Modification of stretch-induced shortening of repolarization by streptomycin in the isolated rabbit heart.

Abstract

The exact mechanism of mechano-electrical feedback and stretch-induced arrhythmias is unknown, but the role of stretch-activated ion channels and specific calcium channels has been proposed. The aim of the present study was to test the hypothesis that stretch-activated ion channels and not calcium channels contribute to stretch-related alterations of repolarization and that these effects can be neutralized by stretch-activated channel block. We studied the interaction of acute ventricular dilatation and the stretch-activated channel blocker streptomycin and the specific calcium channel blocker verapamil in an isolated retrogradely perfused rabbit heart model in which the left ventricular size is modified by abruptly changing the volume of a fluid-filled balloon placed in the left ventricle. Acute ventricular dilatation led to a rate-dependent decrease in repolarization. The mean effective refractory period (ERP) and monophasic action potential duration (MAP90) for cycle lengths between 300 and 1,000 ms decreased from 174.2+/-9 ms and 178.9+/-7 ms to 161.6+/-11 ms and 169.7+/-5 ms, respectively. Streptomycin (80 microM) inhibited this stretch-related shortening of repolarization (ERP: 175.4+/-8 ms; MAP90: 179.7+/-8 ms, p < 0.05) but had almost no effect on already dilated ventricles. Counteraction of the observed electrophysiologic changes could only be achieved by increasing the streptomycin concentration to 200 microM. Streptomycin nearly completely suppressed stretch-related ectopic ventricular complexes. In contrast, verapamil (1 microM) had no effect on stretch-related changes in repolarization and stretch-induced arrhythmias. The present study indirectly implicates stretch-activated ion channels in the genesis of stretch-related changes in repolarization and arrhythmias. The electrophysiologic changes after ventricular dilatation to a degree that increases left ventricular pressure in a clinically relevant range can be influenced by the stretch-activated channel blocker streptomycin but not by specific calcium channel block. This may have clinically important implications for the development of new antiarrhythmic drugs.