Role of nitric oxide in cyclosporine A-induced hypertension.
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.
Oriji
G K
GK
Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Keiser
H R
HR
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D000077300:Bosentan; D006152:Cyclic GMP / Q000652:urine; D016572:Cyclosporine / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D000069463:Olive Oil; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010938:Plant Oils / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D000069463:Olive Oil; D010456:Peptides, Cyclic; D010938:Plant Oils; C110881:S-nitro-N-acetylpenicillamine; D013449:Sulfonamides; D016572:Cyclosporine; D001120:Arginine; D010396:Penicillamine; D006152:Cyclic GMP; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)