El-Mas Mahmoud M, Mohy El-Din Mahmoud M, El-Gowilly Sahar M, Sharabi Fouad M
Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
Eur J Pharmacol. 2004 Mar 8;487(1-3):149-58. doi: 10.1016/j.ejphar.2004.01.025.
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.
血管毒性是免疫抑制剂环孢素A的主要不良反应。本研究旨在确定内皮源性舒张因子（一氧化氮、内皮源性超极化因子[EDHF]和前列腺素）在环孢素诱导的肾血管对乙酰胆碱受体或β-肾上腺素能受体激活反应受损中的相对作用。在不存在和存在N（G）-硝基-L-精氨酸甲酯（L-NAME，一氧化氮合酶抑制剂）、四乙铵（钾通道阻滞剂）或双氯芬酸（环氧化酶抑制剂）的情况下，在苯肾上腺素预收缩的离体灌注大鼠肾脏中评估环孢素对两种血管舒张剂反应所引起的变化。乙酰胆碱（0.03 - 2 nmol）引起的血管舒张被L-NAME、四乙铵或双氯芬酸预处理显著抑制，表明一氧化氮、EDHF和前列腺素在乙酰胆碱血管舒张中起作用。异丙肾上腺素（0.125 - 4 μmol）引起的血管舒张被L-NAME和四乙铵抑制，而双氯芬酸无此作用。环孢素（1 - 4 μM）对两种血管舒张剂引起的血管舒张产生浓度相关的抑制作用。环孢素诱导的乙酰胆碱血管舒张抑制在经L-NAME或四乙铵预处理的组织中减弱，但双氯芬酸预处理的组织中未减弱，提示一氧化氮和EDHF参与环孢素 - 乙酰胆碱相互作用。另一方面，环孢素对异丙肾上腺素血管舒张的抑制几乎被L-NAME消除。在环孢素处理的肾脏中，暴露于一氧化氮合成底物L-精氨酸可使异丙肾上腺素血管舒张完全恢复至对照水平，并显著增加乙酰胆碱血管舒张。结论是，内皮因子对肾血管舒张反应以及环孢素对这些反应的抑制作用的特性和相对贡献在很大程度上取决于血管舒张剂刺激。
