type A receptor antagonis t FR 139317 on FK 506-induced hypertension in mts was studied. FK 506, 5 mg .kg(-1).d(-1) given for 4 weeks, elevated blood pressure from 102+/-13 to 1 52+/-15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mR NA in the mesenteric artery (240% and 230%, respectively). Little change wa s observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased e NOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respect ively). The administration of FR 139317 (10 mg.kg(-1).d(-1)) prevented FK 5 06-induced hypertension in rats. These results indicate that FK 506 may inc rease blood pressure not only by increasing ET-1 production but also by dec reasing NO synthesis in the vasculature.