Inhibition of cardiac Kv1.5 and Kv4.3 potassium channels by the class Ia anti-arrhythmic ajmaline: mode of action

Abstract

Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For ajmaline, inhibitory effects on a variety of cardiac K(+) channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 μM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of ajmaline.

Effects of neferine on Kv4.3 channels expressed in HEK293 cells and ex vivo electrophysiology of rabbit hearts

“…Kv4.3 channels, which are members of the shal-type rapidly activating and inactivating Kv channels, encode the transient outward potassium currents (I to ) in the heart [9] , which are responsible for phase 1 of the cardiac action potential [23] . I to is altered in many heart diseases and is consequently a target of many drugs [24,25] .…”

Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action

“…Kv1.5 currents in Xenopus oocytes were obtained using the double-electrode voltage-clamp technique as reported previously. 21 Microelectrodes had tip resistances ranging from 1 to 5 MΩ. Data were low-pass-filtered at 1 to 2 kHz (−3 dB, four-pole Bessel filter) before digitalization at 5 to 10 kHz.…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…The previous work was briefly introduced in the description ofthe potential synthetic derivatives and chemical structure of compounds, and the SAR studies are listed in the corresponding figures in the perspective of medicinal chemistry. As we can see, multiple scaffolds include 5-methoxypsoralen (60,68), tetrahydroindolone (62)(63)(64)(65), benzopyran sulfonamides (70)(71)(72), dihydropyrazolopyrimidine (73,81), and phenylquinazoline (90)(91)(92). Compounds (86)(87)(88) have been reported to be effective in inhibiting Kv1.5, suggesting potential future directions for investigations about Kv1.5 inhibitors.…”