Diminished acetylcholine-induced vasodilation in renal microvessels of cyclosporine-treated rats.
The mechanisms mediating cyclosporin A (CsA)-induced nephrotoxicity have not been established, but damage to endothelial cells by CsA has been proposed as an important factor. In the study presented here, whether endothelial cell function is impaired in the renal vasculature of CsA-treated rats is investigated. The vasodilatory effects of acetylcholine (ACH) on norepinephrine (NE)-induced microvascular constriction in isolated perfused hydronephrotic rat kidneys pretreated with CsA were therefore examined. Hydronephrosis was established to permit direct visualization of renal microvessels. Nephrotoxicity was induced by s.c. injection of CsA (60 mg/kg/day for 5 days). NE (0.3 microM)-induced afferent arteriolar (AA) constriction was exaggerated in CsA rats as compared with that in vehicle (olive oil)-treated control rats. (reduction in diameter of -34 +/- 3 (SE) versus -26 +/- 2%; P less than 0.05). Similarly, efferent arteriolar (EA) constriction by NE in CsA rats exceeded that of controls (-34 +/- 2 versus -22 +/- 3%; P less than 0.01). The vasodilatory responses evoked by ACH were blunted in CsA rats. The AA response to ACH in CsA rats was significantly decreased (P less than 0.005) at ACH concentrations from 1 nM to 1 microM. Similarly, ACH (1 nM to 100 nM) induced less EA vasodilation in CsA rats (P less than 0.025). In control and CsA rats, the addition of nitro-L-arginine abolished AA and EA vasodilation induced by ACH, suggesting that the sustained vasodilatory responses of AA and EA to ACH are mainly dependent on nitric oxide synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Takenaka
T
T
Nephrology Section, Veterans Affairs Medical Center, Miami, FL 33125.
Hashimoto
Y
Y
Epstein
M
M
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D006869:Hydronephrosis / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D009599:Nitroprusside; D009569:Nitric Oxide; D016572:Cyclosporine; D000109:Acetylcholine; D009638:Norepinephrine