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

초록

Aims: We investigated the effects of BMS-204352 (BMS), a big-conductance calcium-activated potassium (BK(Ca)) channel activator, on L-type Ca(2+) channels. Main methods: Electrophysiological recordings were performed in isolated rat ventricular myocytes. Whole-cell configuration was used. Key findings: BMS caused inhibition of the Ca(2+) current in a dose-dependent manner, with K(d) of 6.00 +/- 0.67 mu M and a Hill coefficient of 1.33 +/- 0.18. BMS did not affect the steady-state activation of L-type Ca(2+) channels. However, for those in steady-state inactivation, BMS shifted the half-maximal potential ( V(1/2)) by - 11 mV, but the slope value (k) was not altered. lberiotoxin, inhibitor of membrane BK(Ca) channels and paxilline, inhibitor of mitochondrial BK(Ca) channel did not affect the inhibitory effect of BMS on L-type Ca(2+) 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 Ca(2+) current. The presence of a selective beta-adrenergic receptor agonist, isoproterenol did not affect the inhibitory effect of BMS on L-type Ca(2+) current. Based on these results, we concluded that the inhibition of L-type Ca(2+) channels by BMS is independent of the inhibition of BK(Ca), channels or intracellular signaling pathways. Significance: It is important to take BMS-204352 (BMS) effects on L-type Ca(2+) channels into consideration when using BMS as a BK(Ca). channel activator or therapeutic target in ventricular myocytes. (C) 2011 Elsevier Inc. All rights reserved.

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