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Tumor necrosis factor-alpha (TNF-alpha) is elevated in the failing heart. Very little is known about regulation of TNF-alpha in cardiomyocytes. TNF-alpha expression by macrophages is diminished by adenosine. Therefore, we hypothesized that a similar mechanism might occur in the heart. Neonatal rat myocytes were stimulated with lipopolysaccharide (LPS), and TNF-alpha was measured by ELISA. In the absence of LPS, myocytes did not release TNF-alpha in the medium. After exposure to LPS, TNF-alpha increased to 70.1+/-3.5 pg/mL at 6 hours. Immunofluorescent staining confirmed that TNF-alpha was expressed in myocytes. Adenosine decreased TNF-alpha in a dose-dependent manner (1 to 100 micromol/L, 37% to 65% decrease, P<.01). Adenosine also decreased TNF-alpha in cell homogenates by 78% (P<.0001). The effect of adenosine could be replicated by the A2 agonist PD-125944 (DPMA), by cAMP agonists 8-bromo-cAMP, forskolin, and Ro 20-1724, but not by A1 and A3 agonists. Conversely, the effect of adenosine could be suppressed by the adenylate cyclase inhibitor MDL-12,330. Adenosine also inhibited TNF-alpha in adult rat ventricular myocytes (-60%, P<.005) and rat papillary muscles (-55%, P<.05). In neonatal myocytes, adenosine normalized LPS-induced calcium changes and improved LPS-induced negative inotropic (P<.01) and negative lusitropic (P<.01) effects. Our results demonstrate that adenosine can significantly diminish TNF-alpha levels in the heart. The effect appears to be mediated by the A2 receptor and transduced through a G protein-adenylyl cyclase pathway. These results may explain some cardioprotective effects of adenosine and provide a novel pharmacological intervention in congestive heart failure.
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