Isoproterenol inhibits bacterial lipopolysaccharide-stimulated release of tumor necrosis factor-alpha from human heart tissue

Recent evidence suggests that inflammatory cytokines, particularly tumor ne crosis factor alpha (TNF-alpha) may play a role in heart disease. Elevated plasma levels of the cytokine have been reported in congestive heart failur e and severe angina and after myocardial infarction. The exact role of TNF- alpha in heart disease and how production is stimulated and regulated in th e heart are current areas of investigation. Regarding regulation of product ion, isoproterenol elevates cyclic AMP and inhibits TNF-alpha release in ma crophages. Therefore we hypothesized that stimulation of beta-adrenergic re ceptors of the sympathetic nervous system would inhibit release of the cyto kine from heart tissue. With Institutional Review Board approval and patien t consent atrial tissue was obtained during preparation for cardiac bypass. The tissue was divided into segments, placed in culture medium, and incuba ted for various times in the presence or absence of lipopolysaccharide (LPS ) (20 mu g/mL) and/or isoproterenol (1 mu M). The medium was removed and an alyzed for biologically active TNF-alpha by the L929 cell cytotoxicity assa y. Tissue samples were weighed and TNF-alpha release was expressed as pg TN F-alpha/mg tissue. Initially, to determine the time course of release, meas urements were made at 2, 5, 10, 15, 30, 60, 120, 180, and 360 minutes after the addition of LPS. Elevated TNF-alpha levels in the culture medium were reliably detected at 360 minutes after exposure to LPS. In atrial tissue ob tained from seven patients TNF-alpha released into the culture medium at 36 0 minutes was 6 +/- 3 pg/mg tissue. In the presence of LPS, levels of the c ytokine in the culture medium increased to 604 +/- 233 pg/mg tissue (P < 0. 05 vs LPS alone). When isoproterenol and LPS were simultaneously added to t he culture medium release of TNF-alpha was reduced by 87 per cent to 82 +/- 40 pg/mg tissue (P < 0.05 vs LPS alone), Our results show that activation of the beta-adrenergic receptor inhibits myocardial production of TNF-alpha . This finding suggests that the sympathetic nervous system inhibits produc tion of the cytokine and that impaired sympathetic function in heart failur e may play a role in the elevated levels of TNF-alpha.