Rossi N F, Churchill P C, McDonald F D, Ellis V R
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
J Pharmacol Exp Ther. 1989 Sep;250(3):896-901.
The use of the immunosuppressant cyclosporine A (CSA) is limited by its toxicity. Both acute and chronic administration of CSA lead to renal vasoconstriction and decreased renal blood flow and glomerular filtration rate. The present studies were designed to elucidate the mechanism(s) involved in acute CSA-induced changes in renal hemodynamics. Infusion of CSA resulted in a concentration-dependent increase in perfusion pressure in isolated rat kidneys perfused at constant flow. Phenoxybenzamine blunted this response, and therefore a small component of CSA-induced renal vasoconstriction can be attributed to CSA-induced norepinephrine release from nerve terminals in this preparation. The response was antagonized profoundly, but not blocked completely, by nifedipine and methoxyverapamil, consistent with the hypothesis that a large component of CSA-induced vasoconstriction is mediated by Ca++ influx through potential-operated channels in vascular smooth muscle cells, and perhaps in nerve terminals as well. However, CSA-induced activation of such channels cannot account entirely for CSA-induced vasoconstriction because, in the presence of K-depolarization and Ca++ channel blockade, CSA still produced a small increase in renovascular resistance. This latter response was blocked entirely by quinacrine but not by meclofenamate. Neither quinacrine nor meclofenamate alone affected CSA-induced renal vasoconstriction. Therefore, products of phospholipase A2 activity, but not products of the cyclooxygenase pathway, may be involved to some small extent. In conclusion, CSA-induced increases in renovascular resistance are complex and appear to be produced not only by actions on vascular smooth muscle cells per se but also by actions on nerve terminals.
免疫抑制剂环孢素A（CSA）的使用因其毒性而受到限制。急性和慢性给予CSA均会导致肾血管收缩、肾血流量和肾小球滤过率降低。本研究旨在阐明急性CSA诱导的肾血流动力学变化所涉及的机制。在以恒定流量灌注的离体大鼠肾脏中输注CSA会导致灌注压力呈浓度依赖性增加。酚苄明减弱了这种反应，因此CSA诱导的肾血管收缩的一小部分可归因于CSA诱导该制剂中神经末梢释放去甲肾上腺素。硝苯地平和甲氧基维拉帕米可显著拮抗该反应，但不能完全阻断，这与以下假设一致：CSA诱导的血管收缩的很大一部分是由Ca++通过血管平滑肌细胞以及可能还有神经末梢中的电压门控通道内流介导的。然而，CSA诱导的此类通道激活不能完全解释CSA诱导的血管收缩，因为在钾离子去极化和Ca++通道阻断的情况下，CSA仍会使肾血管阻力略有增加。后一种反应完全被奎纳克林阻断，但未被甲氯芬那酸阻断。单独使用奎纳克林或甲氯芬那酸均不影响CSA诱导的肾血管收缩。因此，磷脂酶A2活性产物而非环氧化酶途径产物可能在一定程度上参与其中。总之，CSA诱导的肾血管阻力增加是复杂的，似乎不仅是通过对血管平滑肌细胞本身的作用产生的，还通过对神经末梢的作用产生。
