Dual effects of tumor necrosis factor alpha on myocardial injury following prolonged hypoperfusion of the heart

OBJECTIVE: To examine the dose response of TNFα in an ex vivo rat model of myocardial ischemia reperfusion. METHODS AND RESULTS: Seventy-two rat hearts were mounted on Langendorff apparatus and perfused with oxygenated Krebs-Henseleit solutions. Ischemia was induced by reducing the perfusate flow rate. During reperfusion, incremental doses of recombinant TNFα were infused as a part of perfusate. TNFα was blocked with monoclonal TNFα antibody. Myocardial function was measured by dP/dT and relaxation time (IVRT). Cellular injury was assessed by released myoglobin and tissue concentration of malondialdehyde activity of the heart homogenates. Baseline +dP/dT was 1645 ± 125 mmHg/sec, -dP/dT was 945 ± 73 mmHg/sec and IVRT was 65 ± 5 msec. At the conclusion of reperfusion period, lower doses of TNFα increased +dP/dT and lowered IVRT. In contrast, the higher doses of TNFα decreased +dP/dT and prolonged IVRT. Pretreating the hearts with monoclonal TNFα antibody completely abolished the effects of TNFα on myocardial contractility and relaxation comparable to ischemia controls. CONCLUSION: Low dose TNFα improved myocardial function and decreased resultant cellular injury while high dose TNFα decreased myocardial function and increased myocardial injury following ischemia and reperfusion.