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Synergistic effects of LTC4 and TxA2 on coronary flow and myocardial function
W W Nichols1, J L Mehta, L Thompson
1Department of Medicine, University of Florida College of Medicine, Gainesville 32610.
Insights
Leukotriene C4 (LTC4) and thromboxane A2 (TxA2) synergistically reduce coronary blood flow and myocardial function, especially in narrowed arteries. This suggests a significant role in coronary thrombus-related ischemia.
Area of Science:
- Cardiovascular Physiology
- Myocardial Ischemia Research
- Eicosanoid Signaling
Background:
- Leukocytes and platelets in injured myocardium release mediators affecting coronary resistance.
- Peptidoleukotrienes and thromboxane A2 (TxA2) individually reduce coronary blood flow.
- The combined effects of leukotriene C4 (LTC4) and TxA2 on coronary hemodynamics are unknown.
Purpose of the Study:
- To investigate the combined effects of LTC4 and TxA2 on coronary blood flow.
- To assess the impact on myocardial segmental function in patent and narrowed coronary arteries.
- To determine if synergistic interactions occur between LTC4 and TxA2 in vivo.
Main Methods:
- Intracoronary administration of synthetic LTC4 and thromboxane mimic U 46619 in anesthetized dogs.
- Evaluation of coronary blood flow and myocardial segment shortening in patent and narrowed arteries.
- Histopathological analysis of coronary arteries to identify thrombus formation and endothelial damage.
Main Results:
- Both LTC4 and U 46619 caused dose-dependent reductions in coronary blood flow and myocardial shortening.
- Simultaneous administration resulted in greater reductions: 33% in patent and 47% in narrowed arteries.
- Myocardial segment shortening decreased by 26% in the narrowed artery, exceeding the additive effects of individual eicosanoids.
Conclusions:
- Marked synergism exists between LTC4 and TxA2 in reducing coronary blood flow and myocardial function.
- This interaction is particularly pronounced in severely narrowed coronary arteries.
- These findings suggest a critical role for combined LTC4 and TxA2 action in coronary thrombus-induced ischemia.
Abstract:
Accumulation of leukocytes and platelets in the injured myocardium may influence coronary arteriolar resistance via release of peptidoleukotrienes and thromboxane A2 (TxA2). Although leukotriene C4 (LTC4) and TxA2 individually reduce coronary blood flow, the effects of their simultaneous administration are not known. Accordingly, the combined effects of intracoronary administration of synthetic LTC4 and thromboxane "mimic" U 46619 on coronary blood flow in patent and severely narrowed coronary arteries and myocardial segmental function were examined in eight anesthetized dogs. Administration of LTC4 and U 46619 (0.3-3 micrograms) showed concentration-dependent reductions in coronary blood flow and myocardial segment shortening. When these eicosanoids (3 micrograms each) were administered in close sequence, coronary blood flow decreased 33% in the patent artery and 47% in the narrowed artery. This reduction in coronary blood flow in the narrowed coronary artery produced a 26% decrease in myocardial segment shortening. Reductions in narrowed coronary artery blood flow and myocardial segment shortening were greater than the sum of changes caused by LTC4 and U 46619 administered separately (P less than 0.05). The histopathology of the narrowed coronary artery revealed endothelial disruption at the site of occlusion and an in vivo thrombus just distal to the site of occlusion. These data suggest marked synergism between the actions of LTC4 and TxA2, which may be released locally at the site of coronary thrombus, on blood flow in a severely narrowed coronary artery, and on segmental function in the region supplied by this vessel.