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

Chronic treatment with cyclosporine A (CsA), an immunosuppressive agent, causes hypertension. 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/day) in olive oil or vehicle by intraperitoneal 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/NO3), metabolites of nitric oxide (NO), and 3', 5' cyclic guanosine monophosphate (cGMP), which mediates NO action, decreased by 50% (P<.001) and 35% (P<.001), respectively, in the urine. Thoracic aortic rings from rats treated 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) compared with untreated rats. This response was similar to that of aortic rings, denuded of endothelium, from untreated rats in which Ach-induced relaxation 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 rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (L-Arg; 10 mg/kg/day intraperitoneally), the precursor of NO. There were no changes in MAP and tension in rats treated with L-Arg alone. In addition, in the aorta of rats that were treated intraperitoneally with CsA for 7 days, CsA significantly activated protein kinase C (PKC) translocation and decreased NO2/NO3 production. This suggest that PKC mediates, in part, CsA-induced hypertension. In summary, CsA activates PKC, which inhibits endothelial NO formation, with resulting increases in MAP and tension, and this inhibition can be overcome by L-Arg administration.