ENDOTHELIN-1 MEDIATES EX-VIVO CORONARY VASOCONSTRICTION CAUSED BY EXOGENOUS AND ENDOGENOUS CYTOKINES

Treatment of rats with cytokines has been associated with an increase in the circulating levels of endothelin 1 (ET-1). Here we show that ad ministration of tumor necrosis factor alpha (TNF-alpha; 4 mu g.kg(-1)) to anesthetized rats caused within 15 min a strong elevation in the c irculating levels of ET-1. This was associated with a striking coronar y vasoconstriction in hearts from these animals when they were removed and perfused in vitro by the Langendorff technique. This vasoconstric tion was largely overcome by treatment with either the endothelin type A (ET(A)) receptor antagonist FR 139317 or antibody against ET-1. Fur thermore, it was mimicked by in vivo exposure to exogenous ET-1. Endog enously produced TNF-alpha may also cause such a coronary vasoconstric tion, for treatment with interleukin 2 (600 mu g.kg(-1)) produced an i ncrease in coronary perfusion pressure that correlated with the increa ses in circulating TNF-alpha. This coronary vasoconstriction was subst antially reversed by treatment either with antibody against TNF-alpha or with FR 139317. We suggest, therefore, that cytokine-driven changes in the production of ET-1 are key events in the development of vascul ar pathologies.