Endothelin-1 mediates coronary vasoconstriction caused by exogenous and endogenous cytokines

In many pathologic conditions, elevations in the circulating level of endothelin-1 (ET-1) are linked to increased production of cytokines. Therefore, we have investigated the relationship between cytokines and ET-1. Administration of tumor necrosis factor-alpha (TNF-alpha, 4 micrograms/kg) to anesthetized rats caused, within 15 min, a marked elevation in the circulating plasma level of ET-1. This was associated with pronounced coronary vasoconstriction in hearts removed from these animals and perfused in vitro by the Langendorff technique. This coronary vasoconstriction was attenuated by in vivo pretreatment with either ETA receptor antagonists or with an antibody against ET-1 (ET-Ab). Treatment of the anesthetized rats with interleukin-2 (IL-2) to increase the endogenous release of TNF-alpha also elevated the in vitro coronary vascular resistance, an effect that was greatly reduced by administration of an antibody against TNF-alpha (hr-TNF-alpha-Ab) or FR 139317. Finally, in rats with adjuvant-induced arthritis, in which the levels of circulating cytokines are greatly elevated, we also found large increases in the ex vivo coronary perfusion pressure. Significantly, these were abolished by in vivo treatment for 2 days with the nonpeptide ET receptor antagonist SB209670. Cytokines cause marked and acute changes in the production of ET-1, leading to pronounced coronary vasoconstriction. Cytokine-driven changes in the production of ET-1 may therefore be key events in the development of vascular pathologies.