Abstract
Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.
Highlights
A secondary objective was to reveal key biophysical features of this inwardly rectifying K+ conductance that are important for repolarization of the action potential or development of the pacemaker depolarization
For this study, they clearly define the changes in the action potential (AP) and pacemaker depolarization that must be accurately replicated in the mathematical modeling component of this study
Additional characteristics of this current that need to be defined prior to attempting an in silico study of its functional roles are: (i) its ion selectivity properties, and (ii) its kinetics in the range of membrane potentials that include those in which the diastolic depolarization develops – approximately −75 to
Summary
Irisawa led a multidisciplinary group that made a number of seminal discoveries concerning the changes in transmembrane ionic currents that are responsible for the pacemaker depolarization and action potential in the rabbit SAN [4] Papers from this laboratory clearly defined the most important characteristics of primary or leading spontaneous pacemaker activity, and revealed differences between this electrophysiological profile and secondary or follower pacemaking [6]. Their papers identified essential Ca2+ and K+ currents in these spontaneous myocytes and demonstrated how interactions between these and other transmembrane currents were functionally important Key aspects of their original descriptive microelectrode-based data and a comprehensive account of the main changes in ionic currents that are responsible for the pacemaker depolarization and action potential (AP) in the rabbit SAN are the basis of a review by Irisawa and his colleagues [4]
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