Nitric oxide in cyclosporine A-induced hypertension: Role of protein kinase C

Chronic treatment with cyclosporine A (CsA), an immunosuppressive agent, ca uses hypertension. The effect of CsA on vascular responses was determined i n Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by i ntraperitoneal injection for 7 days. Cyclosporine A administration produced a 42% increase (P < .001) in mean arterial pressure (MAP), which reached a plateau after 3 days. Conversely, the level of both nitrate/nitrite (NO2/N O3), metabolites of nitric oxide (NO), and 3', 5' cyclic guanosine monophos phate (cGMP), which mediates NO action, decreased by 50% (P < .001) and 35% (P < .001), respectively, in the urine. Thoracic aortic rings from rats tr eated with CsA, and precontracted with endothelin (10(-9) mol/L), showed a 35% increase (P < .001) in tension, whereas acetylcholine-induced (Ach; 10( -9) mol/L) endothelium-dependent relaxation was inhibited 65% (P < .001) co mpared with untreated rats. This response was similar to that of aortic rin gs, denuded of endothelium, from untreated rats in which Ach-induced relaxa tion was completely abolished (P < .001). Ach-induced formation of both NO2 /NO3 and cGMP by both denuded and CsA-treated aortic rings was inhibited 95 % (P < .001) and 65% P < .001), respectively, compared with intact aortic r ings. The effects of CsA were reversed both in vivo and in vitro by pretrea tment with L-arginine (L-Arg; 10 mg/kg/day intraperitoneally), the precurso r of NO. There were no changes in MAP and tension in rats treated with L-Ar g alone. In addition, in the aorta of rats that were treated intraperitonea lly with CsA for 7 days, CsA significantly activated protein kinase C (PKC) translocation and decreased NO2/NO3 production. This suggest that PKC medi ates, in part, CsA-induced hypertension. In summary, CsA activates PKC, whi ch inhibits endothelial NO formation, with resulting increases in MAP and t ension, and this inhibition can be overcome by L-Arg administration. (C) 19 99 American Journal of Hypertension, Ltd.