Chronic treatment with cyclosporine A (CsA), an immunosuppressive agent, ca
uses hypertension. The effect of CsA on vascular responses was determined i
n 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 i
ntraperitoneal 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/N
O3), metabolites of nitric oxide (NO), and 3', 5' cyclic guanosine monophos
phate (cGMP), which mediates NO action, decreased by 50% (P < .001) and 35%
(P < .001), respectively, in the urine. Thoracic aortic rings from rats tr
eated 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) co
mpared with untreated rats. This response was similar to that of aortic rin
gs, denuded of endothelium, from untreated rats in which Ach-induced relaxa
tion 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 r
ings. The effects of CsA were reversed both in vivo and in vitro by pretrea
tment with L-arginine (L-Arg; 10 mg/kg/day intraperitoneally), the precurso
r of NO. There were no changes in MAP and tension in rats treated with L-Ar
g alone. In addition, in the aorta of rats that were treated intraperitonea
lly with CsA for 7 days, CsA significantly activated protein kinase C (PKC)
translocation and decreased NO2/NO3 production. This suggest that PKC medi
ates, in part, CsA-induced hypertension. In summary, CsA activates PKC, whi
ch inhibits endothelial NO formation, with resulting increases in MAP and t
ension, and this inhibition can be overcome by L-Arg administration. (C) 19
99 American Journal of Hypertension, Ltd.