Abstract
BackgroundThe atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. Although it is known that receptors for the peptide hormone endothelin-1 (ET-1) are expressed in the AVN, there is very little information available on the modulatory effects of ET-1 on AVN electrophysiology. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology.MethodsElectrophysiological experiments were conducted in which recordings were made from rabbit isolated AVN cells at 35–37°C using the whole-cell patch clamp recording technique.ResultsApplication of ET-1 (10 nM) to spontaneously active AVN cells led rapidly (within ∼13 s) to membrane potential hyperpolarisation and cessation of spontaneous action potentials (APs). This effect was prevented by pre-application of the ETA receptor inhibitor BQ-123 (1 µM) and was not mimicked by the ETB receptor agonist IRL-1620 (300 nM). In whole-cell voltage-clamp experiments, ET-1 partially inhibited L-type calcium current (ICa,L) and rapid delayed rectifier K+ current (IKr), whilst it transiently activated the hyperpolarisation-activated current (If) at voltages negative to the pacemaking range, and activated an inwardly rectifying current that was inhibited by both tertiapin-Q (300 nM) and Ba2+ ions (2 mM); each of these effects was sensitive to ETA receptor inhibition. In cells exposed to tertiapin-Q, ET-1 application did not produce membrane potential hyperpolarisation or immediate cessation of spontaneous activity; instead, there was a progressive decline in AP amplitude and depolarisation of maximum diastolic potential.ConclusionsAcutely applied ET-1 exerts a direct modulatory effect on AVN cell electrophysiology. The dominant effect of ET-1 in this study was activation of a tertiapin-Q sensitive inwardly rectifying K+ current via ETA receptors, which led rapidly to cell quiescence.
Highlights
The atrioventricular node (AVN) is a small yet critically important component of the cardiac pacemaker-conduction system that lies at the junction between right atrium and ventricle [1,2]
Membrane capacitance values used for calculation of current densities were obtained and compensated for using capacitance compensation on the recording amplifier; cell capacitance values obtained in this way have been shown previously to match closely those obtained using a ‘surge’ technique [28]
Effects of ET-1 application on spontaneous action potentials (APs) Spontaneous APs were measured in whole-cell membrane potential recording mode from cells selected on the basis of exhibiting regular spontaneous activity during superfusion of control Tyrode’s solution
Summary
The atrioventricular node (AVN) is a small yet critically important component of the cardiac pacemaker-conduction system that lies at the junction between right atrium and ventricle [1,2]. It is normally the only site where electrical activity can pass from atria to ventricles [1,2]. The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology
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