Effects of fluorine-containing opener of ATP-sensitive potassium channels, pinacidil-derivative flocalin, on cardiac voltage-gated sodium and calcium channels

Abstract

Fluorine-containing pinacidil-derivative flocalin is an effective adenosine triphosphate-sensitive potassium (K_ATP)-channel opener with pronounced vasodilatory, cardioprotective effects and low general toxicity. By activating cardiac K_ATP channels, flocalin hyperpolarizes cardiac myocytes, decreases their excitability, reduces Ca²⁺ entry, and inhibits Ca²⁺-dependent signalling processes. Since our previous studies indicated that the drug also influences the rate of rise and amplitude of the cardiomyocyte’s action potential, here we have investigated its possible actions on depolarizing inward currents through voltage-gated sodium (VGSC) and L-type calcium (VGCC) channels. Experiments were conducted on cultured cardiac myocytes prepared from the whole hearts of neonatal rats and maintained in culture for 1–3 days using whole-cell patch-clamp technique with no distinction of myocyte’s type. Flocalin concentration dependently inhibited the Na⁺ inward current through VGSCs with IC₅₀ = 17.4 μM and a maximal extent of 0.54, slowed down its inactivation kinetics, and hyperpolarized steady-state inactivation by 5.6 mV. The drug also inhibited calcium current through L-type VGCCs with IC₅₀ = 24.1 μM and a maximal block of 0.38, without affecting its inactivation but producing 5.3-mV hyperpolarization shifting of steady-state activation. Inhibition of both depolarizing currents by flocalin in addition to its ability to open K_ATP channels enhances the suppressive action of the drug on cardiac excitability and broadens its pharmacological effects. Since, according to our previous data, cardiac K_ATP-channel opening by flocalin occurs with ЕC₅₀ = 8 μM, the possibility of partial blockade of VGSC and L-type VGCCs should be considered when determining the therapeutic concentrations of the compound during its use as a cardioprotector.