Involvement of leucocytes and leukotrienes in ischaemic dysfunction of the coronary microcirculation

Recent evidence suggests that leucocytes may exert an important influence on microvessel flow during pathophysiologic conditions. This is particularly true in the case of coronary occlusive disorders. Diminution of coronary perfusion pressure favours trapping of the large stiff leucocytes in capillaries. Perhaps more importantly, ischaemic changes in the endothelial lining of microvessels promote early sequestration of leucocytes within capillaries of ischaemic regions during underperfusion and, to a much greater degree, during reperfusion. If these trapped leucocytes are activated by the ischaemic environment, the mechanical plugging of microvessels can be significantly complicated by leucocyte release of a variety of materials affecting the function of blood vessels and myocytes. Leukotrienes are a potent group of inflammatory mediators released by activated leucocytes. A subgroup, the peptidoleukotrienes (C₄, D₄, and E₄), has a profound vasoconstrictor influence on coronary microvessels. Members of this group can also cause platelet aggregation. Agents that block peptidoleukotriene synthesis, such as nafazatrom, have been reported to diminish the adverse effects of myocardial ischaemia. However, these agents often have non-specific actions that blur the interpretation of their anti-ischaemic efficacy. Our laboratory has made a number of observations that cast doubt - or at least stimulate further inquiry - on the role of peptidoleukotrienes on promotion of sustained microvessel constriction in ischaemic coronary beds. Most importantly, we found that continuous intracoronary administration of leukotriene C₄ or D₄ led initially to marked diminution of coronary flow and myocardial contractility. However, this was soon followed by a complete, dose-independent escape from these effects even though leukotrienes continued to be infused at a constant rate. The cause of this escape is unclear, but it may involve a specific product released when leukotrienes interact with platelets. In a second series of experiments, we found that the coronary constrictor efficacy of bolus leukotrienes (and also the stable thromboxane A₂ analogue, U46619) was markedly reduced by concomitant myocardial ischaemia. Constrictor responses were rapidly restored with reperfusion, suggesting a transient metabolic blockade of constrictor responsiveness during myocardial ischaemia. Nevertheless, these data indicate that leukotrienes may not act simply as agents that exaggerate underperfusion due to proximal coronary occlusion. Finally, we have measured the leukotriene immunoreactivity in coronary venous blood exiting from beds made ischaemic (and dysfunctional) by partial occlusion of epicardial arteries. Although the occlusion was sufficient to cause release of lactate and other metabolic markers of ischaemia, we were unable to find measurable rises in release of any of the leukotrienes after occlusion lasting 3 h and reperfusions lasting up to 1 h. We conclude that a substantial body of evidence suggests that leucocytes play a significant role in the pathogenesis of ischaemic myocardial damage. In part, this may relate to their actions on microvessel performance, although further investigation is needed to elucidate the mechanisms involved. Our studies do not confirm the potential importance of leukotrienes in myocardial ischaemia. Instead they indicate that microvesssels somehow show a rapid escape from the constrictor influence of certain leukotrienes. In addition, microvessels exhibit little response to the leukotrienes when these beds are experiencing ischaemia. Lastly, we were unable to detect a significant rise in leukotrienes released on coronary venous effluent from markedly ischaemic myocardial regions. Further studies are needed to establish a definite pathologic role for leukotrienes during the course of myocardial ischaemia due to epicardial coronary occlusion.