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

Objectives: beta -Adrenergic receptor agonists such as isoproterenol inhibi t production of tumor necrosis factor (TNF)-alpha in a number of cell types . Because the heart is a source of TNF-alpha, we hypothesized that isoprote renol would inhibit cardiac production of the cytokine. Design:Analysis of cardiac release of TNF-alpha. Setting: Medical research laboratory. Subjects: Rats. Interventions: None. Measurements and Main Results:With the approval of the Institutional Animal Care and Use Committee, rats were anesthetized and hearts were removed and perfused. After 30 mins, bacterial lipopolysaccharide (LPS) with or withou t isoproterenol was infused for 60 mins. At 30, 60, 90, 120, and 150 mins, coronary flow was measured and coronary effluent was analyzed for TNF-alpha . Cardiac production of TNF-alpha was expressed as pg/min. Cyclic adenosine monophosphate (AMP) in the coronary effluent was measured. TNF-alpha messe nger RNA was determined in ventricular tissue. After 30 mins, TNF-alpha was undetectable in the coronary effluent. However, 60 mins after the initiati on of LPS infusion, TNF-cr release was 875 +/- 255 pg/min and increased to 2164 +/- 721 pg/min at 150 mins. Simultaneous infusion of isoproterenol wit h LPS stimulated cyclic AMP release and inhibited TNF-alpha production. For instance, at 60 and 150 mins, TNF-alpha release was 75 +/- 38 and 58 +/- 2 9 pg/min, respectively (p < .05 vs. LPS alone). Simultaneous infusion of is oproterenol with LPS blocked the induction of TNF-<alpha> messenger RNA by LPS. Isoproterenol, begun 30 mins after the initiation of LPS infusion, sti ll suppressed LPS-stimulated TNF-alpha release by 95% at 150 mins. Similar results were obtained with norepinephrine. Conclusions: Activation of beta -adrenergic receptors inhibits cardiac TNF- alpha release. This implies that cytokine production by the heart is inhibi ted by the sympathetic nervous system. In heart failure, the cardiac respon se to the sympathetic nervous system is impaired. This impairment may play a role in the high plasma levels of TNF-alpha found in heart failure.