Heparin decreases blood pressure and response to exogenous endothelin but does not protect against chronic experimental cyclosporine nephropathy

Cyclosporine nephrotoxicity is caused by renal arteriolar vasoconstriction and tubulointerstitial fibrosis. Endothelin has been proposed as a major mediator of these phenomena. Heparin inhibits vascular smooth muscle cell proliferation and lowers blood pressure by regulating endogenous endothelin 1 production. In a model of chronic cyclosporine nephrotoxicity in the rat, animals were treated with cyclosporine alone, cyclosporine plus heparin, and heparin alone for 28 days. Independent experiments determined that these doses of heparin resulted in a marked decrease in responsivity to exogenous endothelin. Despite this, there were no beneficial effects on renal structure or function in this animal model of chronic cyclosporine nephrotoxicity. Thus, the role of endothelin in the pathogenesis of the chronic tubulointerstitial changes and arteriolopathy in this model is probably minor.