Prolongation of monophasic action potential duration and the refractory period in the human heart by tedisamil, a new potassium-blocking agent

Abstract

The effect of intravenous tedisamil (0.3 mg.kg-1), a newly developed potassium-blocking agent, on ventricular repolarization was studied in 10 patients (three women, seven men; mean age 53 +/- 8 years) with coronary artery disease (stenoses < or = 60%). Left ventricular monophasic action potentials, effective refractory periods and surface electrocardiograms were recorded during sinus rhythm and during constant atrial pacing at cycle lengths of 600, 500 and 400 ms. Under tedisamil there was a 12% reduction of heart rate and in parallel a prolongation of QTc interval (+10%) and left ventricular monophasic action potential duration (+16% at 90% repolarization). QRS duration remained unchanged. Tedisamil increased the duration of monophasic action potentials during constant atrial pacing, indicating a direct prolongation effect on left ventricular repolarization independent of sinus node activity. By increasing the atrial pacing rate this prolonging effect diminished. Left ventricular effective refractory periods also increased in a frequency-dependent fashion with a greater prolongation effect at long cycle lengths as compared to short cycle lengths. The ratio between effective refractory period and monophasic action potential duration, however, remained constant, independent of heart rate. We conclude that tedisamil is bradycardiac at the dose tested and has a reverse use dependent prolongation effect on left ventricular repolarization and refractoriness. The electrophysiologic profile is consistent with a class III antiarrhythmic classification.

Antianginal and anti-ischaemic efficacy of tedisamil, a potassium channel blocker

“…Although tedisamil does show a dose dependent bradycardic effect on coronary artery disease patients at rest,3 4 the effects are smaller during exercise 5. In the present study, reductions of 5–15 bpm were seen (unrelated to dose) during exercise, and these findings are consistent with the studies mentioned above.…”

Antiarrhythmic drugs: new agents and evolving concepts

“…At high concentrations, it also blocks the cardiac sodium channel and cAMP-activated chloride channel [151]. Some data suggest that the use-dependent I to block is the major mechanism of tedisamil-induced APD prolongation [152]; there is some reverse usedependence [153,154]. Tedisamil was also found to increase the conduction of the intercellular gap-junction channels in the failing ventriclular muscle -this action could be prevented by blocking signalling by protein kinase A [155].…”

Antiarrhythmics---from cell to clinic: past, present, and future

“…Tedisamil blocks I Kr and the transient outward potassium current (I TO ) 107108 and it prolongs the monophasic action potential in humans 109. Dronedarone, an investigational drug related to amiodarone, may be an agent of particular interest 97.…”