Nitric oxide in cyclosporine A-induced hypertension: endothelin receptors gene expression

Cyclosporine A (CsA) is an immunosuppressive agent, which also causes hyper tension. The effect of CsA on vascular responses was determined in spontane ously hypertensive rats and isolated rat aortic rings. Male rats weighing 2 50-300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by i. p. injection for 7 days. CsA administration produced a 27% increase (P < 0. 001) in mean arterial pressure (MAP) which reached a plateau after 3 days. Conversely, the level of nitrate/nitrite, metabolites of nitric oxide (NO), decreased by 44% (P < 0.001) in the urine. In the presence of endothelin ( ET) 10(-9) M, thoracic aortic rings from rats treated with olive oil, L-Arg inine (L-Arg) or L-Arg+CsA showed a 100% increase (P < 0.001) in tension co mpared to the aortic rings from rats treated with CsA alone; aortic rings f rom rats treated with CsA alone did not respond to ET. The effects of CsA w ere reversed in both in vivo and in vitro by pretreatment with L-Arg (10 mg /kg/day ip), the precursor of NO. There were no changes in MAP and tension in rats treated with L-Arg alone. Possible explanation for lack of response to ET of aortic rings from CsA treated rats may be that CsA affected ET si gnalling pathway; ET receptors mRNA (messenger ribonucleic acid) gene expre ssion was inhibited in aortic rings of rats treated with CsA. In summary, C sA inhibits endothelial NO formation, with resulting increases in MAP, and this inhibition can be overcome by parenteral administration of L-Arg.