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 immunosuppresant, but it is not devoid of serious clinical side effects such as hypertension and nephro toxicity. To clarify the mechanisms involved in the genesis of these side e ffects, we studied the effects of chronic CsA administration on the express ion of some endothelial vasoactive factors in the aorta and kidney. For thi s purpose rats were treated for 30 days with 50 mg/kg/day CsA, and hyperten sion and renal insufficiency developed. In rats receiving CsA, the mRNA exp ression of pre-pro-endothelin-1 increased, whereas that of endothelial nitr ic oxide (NO) synthase decreased, both in the aorta and in the renal cortex (increases in pre-pro-endothelin-l mRNA in aorta and renal cortex, respect ively: 275% +/- 18%, 300% +/- 27%; decreases in endothelial NO synthase mRN A in aorta and renal cortex respectively: 40% +/- 8%, 42% +/- 6%). Moreover , long-term CsA treatment also induced an up-regulation of the endothelin-c onverting enzyme 1 mRNA expression (156% vs control rats) in the renal cort ex, with a significantly increased protein content and enzyme activity. In contrast, no changes were detected in endothelin-converting enzyme 1 mRNA e xpression in aortas from rats receiving the drug. This imbalance between en dothelin-1 and NO systems could explain the hypertension and the deranged k idney function observed after long-term CsA treatment in rats.