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-', 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-a (TNF-a) antibody or continuous infusion in vivo and in vitro of the endothelin ETA receptor selective antagonist FR 139317, greatly decreased the increase in coronary vascular resistance induced by LPS. 4 These data suggest that TNF-cx 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-a 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-a and endothelin-1 which leads to an increase in coronary vascular tone and so a predisposition to myocardial ischaemia. Inactivation of TNF-a by an antibody as well as ETA receptor blockade by a selective antagonist may effectively interfere with this pathway.

Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway

“…Therefore, more detailed studies are needed to better characterize whether IL-10 has antihypertensive properties in this experimental model. TNF-␣ was chronically infused to induce increased ET-1 expression, as previously described (2,10,18,29,47,51). We used prepro-ET-1 mRNA as a biomarker for ET-1 levels, since increased ET-1 plasma values may not reflect local production (12,30).…”

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits

“…Interestingly, it has been shown that TNF-␣ induces a downregulation of eNOS, which results from a destabilization of eNOS mRNA with no effect on transcription (25,60). Morever, TNF-␣ release has been shown to increase plasma levels of ET-1 (6,18,58). Thus the observed reduction of renal eNOS expression and activity as well as ET-1 upregulation could be specific to high-intensity acute exercise.…”

Autonomic Contribution to Endothelin-1 Increase during Laboratory Anger-Recall Stress in Patients with Coronary Artery Disease

“…In another study (41) it was found that aerobic training, known to increase resting peripheral nervous system (PNS) activity (42,43), significantly reduced the production of tumor necrosis factor (TNF)-α by stimulated macrophages. TNF-α can provoke release of ET-1 from macrophages (11,12), and has been observed in combination with ET-1 to promote constriction in the coronary microvascular bed (44). During mental stress in patients with CAD, disinhibition of macrophages consequent to withdrawal of vagal efferent activity may thereby accelerate the production and release of ET-1 from macrophages and/or adjacent endothelial cells that secrete the peptide (17,45).…”