Calcium-dependent modulation of the plateau phase of action potential in isolated ventricular cells of rabbit heart Z. PAPP, 1 N. PEINEAU, 2 G. SZIGETI, 1 J. ARGIBAY, 2 and L . K O V A Â CS 1 1 Department of Physiology, University Medical School of Debrecen, Debrecen, Hungary 2 Laboratoire de Physiologie des Cellules Cardiaques et Vasculaires, FaculteÂdes Sciences, CNRS UMR 6542, Parc de Grandmont, Tours, France ABSTRACT [Ca 2+ ] i -dependent modulation of the action potential has been studied in Fura-2 dialysed ventricular myocytes of the rabbit using the whole-cell current-clamp method. Fifteen consecutive action potentials (AP 1 ±AP 15 ) and [Ca 2+ ] i transients were elicited at a frequency of 0.2 Hz. A single, brief application of caffeine (during AP 9 ) ®rst enhanced and thereafter attenuated the [Ca 2+ ] i transients accompanying AP 9 and AP 10 ±AP 12 , respectively. This approach provided direct comparison between time courses of action potentials: during the initial steady state (e.g. AP 8 ) and when Ca 2+ release from the sarcoplasmic reticulum was increased by caffeine (AP 9 ) or decreased by depletion (AP 10 ). The increase in [Ca 2+ ] i facilitated repolarization and decreased action potential duration. However, action potentials at reduced Ca 2+ release (AP 10 ) had longer duration than during steady state. The caffeine-induced changes in L-type Ca 2+ current (I Ca,L ), during voltage-clamp conditions partially explained the effects of caffeine on action potentials. When I Ca,L was blocked by 500 lmol L ±1 Cd 2+ , enhanced [Ca 2+ ] i transients revealed an extra current component which was outward at +10 mV and inward at the resting membrane potential (most probably the transient inward current). In the presence of Cd 2+ , however, AP 8 and AP 10 had identical time courses, suggesting that I Ca,L alone was responsible for the lengthening of AP 10 . Alterations in the transmembrane Na + gradient resulted in changes of the steady state action potential durations (AP 8 ) consistently with the expected modulation of the Na + ±Ca 2+ exchange current. However, the contribution of this current to the [Ca 2+ ] i -dependent behaviour of action potential plateau could not be demonstrated. Keywords action potential, arrhythmia, [Ca 2+ ] i transient, rabbit heart. Received 23 June 1998 1 , accepted 24 June 1999 The release of Ca 2+ from internal stores is triggered by the action potential (Gibbons & Zygmunt 1992), which in turn is modulated by [Ca 2+ ] i in myocardial cells (Isenberg 1977). Thus, [Ca 2+ ] i -dependent modulation of membrane voltage allows a feedback regulation for Ca 2+ release. However, it may also function as a substrate of arrhythmogenesis when spontaneous Ca 2+ release and/or localized changes in the released fraction of Ca 2+ disturb electrical synchrony (Levy 1989). Characterization of the various [Ca 2+ ] i -dependent ionic ¯uxes of the surface cell membrane under conditions when Ca 2+ handling is disturbed therefore may contribute to our understanding of the regulation of myocardial contractility and of arrhythmias. Ca 2+ release from the sarcoplasmic reticulum may trigger [Ca 2+ ] i -activated chloride currents (Zygmunt & Gibbons 1991, 1992, Sipido et al. 1993, Zygmunt 1994, Papp et al. 1995, Szigeti et al. 1998) and [Ca 2+ ] i - activated non-speci®c cationic currents (Kass et al. 1978a,b, Colquhoun et al. 1981, Ko Èster et al. 1999). Furthermore, [Ca 2+ ] i modulates certain potassium channels (Kass & Tsien 1976, Callewaert et al. 1986), the L-type Ca 2+ -channels (Sipido et al. 1995) and the Na + ±Ca 2+ exchanger molecules (Sheu & Blaustein 1992, Levesque et al. 1994). Although, much is known about the regulation of these charge carrying processes (e.g. Beuckelmann & Wier 1989, Kirby et al. 1993 2 , Le Guennec & Noble 1994, Leitch & Brown 1996), owing to the complex nature of interactions, their contribution to the action potential during altered [Ca 2+ ] i homeostasis remains specula- tive. Correspondence: Zolta Ân Papp, Laboratorium Voor Fysiologie, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. Acta Physiol Scand 1999, 167, 119±129 Ó 1999 Scandinavian Physiological Society 119