Electrophysiological properties and pharmacological modulation of several transmembrane ion currents in mammalian hearts

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Cardiovascular diseases and in particular cardiac arrhythmias as ventricular fibrillation have a leading role in mortality in the developed countries. Accordingly, cardiac arrhythmias represent a major area of cardiovascular research. Drug therapy has traditionally been the major type of treatment for both ventricular and supraventricular arrhythmias. In spite of the important advances in cardiology, the pharmacological treatment of cardiac arrhythmias remained empiric to a large extent because of our incomplete understanding the mechanisms by which antiarrhythmic drugs prevent/suppress, or unfortunately even induce arrhythmias. Therefore, in order to develop new more effective agents with less proarrhythmic potency, it is important to understand the mechanism of action of antiarrhythmic drugs at the organ, tissue, cellular and also subcellular levels. Based on the promising results of recent cellular pathophysiological and pharmacological investigations in the present PhD thesis, we have focused our research especially on pharmacological modulation of repolarizing potassium and sodium-calcium exchanger (NCX) currents as key elements in generating arrhythmias. The aims of the present study were: a) To analyse the contribution of different auxiliary proteins to the altered expression of genes for Kir2.x ion channels in dilated cardiomyopathy. b)To investigate and compare the effects of several newly synthetized NCX blockers on several mammalian hearts. Selection of a lead NCX blocker compound for further analysis. c)To investigate the electrophysiological effects of the lead compound GYKB-6635, a newly synthetized specific NCX inhibitor, on the NCX, L-type Ca2+ and several potassium currents and on the triggered arrhythmias (formation of delayed afterdepolarizations). Our results demonstrate: 1)The endogenous Kir2.x channels associate with SAP97 forming signalling complexes. In DCM, the levels of Kir2.1 and Kir2.3 were upregulated but those of Kir2.2 channels were down-regulated. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM. The SAP97 and Kir2.x ion channels may be novel target molecules in the diagnosis and effective treatment of cardiomyopathy. 2)We have demonstrated in vitro the potential inhibitory NCX blocking effect and of several carbocyclic nucleoside analogues (CNA) having different structures than from already known selective NCX blockers. 3)GYKB-6635 is the first compound that inhibits forward and reverse mode of the NCX current at submicromolar concentrations, and does not affect any other important transmembrane mechanisms involved in Ca2+-homeostasis and cardiac repolarization. In addition, GYKB-6635 compound proved to be effective against DAD related arrhythmias, since in isolated Langendorff perfused heart experiments prevented disturbances of the heart rhythm in ouabain induced arrhythmias in guinea pigs. 4)In conclusion, in the present study we describe a new and highly selective NCX inhibitor compound that may be suitable to test whether NCX blockade offers beneficial antiarrhythmic effects.

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