Endothelin-1 mediates the increase in ex vivo coronary vascular resistance induced by hemorrhagic shock in the anesthetized rat.

Cytokines such as tumor necrosis factor-alpha (TNF-alpha), given exogenously or liberated endogenously, cause the release of endothelin (ET) into the circulation. In the rat, increase in ET causes marked ex vivo coronary vasoconstriction. Hemorrhage also increases the circulating levels of cytokines such as TNF-alpha. Here we show that in rats subjected to hemorrhagic shock there is a marked increase in ex vivo coronary vascular resistance, which is mediated by ET. Hemorrhagic shock was induced in anesthetized rats by withdrawing sufficient blood to reduce mean arterial blood pressure to 40 mm Hg for a period of 30 min, after which all the withdrawn blood was retransfused over a period of 15 min. Hearts were perfused ex vivo at a constant flow of 10 ml/min according to the Langendorff technique. After 90 min in vitro, the coronary perfusion pressure in hearts removed from control rats was 76 +/- 1 mm Hg (n = 5), whereas in hearts taken from rats after hemorrhage it was 114 +/- 6 mm Hg (n = 5; p < 0.05 from control). After the same time in vitro, the coronary perfusion pressure of hearts from rats treated with TNF-alpha (4 micrograms/kg, i.v.) was 122 +/- 4 mm Hg (n = 4; p < 0.05 from control). The increases in coronary perfusion pressure caused by hemorrhagic shock or TNF-alpha were abolished by pretreating rats with the nonselective ET receptor (ETA/ETB) antagonist SB209670 (3 mg/kg, i.v.) (coronary perfusion pressure at 90 min 80 +/- 1 mm Hg after hemorrhage; 73 +/- 4 mm Hg after TNF-alpha, p < 0.05 compared to hemorrhage or TNF-alpha controls, respectively; n = 3-5). Interestingly, pretreatment with polyclonal antibodies to TNF-alpha (3 mg/kg, i.v.) did not significantly attenuate the rise in coronary perfusion pressure caused by hemorrhage. Therefore, hemorrhage followed by retransfusion causes marked coronary vasoconstriction assessed ex vivo owing to the release of ET by factors including TNF-alpha.