Adenosine Inhibits Lipopolysaccharide-Induced Secretion of Tumor Necrosis Factor-α in the Failing Human Heart

Background —The proinflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of congestive heart failure. Recent studies have shown that adenosine inhibits lipopolysaccharide (LPS)-induced expression of TNF-α in macrophages and rat cardiomyocytes. The aim of this study was to determine whether adenosine has a similar effect in the failing human heart.Methods and Results —Left ventricular muscle strips were obtained from seven patients with end-stage congestive heart failure undergoing heart transplantation or insertion of a left ventricular assist device. The muscle strips were incubated at 37°C in 95% O2 /5% CO2 and stimulated with LPS (10 μg/mL). TNF-α release in the supernatant was measured with ELISA, and muscle sections were stained for TNF-α. Muscle strips released TNF-α in the absence of LPS (0.22±0.05 pg · mL−1 · mg wet wt−1 ). TNF-α was immunolocalized to the cardiac myocyte, suggesting that the myocyte is a source for TNF-α production. Adenosine (10 μmol/L) decreased TNF-α by 40% (P <.05). The selective adenosine A2 receptor agonist DPMA (10 μmol/L) decreased TNF-α release by 87% (P <.001), whereas ITu (10 μmol/L), an adenosine-regulating agent that increases endogenous adenosine concentration, inhibited TNF-α release by 93% (P <.001).Conclusions —Adenosine can significantly diminish TNF levels in the failing human heart and may represent a new pharmacological intervention in congestive heart failure.