Role of prostanoids and endothelins in the prevention of cyclosporine-induced nephrotoxicity

Cyclosporine A nephrotoxicity includes both functional toxicity and histolo gical changes, whose seriousness is dependent upon the dose and the duratio n of the drug administration. Several vasoactive agents have been found to be implicated in cyclosporine induced nephrotoxicity, among which prostanoi ds and endothelins are the most important. In previous studies we were able to prevent the early stage (7 days) of cyclosporine (37.4 mu mol [45 mg]/k g/day) induced nephrotoxicity in rats either by the administration, i) of O KY-046, a thromboxane A(2) synthase inhibitor, ii) of ketanserine, an antag onist of S-2 serotonergic, a(1) adrenergic, and H-1 histaminergic receptors and iii) of nifedipine, a calcium channel blocker, or by diet supplementat ion either with evening primrose oil or fish oil. All these protective agen ts elevated ratios of excreted renal prostanoid vasodilators (prostaglandin s E-2,6ketoF(1 alpha)) to vasoconstrictor (thromboxane B-2), a ratio which was decreased by the administration of cyclosporine alone. Nifedipine avert ed the cyclosporine induced increase of urinary endothelin-1 release. All p rotections were associated with the reinstatement of glomerular filtration rate forwards normal levels whereas renal damage defence, consisting of a d ecrease of the cyclosporine induced vacuolizations, was variable. Ketanseri ne and evening primrose oil were the only agents which prevented the animal body weight loss. These data suggest that prostanoids and endothelin-1 may mediate functional toxicity while thromboxane A(2) is involved the morphol ogical changes too, provoked in the early stage of cyclosporine treatment. However, other nephrotoxic factors and additional mechanisms could also be implicated in the cyclosporine induced nephrotoxicity. (C) 2001 Harcourt Pu blishers Ltd.