ADENOSINE REDUCES CARDIAC TNF-ALPHA PRODUCTION AND HUMAN MYOCARDIAL INJURY FOLLOWING ISCHEMIA-REPERFUSION

Myocardial tumor necrosis factor-alpha (TNF-alpha) is an autocrine con tributor 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 t hemselves 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 producti on; (2) ADO decreases ischemia-induced rat myocardial TNF-alpha produc tion; (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 tra beculae were obtained during cardiac surgery and suspended in organ ba ths, paced at 1 Hz, and force development was recorded during I/R (45/ 120 min) with or without ADO pretreatment (125 mu M x 10 min), or TNFB P (1 mu g/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing IIR (20/40 min) with or without ADO pret reatment (125 mu M x 2 min) and rat myocardial expression of TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat my ocardial TNF-alpha levels from 324 +/- 36 to 902 +/- 77 pg/ g (P < 0.0 5; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 +/- 2% of baseline (%BDF; P < 0.05). ADO pretreatmen t decreased ischemia-induced rat myocardial TNF-alpha production (356 +/- 107 pg/g; P < 0.05) and increased postischemic DF of human myocard ium to 39 +/- 3% BDF (P < 0.05). Further substantiating the link betwe en ischemia-induced TNF-alpha production and injury, TNFBP administrat ion 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 m yocardial TNF-alpha production; (2) ADO pretreatment decreases I/R-ind uced rat myocardial TNF-alpha production; (3) ADO improves human myoca rdial function; (4) TNFBP confers similar protection; and (5) inhibiti on/neutralization of TNF-alpha represents a novel strategy for protect ing human myocardium against ischemia and reperfusion injury. (C) 1998 Academic Press.