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Adenosine contributes to neutrophil-mediated loss of myocardial function in post-ischemic guinea-pig hearts
L M Schwartz1, P Raschke, B F Becker
1Department of Physiology, University of Munich, Germany.
Abstract:
Tissue injury associated with myocardial ischemia is assumed to largely result from the toxic effects of active oxygen species generated by accumulated polymorphonuclear leukocytes (PMNs). Recent reports have indicated that adenosine can interfere with the PMN function in vitro. The potential of adenosine to influence PMN-mediated myocardial tissue injury was assessed using a model of ischemia-reperfusion injury developed in the isolated working guinea-pig heart perfused with homologous PMNs. After an initial work phase, hearts were subjected to 30 min low-flow ischemia (1 ml/min) in the absence and presence of PMNs. Work was resumed after 15 min reperfusion in a non-working mode (Langendorff). Adenosine in the coronary effluent reached a maximum of 0.2 microM during low-flow ischemia. Recoveries of external heart work and cardiac output were reduced from about 80% to about 40% by PMNs. Infusion of adenosine deaminase (ADA, 5 U/ml), theophylline (50 microM) or the selective A1-antagonist dipropyl-8-cyclopentylxanthine (0.1 microM) prevented this effect. Furthermore, application of adenosine (0.1 microM) in combination with PMNs also resulted in a loss of pump function, even in the absence of a direct ischemic stimulus. The data indicate that adenosine contributes to post-ischemic, PMN-mediated damage in the isolated working guinea-pig heart model by a receptor-mediated action.
Insights
Adenosine exacerbates myocardial ischemia damage by activating polymorphonuclear leukocytes (PMNs). Blocking adenosine signaling protects heart tissue from PMN-mediated injury during reperfusion.
Area of Science:
- Cardiovascular Science
- Immunology
- Biochemistry
Background:
- Myocardial ischemia-reperfusion injury involves tissue damage.
- Polymorphonuclear leukocytes (PMNs) and active oxygen species are implicated in this injury.
- Adenosine's role in modulating PMN function is under investigation.
Purpose of the Study:
- To assess adenosine's influence on PMN-mediated myocardial tissue injury.
- To investigate the mechanism of adenosine's action in ischemia-reperfusion injury.
Main Methods:
- Utilized an isolated working guinea-pig heart model.
- Subjected hearts to low-flow ischemia and reperfusion, with and without homologous PMNs.
- Administered adenosine, adenosine deaminase (ADA), theophylline, and an A1-antagonist.
Main Results:
- PMNs significantly reduced heart work and cardiac output recovery post-ischemia.
- Adenosine infusion with PMNs worsened pump function, even without ischemia.
- ADA, theophylline, and A1-antagonist blocked PMN-induced damage.
Conclusions:
- Adenosine contributes to PMN-mediated myocardial damage post-ischemia.
- This damage occurs via a receptor-mediated action of adenosine.
- Targeting adenosine signaling may offer therapeutic potential for ischemia-reperfusion injury.