Dual Effects of Tumor Necrosis Factor Alpha on Myocardial Injury Following Prolonged Hypoperfusion of the Heart

Immunol Invest. 2015;44(1):23-35. doi: 10.3109/08820139.2014.921689. Epub 2014 Jun 20.

Abstract

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.

Keywords: Myocardial infarction; TNF alpha; ventricular function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Dose-Response Relationship, Drug
  • Malondialdehyde / metabolism
  • Myocardial Contraction / drug effects*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myoglobin / metabolism
  • Organ Culture Techniques
  • Perfusion
  • Rats
  • Rats, Long-Evans
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antibodies, Monoclonal
  • Myoglobin
  • Tumor Necrosis Factor-alpha
  • Malondialdehyde