Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Hypertension - Tập 32 Số 5 - Trang 849-855 - 1998
G.K. Oriji1, Harry R. Keiser2
1Gibson K. Oriji From the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
2Harry R. Keiser From the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.

Tóm tắt

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 · kg −1 · d −1 ) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase ( P <0.001) 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% ( P <0.001) and 35% ( P <0.001), 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 <0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10 −9 mol/L) was inhibited 65% ( P <0.001) 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 ( P <0.001), but relaxation induced by S -nitroso- N -acetylpenicillamine (SNAP, 10 −8 mol/L) was unaffected ( P <0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% ( P <0.001) and 65% ( P <0.001), 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 · kg −1 · d −1 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.

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Hypertension

Tập 32 Số 5

849-855

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