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 and guinea-pig cardiomyocytes may be related to changes in action potential duration (APD). We investigated the effects of altering APD during the occurrence of isoproterenol-induced aftercontractions, using the KATP channel openers cromakalim and lemakalim or the action potential voltage clamp technique, in guinea-pig and human ventricular cardiomyocytes. Contractile responses were measured at 32 degrees C using a video-based edge-detection system. In guinea-pig myocytes, action potentials, Indo-1 fluorescence and contraction were measured at 22 degrees C. Isoproterenol (< or = 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 produced using K+ channel openers. These compounds reduced or completely abolished the isoproterenol-induced aftercontractions. Increasing isoproterenol in the presence of K+ channel opener restored the main contraction to a level similar to or above those with isoproterenol alone, but without the reappearance of aftercontractions. When cells were stimulated to contract under action potential voltage clamp, isoproterenol-induced aftercontractions were abolished by voltage clamping with action potentials of short duration. It was possible to induce aftercontractions in some cells without application of isoproterenol if voltage clamp-imposed action potentials of very long duration were used. These aftercontractions were also abolished by shortening action potential duration. We conclude that K+ channel openers or the imposition of action potentials of short duration can dissociate positively inotropic beta-adrenoceptor stimulation from aftercontraction formation and that action potentials of long duration can be pro-arrhythmic.
Tweedie
D
D
Imperial College School of Medicine, National Heart & Lung Institute, London UK.
O'Gara
P
P
Harding
S E
SE
MacLeod
K T
KT
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007545:Isoproterenol / Q000494:pharmacology*; D008564:Membrane Potentials; D009200:Myocardial Contraction; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D002118:Calcium