Abstract-Cyclosporine A (CsA) is an immunosuppressive agent that also 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 ⅐ kg Ϫ1 ⅐ d Ϫ1 ) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase (PϽ0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both nitrate/nitrite, metabolites of nitric oxide (NO), and cGMP, which mediates NO action, decreased by 50% (PϽ0.001) and 35% (PϽ0.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA and precontracted with endothelin (10 Ϫ9 mol/L) showed a 35% increase (PϽ0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10 Ϫ9 mol/L) was inhibited 65% (PϽ0.001) compared with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-induced relaxation was completely abolished (PϽ0.001), but relaxation induced by S-nitroso-Nacetylpenicillamine (SNAP, 10 Ϫ8 mol/L) was unaffected (PϽ0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (PϽ0.001) and 65% (PϽ0.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (10 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 IP), the precursor of NO. There were no changes in MAP and tension in rats treated with L-arginine alone. In summary, CsA inhibits endothelial NO activity, with resulting increases in MAP and tension, and this inhibition can be overcome by parenteral administration of L-arginine. (Hypertension. 1998;32:849-855.)Key Words: cyclosporine Ⅲ arginine Ⅲ endothelin Ⅲ acetylcholine Ⅲ nitrates Ⅲ rats Ⅲ aortic rings C yclosporine A (CsA) is a potent immunosuppressive agent that is associated with the development of arterial hypertension.1,2 Numerous articles have reported data that support many possible causes for the hypertension, but none have really clarified the mechanism.3 As a result, effective treatment of CsA-induced hypertension remains empiric.Therefore, this study aimed to answer the following questions: (1) What vasoactive system abnormalities, if any, accompany CsA-induced hypertension in the whole animal? (2) Are similar abnormalities found in isolated aortic rings from CsA-treated animals? (3) Does direct measurement of the vasoactive substance(s) produced by the rings provide evidence of the abnormality? (4) Can CsA toxicity be overcome by administration of an agent that should remedy the abnormality? By performing complementary studies in the whole animal, isolated aortic rings, and the fluid that bathed those rings, we found that CsA toxicity is associated with an inhibition of nitric oxide (NO) activity that can be overcome by pretreatment with L-arginine (L-Arg). Methods AnimalsMale Sprague-Dawley rats weighing 2...

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.