Myocardial dysfunction and coronary vasoconstriction induced by platelet-activating factor in the post-infarcted rabbit isolated heart
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Primary Outcome Assessment in a Pig Model of Acute Myocardial Infarction
Published on: October 14, 2016
J K Mickelson1, P J Simpson, B R Lucchesi
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Insights
Platelet-activating factor (AGEPC) infusion in rabbit hearts with myocardial injury increased thromboxane B2 and leukotrienes. Longer reperfusion times amplified these effects, suggesting a role in myocardial dysfunction.
Area of Science:
- Cardiovascular Physiology
- Inflammation Biology
- Myocardial Infarction Research
Background:
- Myocardial infarction (MI) involves ischemic injury and subsequent reperfusion.
- Reperfusion can trigger inflammatory responses and exacerbate cardiac dysfunction.
- The role of platelet-activating factor (PAF) and its metabolites in post-MI inflammation is not fully understood.
Purpose of the Study:
- To investigate the effects of platelet-activating factor (PAF) on myocardial function and mediator release in a rabbit model of myocardial infarction and reperfusion.
- To determine the influence of post-ischemic reperfusion duration on PAF-induced responses.
- To explore the potential sources of inflammatory mediators in the injured myocardium.
Main Methods:
- Myocardial injury was induced in rabbits by coronary artery occlusion followed by reperfusion.
- Isolated hearts were perfused and stimulated with PAF (AGEPC).
- Thromboxane B2 (TxB2) and leukotrienes (LT) were measured in lymphatic effluent.
- Histological analysis assessed leukocyte infiltration and platelet aggregation.
Main Results:
- PAF infusion in infarcted hearts increased coronary perfusion pressure and ventricular diastolic pressure, while decreasing systolic pressure.
- PAF triggered significant release of TxB2 and LT, with responses intensifying with longer reperfusion times (up to 6 hours).
- Histology revealed increased leukocyte migration to infarcted areas and intravascular platelet aggregates.
Conclusions:
- PAF administration exacerbates myocardial dysfunction and promotes the release of TxB2 and LT in acutely infarcted and reperfused rabbit hearts.
- Leukocytes and platelets infiltrating the injured myocardium may be sources of these inflammatory mediators upon PAF exposure.
- These mediators could contribute to increased coronary resistance and myocardial dysfunction during acute MI and reperfusion.
Abstract:
Myocardial injury was produced in separated groups of anesthetized rabbits by occlusion of the left circumflex coronary artery for 1 h followed by reperfusion for 2, 4, or 6 h after release of the occlusive ligature. The ischemically-injured and reperfused hearts subsequently were isolated and perfused using a modified Langendorff apparatus. Platelet-activating factor in the form of AGEPC (1-0-hexadecyl-2-acetyl-sn-glyceryl-phosphorylcholine), 40 nmol in 1 ml, was infused above the coronary ostia over 15 s. Thromboxane B2 (TxB2- and peptidoleukotrienes (LT) were measured in the lymphatic effluent from the heart. Noninfarcted hearts (isolated hearts and sham-operated animals) served as procedural controls and lyso-GEPC (1-0-hexa-decyl-2-0-lyso-sn-glyceryl-phosphorylcholine), 40 nmol in 1 ml, served as the agonist control. After the infusion of AGEPC in the infarcted hearts, coronary perfusion pressure and left ventricular end-diastolic pressure increased while left ventricular peak systolic pressure decreased. The observed changes coincided with TxB2 peak release at 1 min and LT peak release at 2 min. The longer post-ischemic reperfusion time was associated with increasingly greater changes in these parameters. In hearts isolated after 6 h of reperfusion, the functional changes and the appearance of TxB2 and LT in response to the administration of AGEPC reached a significant level (ANOVA) with respect to those base-line values and the values obtained with hearts from sham-operated animals. Minimal changes occurred in noninfarcted hearts or with the administration of the biologically inactive phospholipid, lyso-GEPC. Histologic evaluation of cardiac tissue showed a progressive time-dependent migratory increase of leukocytes from the intra- and perivascular areas toward the region of infarcted myocardium. Platelet aggregates were seen in the intravascular spaces. The data are consistent with the suggestion that the infiltrating leukocytes and platelets may serve as a source for the synthesis and release of TxB2 and LT in acutely infarcted hearts upon exposure to AGEPC. If it is possible for AGEPC to be synthesized and released from vascular endothelial or inflammatory cells leading to the formation of thromboxane A2 and LT from reperfused myocardium, then these substances may participate in increasing coronary artery resistance and in the development of myocardial dysfunction during the evolution of an acute myocardial infarction and especially during the phase of perfusion.
