Role of metoprolol, B1-adrenoceptor antagonist, thromboxane A2 and nitric oxide in CsA-induced hypertension.

Chronic treatment with cyclosporine A (CsA), a potent immunosuppressive agent, is associated with the development of arterial 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 (25mg/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 (NO(2)/NO(3)), 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(-9)M of CsA was added acutely to intact aortic rings from untreated rats, NO(2)/NO(3) 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 metoprolol (15 mg/kg/day ip), B1-adrenoceptor antagonist. There were no changes in MAP and tension in rats treated with metoprolol 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 metoprolol.