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The cardiac actions of platelet activating factor : possible involvement in endotoxix shock Pugsley, Michael Kenneth


Endotoxic shock involves impairment of the cardiovascular system. Shock is a complex pathophysiological process involving many mechanisms, including interactions between endotoxin, the production of eicosanoids and PAF, and involvement of the immune system, specifically the monocytic cell types e.g. macrophages. Many studies, especially those of Salari and Walker (1989), have shown that endotoxin-stimulated macrophages produce substances which mediate cardiac dysfunction in isolated rat hearts and that PAF antagonists afford the greatest protection against these substances. The studies described in this thesis began with characterization of the pharmacological actions of PAF on rat hearts since Salari and Walker showed that PAF was probably being produced as the result of endotoxin action on macrophages. Rat hearts were used in the Salari and Walker study and the literature is sparse concerning the actions of PAF on the rat heart. Both in vitro and in vivo actions of PAF were examined on the rat heart and circulatory system. To assess whether PAF was acting directly or indirectly on the heart, a series of experiments were performed. It was determined that PAF acted directly on coronary vasculature and on myocytes. The effects of a series of antagonists of PAF, leukotrienes, thromboxanes as well as cyclooxygenase inhibitors on responses to PAF were studied. Each antagonist was examined at two concentrations (0.01 and 1.0 µM). Only ibuprofen had a protective action. In view of the lack of action of PAF antagonists on the cardiac actions of PAF, the LD₅₀ for PAF was determined in a population of Swiss CD₁ mice in order to determine the ED50 value for novel PAF antagonists. The PAF antagonist, RP 59227 was also examined for antiarrhythmic activity in anesthetised acutely prepared rats. The drug did not significantly reduce the incidence of ventricular tachycardia; however, ventricular fibrillation was reduced to 30% of control. We have also examined the actions of endotoxin on the heart in vitro and in vivo. Endotoxin had very little action in vitro and in vivo on the ECG. However, endotoxin produced the expected and sustained decrease in blood pressure and this was attenuated by ibuprofen. On the other hand, ibuprofen did not change PAF actions in vivo. These studies suggest that endotoxin does not mimic the actions of PAF. However, the possibility remains that a slow release of PAF, via the stimulation of monocytes, is involved in endotoxin action.

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