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different recovery kinetics from IKr block have been explored to improve their rate-dependent profile. KCB-328 (Figure 17)24 has faster recovery kinetics than dofetilide. It unbinds from IKr channels more readily, with little reverse rate dependence.

6.33.7.1.3.2 Selective IKs blockers

IKs is directly activated by increased sympathetic nervous activity. Moreover, the slow deactivation kinetics of IKs favors its accumulation at higher heart rates. Thus its blockade and the accompanying action potential duration prolongation may result in increased effectiveness against catecholamine-induced tachyarrhythmias. Although IKs blockers like chromanol 293B (46) and HMR 1556 (47) have not been tested clinically, they are antiarrhythmic in various animal models.25 HMR 1556 has ototoxic side effects such as hearing impairment in cats, a finding in keeping with the fact that IKs is found in the ear. Nonfunctioning mutations of the channel are associated with both arrhythmias related to long QTand hearing deficits.

6.33.7.1.3.3 IKur blockers

The occurrence of torsades limits the undoubted antiarrhythmic effect of action potential widening. Therefore, it is important to discover compounds that have this action, but do not induce torsades. The nature and complexity of the potassium channels that contribute to action potential duration emphasize a need to target each of these subtypes of channels individually, and then systematically study the effect of block when using combinations of specific subtype blockers. An example is the role of IKur in controlling action potential duration in atria, versus ventricles. IKur is found primarily in atria, and so it is suggested that IKur blockers would have selective class 3 actions in atria, without adverse QT prolonging effects in ventricles. This supposes that IKur regulates atrial repolarization and as a result increases atrial refractoriness thereby terminating, or preventing, atrial arrhythmias. For example, a novel IKur blocker, DPO-1 (48) preferentially increased atrial refractoriness without prolonging the ventricular refractory period, or QT interval, in nonhuman primates.26 Thus, there is a predictable trend for the continuous development of atrial selective drugs that should potentially be safer in that they should have limited ventricular effects, and could be used prophylactically for atrial arrhythmias.

With chronic atrial tachyarrhythmias, there is a change in the density and importance of IKur, such that electrogenesis in chronically arrhythmic atria is different from that in normal atria. Thus, an IKur blocker may have differential effects in preventing the reoccurrence of atrial arrhythmias, or terminating acute atrial fibrillation.

6.33.7.1.3.3 IKACh blockers

The potential of IKACh blockade was aided by the discovery of tertiapin, a bee venom peptide, shown to block IKACh at nanomolar concentrations. Tertiapin prolongs guinea pig atrial, but not ventricular, action potentials.27 The

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