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.
Oriji
G K
GK
Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Keiser
H R
HR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000652:urine; D016572:Cyclosporine / Q000633:toxicity*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D011493:Protein Kinase C; D006152:Cyclic GMP; D000109:Acetylcholine