Role of the transient outward current (Ito) in shaping canine ventricular action potential--a dynamic clamp study

Transmural electrical dispersion determines the repolarization sequence across the ventricular wall, and plays an important role in the development of arrhythmias under pathological conditions. While it is clear that the transmural gradient of the transient outward current (I(to)) underlies the dramatic difference in phase 1 repolarization across the ventricle, its contribution to the transmural action potential duration (APD) dispersion is not clear. We investigated this problem using the dynamic clamp technique in canine ventricular myocytes. The dynamic clamp allows quantitative 'insertion' of simulated conductances in real, biological cells, bridging pure computer modelling and experimental electrophysiology. 'Insertion' of an epicardial level of I(to) in endocardial cells produced a prominent phase 1 repolarization and a 'spike-and-dome' action potential morphology, but did not significantly affect the APD. Increasingly larger I(to) densities prolonged, and then dramatically shortened the endocardial APD. We also used the dynamic clamp to subtract, or 'block' the native I(to) in epicardial cells. Such 'blockade' eliminated the epicardial action potential notch, but had no significant effect on the APD. We conclude that I(to), while being a key regulator of phase 1 repolarization, does not significantly affect the APD of canine ventricular myocytes, and that the I(to) gradient is not a significant contributor to the transmural APD dispersion in the canine ventricle. By allowing computer simulation on a biological background, the dynamic clamp is a new and effective tool to study the ionic basis of the electrical properties of cardiac cells.