Nitric oxide in CsA-induced hypertension: role of β -adrenoceptor antagonist and thromboxane A2

Abstract

Cyclosporine A (CsA) is an immunosuppressive agent, which also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-–Dawley rats and rat aortic rings. Male rats weighing 250-–300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by intraperitoneal (ip) injection for 7 days. CsA administration produced a 42% increase (P<0.001) in mean arterial pressure (MAP) which reached a plateau after 3 days. The level of both nitrate/nitrite (NO2/NO3), metabolites of nitric oxide (NO), decreased by 50% (P<0.001), but the level of thromboxane A2-(TBXA2) increased by 75% (P<0.001), in the urine. When 10−9M of CsA was added acutely to intact aortic rings from untreated rats, NO2/NO3 production decreased by 83% (P<0.011), but TBXA2- production increased by 86% (P<0.001). The effects of CsA were reversed both in vivo and in vitro by pretreatment with propranolol (15 mg/kg/day ip), β -adrenoceptor antagonist. There were no changes in MAP and tension in rats treated with prop alone. In addition, in aorta of rats that were treated with CsA ip for 7 days, CsA significantly activated protein kinase C (PKC) translocation. This suggests that PKC mediate, in part, CsA-induced hypertension. In summary, CsA inhibits endothelial NO formation, activate PKC, and increase TBXA2 production, with resulting increase in MAP, and this changes can be overcome by pretreatment with propranolol.