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Mechanism of cyclosporine A-induced renal vasoconstriction in the rat

NF Rossi, PC Churchill, FD McDonald and VR Ellis

Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.

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.

Volume 250, Issue 3, pp. 896-901, 09/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1989 by the American Society for Pharmacology and Experimental Therapeutics.