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

• Published in: Life sciences (1973) 2011-08, Vol.89 (9-10), p.331-336
• Main Authors: Son, Youn Kyoung, Choi, Seong Woo, Jung, Won-Kyo, Jo, Su-Hyun, Jung, In Duk, Park, Yeong-Min, Choi, Il-Whan, Sin, Jeong-Im, Shim, Eun Bo, Kim, Nari, Han, Jin, Park, Won Sun
• Format: Article
• Language: English
• Subjects: agonists; Animals; calcium; Calcium Channel Blockers - pharmacology; calcium channels; Calcium Channels, L-Type - metabolism; cAMP-dependent protein kinase; Cell Culture Techniques; Cells, Cultured; cGMP-dependent protein kinase; Dose-Response Relationship, Drug; Heart Ventricles - cytology; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Indoles - pharmacology; Ion Channel Gating - drug effects; Male; myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; potassium; potassium channels; Potassium Channels, Calcium-Activated - agonists; protein kinase C; Rats; Rats, Sprague-Dawley; signal transduction
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.06.017

AIMS: We investigated the effects of BMS-204352 (BMS), a big-conductance calcium-activated potassium (BKCₐ) channel activator, on L-type Ca²⁺ channels. MAIN METHODS: Electrophysiological recordings were performed in isolated rat ventricular myocytes. Whole-cell configuration was used. KEY FINDINGS: BMS caused inhibition of the Ca²⁺ current in a dose-dependent manner, with Kd of 6.00±0.67μM 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 −11mV, 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. SIGNIFICANCE: It 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.