Myocardial
tumor necrosis factor-alpha (
TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in
ischemia-reperfusion injury (I/R),
sepsis, chronic
heart failure, and cardiac allograft rejection. Cardiac resident macrophages and cardiomyocytes themselves produce
TNF-alpha. In this regard,
adenosine (
ADO) has been reported to reduce macrophage
TNF-alpha production. Our purposes were to determine whether (1) I/R induces rat myocardial
TNF-alpha production; (2)
ADO decreases
ischemia-induced rat myocardial
TNF-alpha production; (3)
ADO functionally protects human myocardium against I/R; and (4)
TNF-alpha-
binding protein (TNFBP; p55) confers similar protection when substituted for
ADO pretreatment. To study this, human atrial trabeculae were obtained during cardiac surgery and suspended in organ
baths, paced at 1 Hz, and force development was recorded during I/R (45/120 min) with or without
ADO pretreatment (125 microM x 10 min), or TNFBP (1 microgram/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing I/R (20/40 min) with or without
ADO pretreatment (125 microM x 2 min) and rat myocardial expression of
TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat myocardial
TNF-alpha levels from 324 +/- 36 to 902 +/- 77 pg/g (P < 0.05; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 +/- 2% of baseline (%BDF; P < 0.05).
ADO pretreatment decreased
ischemia-induced rat myocardial
TNF-alpha production (356 +/- 107 pg/g; P < 0.05) and increased postischemic DF of human myocardium to 39 +/- 3% BDF (P < 0.05. Further substantiating the link between
ischemia-induced
TNF-alpha production and injury, TNFBP administration similarly improved post-I/R function of human myocardium (55 +/- 5% BDF; P < 0.05
vs. I/R alone). We conclude that (1) I/R induces rat myocardial
TNF-alpha production; (2)
ADO pretreatment decreases I/R-induced rat myocardial
TNF-alpha production; (3)
ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/neutralization of
TNF-alpha represents a novel strategy for protecting human myocardium against
ischemia and
reperfusion injury.