Stimulation of β-adrenergic receptors inhibits tumor necrosis factor alpha release from the isolated rat heart

Introduction: β-adrenergic receptor agonists such as isoproterenol inhibit production of tumor necrosis factor alpha (TNF)in a number of isolated cell types such as macrophages and monocytes. Since the heart has been shown to be a source of the cytokine, we hypothesized that isoproterenol would inhibit cardiac production of TNF. Methods: With IACUC approval, rats were anesthetized with pentobarbital. Hearts were removed and perfused Langendorf style at a constant pressure of 90 cm H₂O with a buffer gassed with 95%CV 5%CO₂. After a 30 min. equilibration, bacterial lipopolysaccharide (LPS), 100 ng/ml, with or without isoproterenol, 1 μM , was infused for 60 min. At 30, 60, 90, 150 min. after the start of infusion, coronary flow was measured and coronary effluent analyzed for TNF by the L929 cell cytotoxicity assay. Cardiac production of TNF is expressed as pg/min.(concentration multiplied by coronary flow). Data were analyzed by two-way ANOVA with repeated measures. Values are mean ± S.E. for a minimum of 3 rats per group. Results: Following the 30 min. equilibration period, basal levels of TNF released by the heart were undetectable in the coronary perfusate. However, 60 min. after the initiation of LPS infusion, TNF release was 875 ± 255 pg/min. and increased to 2164 ± 721 pg/min. at 150 min. Simultaneous infusion of isoproterenol with LPS almost completely inhibited TNF release. For instance at 60 and 150 min, TNF release was 75 ± 38 and 58 ± 29 pg/min. respectively (p < 0.05 vs. LPS alone). In other experiments, isoproterenol was begun 30 min. after the initiation of LPS infusion. In these experiments, isoproterenol still suppressed LPS-stimulated TNF release by 95% at 150 min. Conclusion: Stimulation of cardiac β-adrenergic receptors inhibits TNF production by the heart. This finding implies that cardiac cytokine production is inhibited by the sympathetic nervous system. In congestive heart failure the cardiac response to sympathetic stimulation is impaired. This impairment of the inhibitory action of the sympathetic nervous system on cytokine production may play a role in the high plasma levels of TNF found in patients with heart failure.