Adenosine Inhibits Lipopolysaccharide-Induced Cardiac Expression of Tumor Necrosis Factor-

From the Division of Cardiology (D.R.W., A.C., C.M., B.L., A.M.F.) and the Division of Neuropathology (V.J.S.), University of Pittsburgh (Pa) Medical Center.

Correspondence to Arthur M. Feldman, MD, PhD, University of Pittsburgh Medical Center, Division of Cardiology, S572 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail feldma{at}card2.cath.upmc.edu

Abstract—Tumor necrosis factor- (TNF-) is elevated in the failing heart. Very little is known about regulation of TNF- in cardiomyocytes. TNF- 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- was measured by ELISA. In the absence of LPS, myocytes did not release TNF- in the medium. After exposure to LPS, TNF- increased to 70.1±3.5 pg/mL at 6 hours. Immunofluorescent staining confirmed that TNF- was expressed in myocytes. Adenosine decreased TNF- in a dose-dependent manner (1 to 100 µmol/L, 37% to 65% decrease, P<.01). Adenosine also decreased TNF- 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- 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- 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.

Key Words: adenosine • tumor necrosis factor- • cytokine • cardiomyocyte • myocardium

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