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Contribution of platelet activating factor to myocardial ischemia-reperfusion injury

University of British Columbia

Myocardial ischemia-reperfusion (MIR) injury, which occurs during events such as myocardial infarction (MI) treated with reperfusion therapy, can cause substantial cardiovascular dysfunction, often leading to death during the first 24 hours. Preliminary evidence suggests that the inflammatory mediator platelet activating factor (PAF) may contribute substantially to MIR injury. However, there remains more to be learned about both the mechanism through which PAF alters cardiac function, and the contribution of PAF to MIR injury, in order to determine if PAF antagonism can be useful as treatment for MIR. Part 1: The relative concentration-dependent cardiac function responses to PAF in the isolated rat heart were investigated. It was found that low to high PAF concentrations (10 nM-10 μM) significantly increased coronary vascular resistance. Moderate to high PAF concentrations (1. μM-10 μM) significantly increased capillary permeability. Only a high concentration (10 μM) of PAF caused significant myocardial contractile depression and bradycardia. These effects were prevented by PAF antagonist TCV-309. Part 2: The contribution of PAF in the ischemic-reperfused ex vivo rabbit heart to (a) cardiac dysfunction during the first 5 h of reperfusion, and (b) apoptotic cell death in the heart, a previously unstudied form of injury, were investigated. Finally, it studied (c) the interrelationship of PAF and nitric oxide (NO), during MTR. It was shown that (a) PAF causes myocardial contractile depression and increases coronary vascular resistance through to 5 h reperfusion, (b) PAF can contribute to apoptotic cell death during MLR and (c) PAF can reduce the mRNA expression of an important enzyme that produces NO, namely endothelial nitric oxide (eNOS), thereby indicating that PAF and NO may be linked in MIR injury. Part 3: The contribution of PAF to MIR injury was studied in a clinically relevant animal model: in vivo swine managed similarly to patients undergoing reperfusion treatment for MI, and treated with a clinically used PAF antagonist (TCV-309) at a therapeutically-modeled time. The swine were survived for 8 days, in order to determine the previously unstudied long-term effects of treatment with PAF antagonist for myocardial infarction. It was found that PAF antagonist significantly improved systemic arterial blood pressure, reduced the requirements for inotropic and antiarrhythmic support and improved long-term survival. It is hoped that this information can provide a better understanding of the role of PAF in MIR injury, and will help in the consideration of PAF antagonism as treatment for myocardial infarction.

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2009-12-16

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http://hdl.handle.net/2429/16761

Pharmacology

University of British Columbia

UBCV

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