Adenosine inhibits lipopolysaccharide-induced secretion of tumor necrosis factor-alpha in the failing human heart.
BACKGROUND
The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of congestive heart failure. Recent studies have shown that adenosine inhibits lipopolysaccharide (LPS)-induced expression of TNF-alpha in macrophages and rat cardiomyocytes. The aim of this study was to determine whether adenosine has a similar effect in the failing human heart.


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 degrees C in 95% O2/5% CO2 and stimulated with LPS (10 microg/mL). TNF-alpha release in the supernatant was measured with ELISA, and muscle sections were stained for TNF-alpha. Muscle strips released TNF-alpha in the absence of LPS (0.22+/-0.05 pg x mL(-1) x mg wet wt[-1]). TNF-alpha was immunolocalized to the cardiac myocyte, suggesting that the myocyte is a source for TNF-alpha production. Adenosine (10 micromol/L) decreased TNF-alpha by 40% (P<.05). The selective adenosine A2 receptor agonist DPMA (10 micromol/L) decreased TNF-alpha release by 87% (P<.001), whereas ITu (10 micromol/L), an adenosine-regulating agent that increases endogenous adenosine concentration, inhibited TNF-alpha 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.
Wagner
D R
DR
University of Pittsburgh Medical Center, Division of Cardiology, Pa 15213, USA.
McTiernan
C
C
Sanders
V J
VJ
Feldman
A M
AM
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002317:Cardiovascular Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C056426:CGS 24012; D000241:Adenosine; D014372:Tubercidin