The mitochondrial Ca2+-activated K+ channel activator, NS 1619 inhibits L-type Ca2+ channels in rat ventricular myocytes

Park, Won Sun; Kang, Sung Hyun; Son, Youn Kyoung; Kim, Nari; Ko, Jae‐Hong; Kim, Hyoung Kyu; Ko, Eun A.; Kim, Chi Dae; Han, Jin

doi:10.1016/j.bbrc.2007.07.057

Cited by 49 publications

(39 citation statements)

References 24 publications

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“…Many reports have confirmed the cardioprotective effect of BK channel activation by NS1619. However, questions regarding the selectivity of the compound have been raised [6][7][8][9][10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…The selectivity of this benzimidazolone has been questioned. At higher concentrations, NS1619 directly inhibits L-type Ca 2+ channels in rat ventricular myocytes [6], Ca 2+ -activated chloride currents [7], and voltage-activated Ca 2+ , K + , and Na + channels [8][9][10]. Moreover, it was suggested that NS1619 may have mitochondrial effects unrelated to mitoBK channels [11,12] and that this could explain some of the cardioprotective effects of NS1619 [13].…”

Section: Introductionmentioning

confidence: 99%

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Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury

Bentzen

Osadchii

Jespersen

et al. 2008

Pflugers Arch - Eur J Physiol

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Activation of the large-conductance Ca(2+)-activated K(+) channel (BK) in the cardiac inner mitochondrial membrane has been suggested to protect the heart against ischemic injury. However, these findings are limited by the low selectivity profile and potency of the BK channel activator (NS1619) used. In the present study, we address the cardioprotective role of BK channels using a novel, potent, selective, and chemically unrelated BK channel activator, NS11021. Using electrophysiological recordings of heterologously expressed channels, NS11021 was found to activate BK alpha + beta1 channel complexes, while producing no effect on cardiac K(ATP) channels. The cardioprotective effects of NS11021-induced BK channel activation were studied in isolated, perfused rat hearts subjected to 35 min of global ischemia followed by 120 min of reperfusion. 3 microM NS11021 applied prior to ischemia or at the onset of reperfusion significantly reduced the infarct size [control: 44.6 +/- 2.0%; NS11021: 11.4 +/- 2.0%; NS11021 at reperfusion: 19.8 +/- 3.3% (p < 0.001 for both treatments compared to control)] and promoted recovery of myocardial performance. Co-administration of the BK-channel inhibitor paxilline (3 microM) antagonized the protective effect. These findings suggest that tissue damage induced by ischemia and reperfusion can be reduced by activation of cardiac BK channels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury

Bentzen

Osadchii

Jespersen

et al. 2008

Pflugers Arch - Eur J Physiol

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“…The exposure time of each L-cysteine application was 10 min. In some experiments, the effects of various agents, including the thiol-modifying agent diamide (200 M), the L-type calcium channel blocker nifedipine (1 M), the nitric-oxide (NO) synthase inhibitor N -nitro-Larginine (100 M), the purinergic agonist ATP (50 M), the purinergic antagonist suramin (200 M), or the calcium-activated K wards et al, 1994;Patel et al, 1998;Ng et al, 2006;Park et al, 2007;30 M), were examined during recording of spontaneous contractions in the presence or absence of L-cysteine (1 mM). In our preliminary studies, we tested different concentrations of diamide and determined that 200 M was a suitable concentration to obtain a reproducible inhibitory effect on the responses to L-cysteine.…”

Section: Methodsmentioning

confidence: 99%

Differential Effect of l-Cysteine in Isolated Whole-Bladder Preparations from Neonatal and Adult Rats

Buyuknacar

Göçmen²,

Groat³

et al. 2010

J Pharmacol Exp Ther

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The present study was undertaken to compare the effects of the thiol reagents L-cysteine and (diazene dicarboxylic acid bis 5N,N-dimethylamide) diamide on contractile activity of neonatal and adult rat bladders. In vitro whole-bladder preparations from Wistar rats were used to study the modulation of spontaneous bladder contractions by thiol reagents. After blocking cholinergic and adrenergic transmission with atropine and guanethidine, L-cysteine facilitated spontaneous bladder contractions in neonatal rat bladders. The effect of L-cysteine was suppressed by diamide. Diamide alone did not change basal activity of the neonatal rat bladder. The facilitatory effects of L-cysteine were reduced by the L-type Ca 2ϩ channel-blocking agent nifedipine and the calciumactivated K ϩ channel opener NS1619 [1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one]. ATP or suramin, a purinergic receptor antagonist, significantly inhibited the effect of L-cysteine in neonatal bladders, whereas the nitric-oxide synthase inhibitor N -nitro-L-arginine was ineffective. L-cysteine did not elicit any detectable effects in the adult rat bladder; whereas diamide caused a large-amplitude sustained tonic contraction. The contraction induced by diamide in adult bladder did not occur when the preparation was pretreated with L-cysteine. Also, L-Cysteine administered during the diamide-evoked contraction completely inhibited the contraction to diamide. In conclusion, our results suggest that L-cysteine has markedly different effects in isolated wholebladder preparations from neonatal and adult rats. Thus thiol-sensitive mechanisms may modulate contractility by regulation of Ca 2ϩ and K ϩ channels and/or purinergic transmission in the neonatal bladder. The effects of L-cysteine and diamide were reversed in adult bladders, indicating that the regulation of bladder contractility by thiols is markedly altered during postnatal development.

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“…For example, verapamil, a phenylalkylamine Ca 2+ channel inhibitor, directly inhibits Kv and BK Ca channels in vascular smooth muscle cells (30,31) and inhibited delayed rectifier K + current in cardiac myocytes (32,33). NS 1619 and BMS-204352, BK Ca channel activators, directly inhibited the cardiac L-type Ca 2+ channel (34,35). Therefore, caution is required when using ion channel activators/inhibitors, which are known to have side effects on other channels.…”

Section: +mentioning

confidence: 99%

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

et al. 2012

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Abstract. We examined the effects of mibefradil, a T-type Ca 2+ channel inhibitor, on voltagedependent K + (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch clamp technique. Mibefradil reduced the Kv current amplitude in a dose-dependent manner, with an apparent K d value of 1.08 μM. Kv current inhibition by mibefradil was highly voltagedependent over the full activation voltage range (−30 to +10 mV). The decay rate of Kv channel inactivation was accelerated by mibefradil without altering the kinetics of current activation. The rate constants of association and dissociation were 2.23 ± 0.07 μM , respectively. Mibefradil had no significant effect on the steady-state activation or inactivation curves. In the presence of mibefradil, the recovery time constant from inactivation was decreased, and the application of train pulses (1 or 2 Hz) increased mibefradil-induced Kv channel inhibition, suggesting that the inhibitory effects of mibefradil were use-dependent. The inhibitory effect of mibefradil on Kv channels was unaffected by extracellular Ca 2+ -free conditions. Moreover, the absence of ATP inside the pipette did not alter the blocking effect of mibefradil. Therefore, we suggest that mibefradil directly inhibited the Kv current, independently of Ca 2+ channel inhibition.

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The mitochondrial Ca2+-activated K+ channel activator, NS 1619 inhibits L-type Ca2+ channels in rat ventricular myocytes

Cited by 49 publications

References 24 publications

Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury

Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury

Differential Effect of l-Cysteine in Isolated Whole-Bladder Preparations from Neonatal and Adult Rats

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

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