ROLE OF NITRIC-OXIDE IN CYCLOSPORINE-A-INDUCED HYPERTENSION

Cyclosporine A (CsA) is an immunosuppressive agent that also causes hy pertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg . kg(-1) . d(-1)) in olive o il or vehicle by intraperitoneal injection for 7 days. CsA administrat ion produced a 42% increase (P<0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both ni trate/nitrite, metabolites of nitric oxide (NO), and cGMP, which media tes NO action, decreased by 50% (P<0.001) and 35% (P<0.001), respectiv ely, in the urine. Thoracic aortic rings from rats treated with CsA an d precontracted with endothelin (10(-9) mol/L) showed a 35% increase ( P<0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10(-9) mol/L) was inhibited 65% (P<0.001) compa red with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-indu ced relaxation was completely abolished (P<0.001), but relaxation indu ced by S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) mol/L) was unaffe cted (P<0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (P<0.0 01) and 65% (P<0.001), respectively, compared with intact aortic rings , The effects of CsA were reversed both in vivo and in vitro by pretre atment with L-arginine (10 mg . kg(-1) . d(-1) IP), the precursor of N O. There were no changes in MAP and tension in rats treated with L-arg inine alone. In summary, CsA inhibits endothelial NO activity, with re sulting increases in MAP and tension, and this inhibition can be overc ome by parenteral administration of L-arginine.