Role of prostanoids and endothelins in the prevention of cyclosporine-induced nephrotoxicity.
Cyclosporine A nephrotoxicity includes both functional toxicity and histological changes, whose seriousness is dependent upon the dose and the duration of the drug administration. Several vasoactive agents have been found to be implicated in cyclosporine induced nephrotoxicity, among which prostanoids and endothelins are the most important. In previous studies we were able to prevent the early stage (7 days) of cyclosporine (37.4 micromol [45 mg]/kg/day) induced nephrotoxicity in rats either by the administration, i) of OKY-046, a thromboxane A(2)synthase inhibitor, ii) of ketanserine, an antagonist of S(2)serotonergic, a(1)adrenergic, and H(1)histaminergic receptors and iii) of nifedipine, a calcium channel blocker, or by diet supplementation either with evening primrose oil or fish oil. All these protective agents elevated ratios of excreted renal prostanoid vasodilators (prostaglandins E(2), 6ketoF(1 alpha)) to vasoconstrictor (thromboxane B(2)), a ratio which was decreased by the administration of cyclosporine alone. Nifedipine averted the cyclosporine induced increase of urinary endothelin-1 release. All protections were associated with the reinstatement of glomerular filtration rate forwards normal levels whereas renal damage defence, consisting of a decrease of the cyclosporine induced vacuolizations, was variable. Ketanserine 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 morphological 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.
Darlametsos
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Centre Franco-Hellénique de Recherches Biomédicales, Nikolaos Papanikolaou, Corporation of the Municipality Agrinion, Agrinion, 30100, Greece. darlamet@otenet.gr
Varonos
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D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D016232:Endothelins / Q000502:physiology*; D007668:Kidney / Q000187:drug effects*; D009638:Norepinephrine / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D012084:Renin-Angiotensin System; D013931:Thromboxanes / Q000502:physiology
D016232:Endothelins; D011453:Prostaglandins; D013931:Thromboxanes; D016572:Cyclosporine; D009638:Norepinephrine