THE EFFECT OF ALTERATIONS TO ACTION-POTENTIAL DURATION ON BETA-ADRENOCEPTOR-MEDIATED AFTERCONTRACTIONS IN HUMAN AND GUINEA-PIG VENTRICULAR MYOCYTES

Aftercontractions induced by beta-adrenoceptor stimulation in human an d guinea-pig cardiomyocytes may be related to changes in action potent ial duration (APD). We investigated the effects of altering APD during the occurrence of isoproterenol-induced aftercontractions, using the K-ATP channel openers cromakalim and lemakalim or the action potential voltage clamp technique, in guineapig and human ventricular cardiomyo cytes. Contractile responses were measured at 32 degrees C using a vid eo-based edge-detection system, In guinea-pig myocytes, action potenti als, Indo-1 fluorescence and contraction were measured at 22 degrees C . Isoproterenol (less than or equal to 12 nM) had variable effects on APD but induced aftercontractions, the majority (14/19 cells) of which occurred during the action potential. Short action potentials were pr oduced using K+ channel openers. These compounds reduced or completely abolished the isoproterenol-induced aftercontractions. Increasing iso proterenol in the presence of K+ channel opener restored the main cont raction to a level similar to or above those with isoproterenol alone, but without the reappearance of aftercontractions. When cells were st imulated to contract under action potential voltage clamp, isoproteren ol-induced aftercontractions were abolished by voltage clamping with a ction potentials of short duration. It was possible to induce aftercon tractions in some cells without application of isoproterenol if voltag e clamp-imposed action potentials of very long duration were used. The se aftercontractions were also abolished by shortening action potentia l duration. We conclude that K+ channel openers or the imposition of a ction potentials of short duration can dissociate positively inotropic beta-adrenoceptor stimulation from aftercontraction formation and tha t action potentials of long duration can be proarrhythmic. (C) 1997 Ac ademic Press Limited.