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1 Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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 (Ito) 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 Ito 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 Ito densities prolonged, and then dramatically shortened the endocardial APD. We also used the dynamic clamp to subtract, or ‘block’ the native Ito in epicardial cells. Such ‘blockade’ eliminated the epicardial action potential notch, but had no significant effect on the APD. We conclude that Ito, while being a key regulator of phase 1 repolarization, does not significantly affect the APD of canine ventricular myocytes, and that the Ito 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.
(Received 11 October 2004;
accepted after revision 12 January 2005;
first published online 13 January 2005)
Corresponding author H.-S. Wang: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA. Email: wanghs{at}uc.edu
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