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.
Oriji
Gibson K
GK
Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. doriji@aol.com
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D013928:Thromboxane A2; D016572:Cyclosporine; D011493:Protein Kinase C; D008790:Metoprolol