The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Hong, Da Hye; Yang, Dongki; Choi, Il‐Whan; Son, Youn Kyoung; Jung, Won‐Kyo; Kim, Dae-Joong; Han, Jin; Na, Sung Hun; Park, Won Sun

doi:10.1254/jphs.12104fp

Cited by 20 publications

(11 citation statements)

References 36 publications

(30 reference statements)

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“…In contrast to mibefradil, NNC 55-0396 does not produce the metabolite responsible for inhibiting the L-type Ca 2+ channel (20) and was shown to improve tremor and myogenic tone (39,40). However, previous work and the present study have revealed that both mibefradil and NNC 55-0396 inhibit K V channels in arterial smooth muscle cells (19), suggesting that the structural similarities between mibefradil and NNC 55-0396 may contribute to K V -channel inhibition.…”

Section: +contrasting

confidence: 79%

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Son

Hong

et al. 2014

J Pharmacol Sci

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Abstract.We demonstrated the inhibitory effect of NNC 55-0396, a T-type Ca 2+ channel inhibitor, on voltage-dependent K + (K V ) channels in freshly isolated rabbit coronary arterial smooth muscle cells. NNC 55-0396 decreased the amplitude of K V currents in a concentration-dependent manner, with an IC 50 of 0.080 mM and a Hill coefficient of 0.76. NNC 55-0396 did not affect steady-state activation and inactivation curves, indicating that the compound does not affect the voltage sensitivity of K V channel gating. Both the K V currents and the inhibitory effect of NNC 55-0396 on K V channels were not altered by depletion of extracellular Ca 2+ or intracellular ATP, suggesting that the inhibitory effect of NNC 55-0396 is independent of Ca 2+ -channel activity and phosphorylation-dependent signaling cascades. From these results, we concluded that NNC 55-0396 dose-dependently inhibits K V currents, independently of Ca 2+ -channel activity and intracellular signaling cascades.

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Section: +contrasting

confidence: 79%

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Son

Hong

et al. 2014

J Pharmacol Sci

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“…Mibefradil is also a LVA, T‐type Ca 2+ channel blocker (Mehrke et al, ; Martin et al, ), although its selectivity on LVA channels as compared to HVA channels is much smaller than that of NNC55‐0396, and effects on Ca v 1, Ca v 2,1, Ca v 2.2, and Ca v 2.3 channels have also been reported (e.g., Bezprozvanny and Tsien, ; Randall and Tsien, ; Jiménez et al, ). Moreover, mibefradil has been shown to also exert blocking effects on various types of Na + channels and K + channels (e.g., Liu et al, ; Eller et al, ; Hong et al, ; McNulty and Hanck, ). To avoid the consequences of such nonspecific actions on channels different from voltage‐gated Ca 2+ channels, we evaluated the effects of mibefradil not on original DAPs but on reconstructed DAPs generated by means of double‐ramp current stimuli in the presence of complete Na + ‐channel block with 1‐μM TTx (see above): it will be recalled, indeed, that the DAP reproduced in stellate cells under these conditions was still markedly Ca 2+ ‐dependent (see previous paragraph and Fig.…”

Section: Resultsmentioning

confidence: 99%

Two distinct types of depolarizing afterpotentials are differentially expressed in stellate and pyramidal‐like neurons of entorhinal‐cortex layer II

2015

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Two types of principal neurons, stellate cells and pyramidal-like cells, are found in medial entorhinal-cortex (mEC) layer II, and are believed to represent two distinct channels of information processing and transmission in the entorhinal cortex-hippocampus network. In this study, we found that depolarizing afterpotentials (DAPs) that follow single action potentials (APs) evoked from various levels of holding membrane voltage (Vh ) show distinct properties in the two cells types. In both, an evident DAP followed the AP at near-threshold Vh levels, and was accompanied by an enhancement of excitability and spike-timing precision. This DAP was sensitive to voltage-gated Na(+)-channel block with TTx, but not to partial removal of extracellular Ca(2+). Application of 5-μM anandamide, which inhibited the resurgent and persistent Na(+) -current components in a relatively selective way, significantly reduced the amplitude of this particular DAP while exerting poor effects on the foregoing AP. In the presence of background hyperpolarization, DAPs showed an opposite behavior in the two cell types, as in stellate cells they became even more prominent, whereas in pyramidal-like cells their amplitude was markedly reduced. The DAP observed in stellate cells under this condition was strongly inhibited by partial extracellular-Ca(2+) removal, and was sensitive to the low-voltage-activated Ca(2+)-channel blocker, NNC55-0396. This Ca(2+) dependence was not observed in the residual DAP evoked in pyramidal-like cells from likewise negative Vh levels. These results demonstrate that two distinct mechanism of DAP generation operate in mEC layer-II neurons, one Na(+)-dependent and active at near-threshold Vh levels in both stellate and-pyramidal-like cells, the other Ca(2+)-dependent and only expressed by stellate cells in the presence of background membrane hyperpolarization.

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“…Several research groups, including ours, have attempted to identify the side effects of chemicals that affect vascularKvchannelsbesidestheirownfunction.Forexample, curcumin (spice), the phosphoinositide-3 kinase inhibitor LY294002, the L-type Ca 2+ channels inhibitor verapamil, the T-type Ca 2+ channels inhibitor mibefradil, the protein kinase C inhibitor bisindolylmaleimide (I), and the guanylyl cyclase activator YC-1 directly inhibited vascular Kv channels in the open state. [26][27][28][29][30][31] In addition, the Ca 2+ channels inhibitor efonidipine and NNC 55-0396, as well as the tyrosine kinase inhibitor genistein and the protein kinase A inhibitor H-89 directly inhibited the vascular Kv channel in the closed state. 13,14,32,33) Furthermore, our group also reported that the protein kinase C inhibitor staurosporine and the calmodulin inhibitor trifluoperazine inhibited the vascular Kv channel in both open and closed states.…”

Section: Discussionmentioning

confidence: 99%

The Effects of the Selective Serotonin Reuptake Inhibitor Fluvoxamine on Voltage-Dependent K<sup>+</sup> Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Hong

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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We demonstrated the inhibitory effect of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Fluvoxamine reduced the amplitude of Kv currents in a concentration-dependent manner with an IC 50 value of 3.71 1.09 µM and a Hill coefficient of 0.62 0.14. Although fluvoxamine did not significantly affect the steady-state activation curve, it shifted the steady-state inactivation curve toward a more negative potential. Pretreatment with another SSRI, paroxetine, did not affect the basal Kv current and did not alter the inhibitory effect of fluvoxamine on Kv channels. We concluded that fluvoxamine inhibits the Kv current in a concentration-dependent manner and in a closed (inactivated) state of the Kv channels independent of serotonin reuptake inhibition.Key words fluvoxamine;voltage-dependentK + channel; coronary artery; smooth muscle; selective serotonin reuptake inhibitorFluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been used for the treatment of major depression, anxiety, and panic disorder since 1983 in many countries, including those in Europe and Japan.1,2) The antidepressant activity of fluvoxamine is derived from inhibition of serotonin reuptake in the central nervous system with negligible effects on other neurotransmitter reuptake systems.3,4) A recent study indicated that fluvoxamine showed high affinity for the σ1 receptor, which has a neuromodulatory role on the neurotransmitter system and an antidepressant-like effect. 5-7)Although fluvoxamine has beneficial effects in the treatment of depression, its administration is associated with common side effects, including nausea, anorexia, palpitations, headache, and dizziness. 8)Fluvoxamine also affects ion channels, such as the human ether-a-go-go related (hERG) K + and Kv1.5 channels. 9,10) However, these studies were performed primarily in cultured cell lines rather than in native cells. Therefore, questionsremainabouttheeffectoffluvoxamineonionchannels from freshly isolated cells, particularly vascular smooth muscle cells. 11,12) Our previous reports suggested that Kv channels participate in the regulation of resting membrane potential and thus resting tone in some arteries. 13,14) In addition, pathological states such as hypertension, diabetes, and hypoxia, are closely related with alteration of Kv channel activity and expression in the vasculature.15) Therefore, the adverse effects of drugs on Kv channels should be clearly determined to correctly interpret experimental data regarding vascular disorders.Considering the usefulness of fluvoxamine as a SSRI and the physiological importance of Kv channels, the effects of fluvoxamine on vascular Kv channel should be clearly examined to avoid toxic effect on the vasculature when applying fluvoxamineasantidepressantdrug.In the present study, we investigated the effects of fluvoxamine on Kv channels using freshly isolated coronary ...

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The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Cited by 20 publications

References 36 publications

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Two distinct types of depolarizing afterpotentials are differentially expressed in stellate and pyramidal‐like neurons of entorhinal‐cortex layer II

The Effects of the Selective Serotonin Reuptake Inhibitor Fluvoxamine on Voltage-Dependent K<sup>+</sup> Channels in Rabbit Coronary Arterial Smooth Muscle Cells

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