title: Cyclosporine produces endothelial dysfunction by increased production of superoxide.
abstract: Vasoconstriction and hypertension are major side effects of cyclosporine therapy. The mechanism or mechanisms responsible for the vascular effects of cyclosporine are unclear. The vascular effects of cyclosporine may arise as a consequence of endothelial dysfunction induced by the agent. To test this possibility, we compared in vessels prepared in myographs endothelium-mediated relaxations of mesenteric resistance arteries of Wistar-Kyoto rats treated for 21 to 28 days with subcutaneous injections of cyclosporine (25 mg/kg per day), or vehicle. Endothelium-dependent relaxations in response to acetylcholine were impaired in arteries from cyclosporine-treated rats; the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine activation (pD2) were 31.6 +/- 0.1 versus 5 +/- 0.1 nmol/L in control arteries (P < .05). Nitro-L-arginine produced comparable 10-fold decreases in sensitivity to acetylcholine in arteries from both rat groups, indicating that the relaxations were mediated by endothelium-derived nitric oxide. Acetylcholine-induced relaxations in cyclosporine-treated arteries were normalized by pretreatment of the arteries with superoxide dismutase (150 IU/mL; pD2, 3.6 +/- 0.1; P < .05); superoxide dismutase had no effect on relaxations in control arteries. SQ 29,548, an inhibitor of prostaglandin H2/thromboxane A2 receptors; H-7, an inhibitor of protein kinase C; and indomethacin did not alter relaxations in response to acetylcholine in either group of arteries. Cyclosporine-treated arteries were more sensitive than control arteries to nitroprusside, an agent that induces relaxation via nitric oxide (pD2, 1.3 and 6.2 mumol/L, respectively; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City 66103.
authors.forename: D
authors.initials: D
authors.lastname: Diederich
authors.forename: J
authors.initials: J
authors.lastname: Skopec
authors.forename: A
authors.initials: A
authors.lastname: Diederich
authors.forename: F X
authors.initials: FX
authors.lastname: Dai
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology
chemical_list: D013481:Superoxides; D009599:Nitroprusside; D016572:Cyclosporine; D000109:Acetylcholine