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

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, IB,Na, carried by nonselective cation channels (NSCCs), contributes to AVN cell pacemaking. The study of the physiological contribution of IB,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, IB,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 micromol/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 IB,Na-selective conditions, 10 micromol/L SKF-96365 inhibited IB,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 (ICa,L) at +10 mV was inhibited by 38.6 ± 8.1% (n = 8), while the rapid delayed rectifier current, IKr, tails at -40 mV following depolarization to +20 mV were inhibited by 55.6 ± 4.6% (n = 8). The hyperpolarization-activated current, If, was unaffected by SKF-96365. Collectively, these results indicate that SKF-96365 exerts a moderate inhibitory effect on IB,Na and slows AVN cell pacemaking. However, additional effects of the compound on ICa,L and IKr confound the use of SKF-96365 to dissect out selectively the physiological role of IB,Na in the AVN.