Relative roles of endothelial relaxing factors in cyclosporine-induced impairment of cholinergic and beta-adrenergic renal vasodilations.
Vascular toxicity is a major adverse effect for the immunosuppressant drug cyclosporine A. The present study sought to characterize the relative roles of the endothelium-derived relaxing factors (nitric oxide, endothelium-derived hyperpolarizing factor [EDHF], and prostaglandins) in the cyclosporine-induced impairment of renovascular responsiveness to acetylcholine receptor or beta-adrenoceptor activation. Changes evoked by cyclosporine in the responses to either vasorelaxant were evaluated in phenylephrine-preconstricted isolated perfused rat kidneys in the absence and presence of N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor), tetraethylammonium (K(+) channel blocker), or diclophenac (cyclooxygenase inhibitor). Acetylcholine (0.03-2 nmol) vasodilations were significantly inhibited by prior treatment with l-NAME, tetraethylammonium, or diclophenac, suggesting a role for nitric oxide, EDHF, and prostaglandins in acetylcholine vasodilations. Isoprenaline (0.125-4 micromol) vasodilations were inhibited by l-NAME and tetraethylammonium versus no effect for diclophenac. Cyclosporine (1-4 microM) produced a concentration-related inhibition of vasodilations relaxations produced by either vasodilator. Cyclosporine-induced inhibition of acetylcholine vasodilations was attenuated in tissues pretreated with l-NAME or tetraethylammonium but not diclophenac, implicating nitric oxide and EDHF in cyclosporine-acetylcholine interaction. On the other hand, the inhibition of isoprenaline vasodilations by cyclosporine was virtually abolished by l-NAME. In cyclosporine-treated kidneys, exposure to l-arginine, the substrate of nitric oxide synthesis, fully restored isoprenaline vasodilations to control levels and significantly increased acetylcholine vasodilations. It is concluded that the identity and relative contributions of endothelial factors to renal vasodilatory responses as well as to the inhibition of these responses by cyclosporine largely depend on the vasodilator stimulus.
El-Mas
Mahmoud M
MM
Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt. elmasm@mail.ecu.edu
Mohy El-Din
Mahmoud M
MM
El-Gowilly
Sahar M
SM
Sharabi
Fouad M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001685:Biological Factors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000294:innervation; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D011453:Prostaglandins; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D010656:Phenylephrine; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D007545:Isoproterenol; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester