Multiple ion channel block by the cation channel inhibitor SKF-96365 in myocytes from the rabbit atrioventricular node

Hongwei Cheng,Claire Fellingham,Jules C Hancox,Alexander E Curtis

doi:10.14814/phy2.12819

Hongwei Cheng, Claire Fellingham + Show 2 more

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https://doi.org/10.14814/phy2.12819

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Journal: Physiological Reports	Publication Date: Jun 1, 2016
Citations: 23	License type: cc-by

Affiliation: University of Bristol

Abstract

The atrioventricular node (AVN) of the cardiac conduction system coordinates atrial–ventricular excitation and can act as a subsidiary pacemaker. Recent evidence suggests that an inward background sodium current, I B,Na, carried by nonselective cation channels (NSCCs), contributes to AVN cell pacemaking. The study of the physiological contribution of I B,Na has been hampered, however, by a lack of selective pharmacological antagonists. This study investigated effects of the NSCC inhibitor SKF‐96365 on spontaneous activity, I B,Na, and other ionic currents in AVN cells isolated from the rabbit. Whole‐cell patch‐clamp recordings of action potentials (APs) and ionic currents were made at 35–37°C. A concentration of 10 μmol/L SKF‐96365 slowed spontaneous action potential rate by 13.9 ± 5.3% (n = 8) and slope of the diastolic depolarization from 158.1 ± 30.5 to 86.8 ± 30.5 mV sec−1 (P < 0.01; n = 8). Action potential upstroke velocity and maximum diastolic potential were also reduced. Under I B,Na‐selective conditions, 10 μmol/L SKF‐96365 inhibited I B,Na at −50 mV by 36.1 ± 6.8% (n = 8); however, effects on additional channel currents were also observed. Thus, the peak l‐type calcium current (I Ca,L) at +10 mV was inhibited by 38.6 ± 8.1% (n = 8), while the rapid delayed rectifier current, I Kr, tails at −40 mV following depolarization to +20 mV were inhibited by 55.6 ± 4.6% (n = 8). The hyperpolarization‐activated current, I f, was unaffected by SKF‐96365. Collectively, these results indicate that SKF‐96365 exerts a moderate inhibitory effect on I B,Na and slows AVN cell pacemaking. However, additional effects of the compound on I Ca,L and I Kr confound the use of SKF‐96365 to dissect out selectively the physiological role of I B,Na in the AVN.

Highlights

The atrioventricular node (AVN) is a small but important component of the cardiac pacemaker conduction system; slow impulse conduction through the AVN coordinates the normal sequence of atrial and ventricular excitation and can protect the ventricles from too fast a rate during supraventricular tachycardias (Childers 1977; Meijler and Janse 1988)
The slow time-base recording in panel A shows that application of SKF-96365 rapidly led to a reduction in action potentials (APs) overshoot and a depolarization of maximum diastolic potential (MDP)
As IB,Na is carried by nonselective cation channels (NSCCs) (Hagiwara et al 1992; Cheng et al 2016) and SKF-96365 is a recognized NSCC inhibitor (Alexander et al 2009), it was a plausible candidate to investigate for this purpose, as it has been reported to influence AVN conduction (Sabourin et al 2011)

Summary

Introduction

The atrioventricular node (AVN) is a small but important component of the cardiac pacemaker conduction system; slow impulse conduction through the AVN coordinates the normal sequence of atrial and ventricular excitation and can protect the ventricles from too fast a rate during supraventricular tachycardias (Childers 1977; Meijler and Janse 1988). The AVN can act as a subsidiary pacemaker, should the primary pacemaker, the sinoatrial node (SAN), fail (Childers 1977; Meijler and Janse 1988). The hyperpolarization-activated current, If, is present in a proportion of AVN cells from the rabbit, albeit at a lower density than in the primary pacemaker, the SAN a 2016 The Authors.

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