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

Prostaglandins Leukot Essent Fatty Acids. Nov-Dec 2001;65(5-6):259-63. doi: 10.1054/plef.2001.0323.

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(-9) M of CsAwas 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), beta-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 increaseTBXA2 production, with resulting increase in MAP, and this changes can be overcome by pretreatment with propranolol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Cyclosporine / adverse effects*
  • Hypertension / chemically induced*
  • Hypertension / metabolism
  • Immunosuppressive Agents / adverse effects*
  • In Vitro Techniques
  • Male
  • Nitric Oxide / metabolism*
  • Propranolol / pharmacology
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thromboxane A2 / metabolism*

Substances

  • Adrenergic beta-Antagonists
  • Immunosuppressive Agents
  • Nitric Oxide
  • Thromboxane A2
  • Cyclosporine
  • Propranolol
  • Protein Kinase C