Iszkémia/reperfúzió indukálta károsodások farmakológiai befolyásolási lehetőségei

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Cardiac ischemia/reperfusion is among the most common causes of morbidity and mortality. Decreased oxygen supply and perfusion can cause serious injuries. The overall aims of our studies were to investigate pharmacological approaches capable of reducing ischemia/reperfusion induced damage. In the first part of our experiments we examined the effect of the combined treatment of FK506 (tacrolimus) and EGb 761 (standardized Ginkgo biloba extract). Our results suggest that the combination of these drugs significantly reduces arrhythmias and improves postischemic heart function. The combined therapy could enable to use FK506 in subtoxical doses. This suggests that pharmaceutical interventions incorporating both classes of drug may provide a new and powerful approach to management of ischemic injury associated with heart disease and surgical intervention. It is a general clinical process to use NO in treatment of ischemic heart diseases. Henceforth in the second part of our experiment we studied the role of an other gaseous endogenous monoxide, carbon monoxide, produced by heme oxygenase in prevention of reperfusion induced arrhythmias. Our results indicate that production of endogenous CO significantly decreased in hearts developed ventricular fibrillation. In hearts perfused with PBN, a significant increase in endogenous CO production via the HO-1 mRNA expression was observed, and with the elevation of endogenous CO production, the development of VF was not recorded during reperfusion. Thus, our findings suggest that pharmacological stimulation of the expression of HO-1 could prevent the development of reperfusion-induced arrhythmias. Our last experiments were planed to reveal the way of inhibition of ischemia/reperfusion induced apoptosis. A number of cascade mechanisms have been identified in the induction or inhibition of apoptosis but caspases play a crucial role in this process. Drugs capable of influencing apoptosis are of great importance concerning therapeutic treatment. The most useful method for inhibition of apoptosis could be the inhibition of its universal effectors: the caspases. Both our results and publications of other groups suggest that caspase inhibitors may function as potent agents in treatment of acut ischemic diseases, although it must be noted that apoptosis occurs continuously and almost in all of our organs consequently general inhibition of apoptosis may cause serious clinical injuries.