MOLECULAR BASIS FOF TRANSIENT OUTWARD CURRENT ACTIVATION AND INACTIVATION . Atrial and ventricular arrhythmias represent a significant cause of morbidity and mortality in patients with congestive heart failure. Recent studies have raised widespread concern about the averse effects of current Class I antiarrhythmic drugs used to treat these arrhythmias. These concerns have spurred interest in Class III agents whose action is mediated through action potential prolongation, usually via blockade of K+ channels. The affinity of sch compounds typically shows a complex dependency upon the conformational state of the channel. Our limited understanding of the action of these agents is limited by our understanding of the voltage dependent and voltage insensitive transitions which accompany activation. A quantitative and molecularly based model of the activation process and its coupling to inactivation is a prerequisite for elucidating the nature of the complex blocking action of Class III agents. Therefore, this proposal seeks to characterize the cardiac transient outward K+ current, Ito, which plays a significant role in determining human action potential duration. Block of I to appears to e less likely to induce triggered activity than block of delayed rectifier K+ channels. Because of the unique similarities between the human and ferret cardiac I to and the near identity of our ferret (FK1) and the human (HK1) clone, our objective will be to develop a molecularly based biophysical model of Ito/FK1. This study will combine voltage-clamp, single channel, studies of I to in isolated ferret ventricular myocytes for model development. We will test the ability of this model to define the mechanism of action of a closed channel blocking compound (4-aminopyridine). Inactivation will be modeled as coupled to action to characterize both the development of and recovery from inactivation. Ultimately, elucidation of channel structural and functional features may help identify newer and more efficacious channel blockers.
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