Antiarrhythmic properties of novel antianginal drugs in dog and human cardiac preparations

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Chronic stable angina is an insidious manifestation of coronary artery disease. Pharmacological treatment is the cornerstone of stable angina and is an essential component of the treatment strategy, which also involves beta-blockers, nitrates (or related derivatives) and calcium channel blockers. New classes of treatments (ivabradine, ranolazine) with entirely different mechanisms of action have now been added. Ranolazine reduces ischemia via inhibition of the late phase of the inward sodium current (late INa) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Ivabradine is a novel, heart rate-lowering drug which inhibits the pacemaker (If) current in the heart with high selectivity and with minimal effect on haemodynamic parameters. The primary aim of our studies, summarized in this thesis was to investigate in detail the cellular electrophysiological effects of ranolazine and ivabradin in dog and human heart preparations. Using conventional microelectrode technique action potential characteristics were studied. Our results demonstrate that ranolazine and ivabradine at relatively high concentrations in dog and human cardiac preparations produce a concentration- and frequency-dependent depression of Vmax and able to prolong action potential duration i.e. exerts Class I and III antiarrhythmic actions. Ranolazine produces depression of Vmax with rather fast onset and offset kinetics, i.e. exerts Class I/B antiarrhythmic action (similar to that of mexiletine) not only in normal and remodelled atria, but also in the ventricle. Other important finding is that due to its multiple ion channel blocking property, ranolazine alters the repolarization in a complex manner in remodelled atria. Ivabradine (at high concentrations) can be considered as a Na+ channel blocker antiarrhythmic drug with slow kinetic onset and recovery i.e. exerts Class I/C antiarrhythmic action (similar to that of flecainide or propafenone). Depression of Vmax and conduction were more pronounced in case of elevated potassium concentration, e.g. when the resting membrane potential is partly depolarized, even as in the presence of an ischaemic cardiac substrate. Our results support the action potential lengthening effect of ivabardine also in dog and human cardiac preparations especially in case of attenuated repolarization reserve. Ranolazine decreases (and ivabradine does not increase) the dispersion of repolarization between Purkinje fibres and the subendocardial muscle layers), which can contribute to the antiarrhythmic property of the drugs. We provide evidence that these antianginal drugs are not devoid of subsidiary antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.

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