The inhibitory effect of Ca2+-activated K+ channel activator, BMS on L-type Ca2+ channels in rat ventricular myocytes

AimsWe investigated the effects of BMS-204352 (BMS), a big-conductance calcium-activated potassium (BKCa) channel activator, on L-type Ca2+ channels.Main methodsElectrophysiological recordings were performed in isolated rat ventricular myocytes. Whole-cell configuration was used.Key findingsBMS caused inhibition of the Ca2+ current in a dose-dependent manner, with Kd of 6.00 ± 0.67 μM and a Hill coefficient of 1.33 ± 0.18. BMS did not affect the steady-state activation of L-type Ca2+ channels. However, for those in steady-state inactivation, BMS shifted the half-maximal potential (V1/2) by − 11 mV, but the slope value (k) was not altered. Iberiotoxin, inhibitor of membrane BKCa channels and paxilline, inhibitor of mitochondrial BKCa channel did not affect the inhibitory effect of BMS on L-type Ca2+ channels. Pretreatment with inhibitors of protein kinase A (PKA), protein kinase C (PKC), and protein kinase G (PKG) did not significantly alter the inhibitory effect of BMS on L-type Ca2+ current. The presence of a selective β-adrenergic receptor agonist, isoproterenol did not affect the inhibitory effect of BMS on L-type Ca2+ current. Based on these results, we concluded that the inhibition of L-type Ca2+ channels by BMS is independent of the inhibition of BKCa channels or intracellular signaling pathways.SignificanceIt is important to take BMS-204352 (BMS) effects on L-type Ca2+ channels into consideration when using BMS as a BKCa channel activator or therapeutic target in ventricular myocytes.