Imbalance in endothelial vasoactive factors as a possible cause of cyclosporin toxicity: a role for endothelin-converting enzyme.

Cyclosporin A (CsA) is a powerful, widely used immunosuppressant, but it is not devoid of serious clinical side effects such as hypertension and nephrotoxicity. To clarify the mechanisms involved in the genesis of these side effects, we studied the effects of chronic CsA administration on the expression of some endothelial vasoactive factors in the aorta and kidney. For this purpose rats were treated for 30 days with 50 mg/kg/day CsA, and hypertension and renal insufficiency developed. In rats receiving CsA, the mRNA expression of pre-pro-endothelin-1 increased, whereas that of endothelial nitric oxide (NO) synthase decreased, both in the aorta and in the renal cortex (increases in pre-pro-endothelin-1 mRNA in aorta and renal cortex, respectively: 275%+/-18%, 300%+/-27%; decreases in endothelial NO synthase mRNA in aorta and renal cortex respectively: 40%+/-8%, 42%+/-6%). Moreover, long-term CsA treatment also induced an up-regulation of the endothelin-converting enzyme 1 mRNA expression (156% vs. control rats) in the renal cortex, with a significantly increased protein content and enzyme activity. In contrast, no changes were detected in endothelin-converting enzyme 1 mRNA expression in aortas from rats receiving the drug. This imbalance between endothelin-1 and NO systems could explain the hypertension and the deranged kidney function observed after long-term CsA treatment in rats.