The contribution of tumour necrosis factor‐α and endothelin‐1 to the increase of coronary resistance in hearts from rats treated with endotoxin

Abstract

1 Inflammatory disease states predispose to myocardial infarction. Here we have investigated the effects of a systemic inflammatory response syndrome, i.e. lipopolysaccharide (LPS)-induced circulatory shock in rats, on coronary vascular tone. 2 Anaesthetized rats were given LPS (10 mg kg⁻¹, i.v.) and the hearts excised 180 min later for isolated perfusion at constant flow by the Langendorff technique. Once the ex vivo perfusion was started, the perfusion pressure strongly increased in these hearts compared to hearts from control rats (130±3 vs. 49±3 mmHg after 10 min). This increase in coronary resistance was not associated with a reduction in endothelial cell function, for the vasodilator responses to bradykinin were unchanged. 3 When hearts were removed 30 min after the injection of LPS, the LPS-induced rise in perfusion pressure was delayed. No changes in perfusion pressure were seen when the hearts were removed 15 min after the injection of LPS. Pre-treatment with cycloheximide or an anti-tumour necrosis factor-α (TNF-α) antibody or continuous infusion in vivo and in vitro of the endothelin ET_A receptor selective antagonist FR 139317, greatly decreased the increase in coronary vascular resistance induced by LPS. 4 These data suggest that TNF-α may induce the release of endothelin-1 (ET-1) and that this mediates at least part of the coronary vasoconstriction. This hypothesis is supported by the demonstration that LPS administration increased the circulating levels of both TNF-α and ET-1. 5 We conclude, therefore, that in inflammatory disease states, such as LPS-induced septic shock, there is the sequential release of TNF-α and endothelin-1 which leads to an increase in coronary vascular tone and so a predisposition to myocardial ischaemia. Inactivation of TNF-α by an antibody as well as ET_A receptor blockade by a selective antagonist may effectively interfere with this pathway.