NPPB block of the intermediate-conductance Ca2+-activated K+ channel

Fioretti, Bernard; Castigli, Emilia; Calzuola, Isabella; Harper, Alexander A.; Franciolini, Fabio; Catacuzzeno, Luigi

doi:10.1016/j.ejphar.2004.06.034

Cited by 42 publications

(49 citation statements)

References 21 publications

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“…The strong suppression by clotrimazole was probably not due to its inhibitory action on cytochrome P450 or voltage-gated K ϩ channels (Yuan et al, 1995;Eichler et al, 2003), since the AChinduced hyperpolarization was not affected by 17-octadecynoic acid, a known cytochrome P450 inhibitor (Jiang et al, 2005). In addition, the estimated IC 50 (116 nM) of clotrimazole is very close to that determined from HEK-293 cells that expressed human IK channels (153 nM; Jensen et al, 1998), and it is ϳ2-fold of that determined from the IK expressed in glioblastoma GL-15 cell lines (63 nM; Fioretti et al, 2004). Taken together, we have for the first time a quantitative estimation that IK activation is responsible for approximately 95% of the hyperpolarization induced by ACh in the endothelial cells.…”

Section: Discussionsupporting

confidence: 51%

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Jiang

Shi²,

Guan

et al. 2006

J Pharmacol Exp Ther

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Acetylcholine (ACh) induces hyperpolarization and dilation in a variety of blood vessels, including the cochlear spiral modiolar artery (SMA) via the endothelium-derived hyperpolarization factor (EDHF). We demonstrated previously that the ACh-induced hyperpolarization in the SMA originated in the endothelial cells (ECs) by activating a Ca 2ϩ -activated K ϩ channel (K Ca ); the hyperpolarization in smooth muscle cells was mainly an electrotonic spread via gap junction coupling. In the present study, using intracellular recording, immunohistology, and vascular diameter tracking techniques on in vitro SMA preparations, we found that 1) ACh-induced hyperpolarization was suppressed by intermediate-conductance K Ca (IK) blockers clotrimazole (IC 50 ϭ 116 nM) and nitrendipine and by the calmodulin antagonist trifluoperazine, but it was not suppressed by the bigconductance K Ca blocker iberiotoxin. The immunoreactivity to anti-SK4/IK1 antibody was localized mainly in ECs.2) The three dihydropyridines-nifedipine, nitrendipine, and nimodipine-all concentration-dependently inhibited the ACh-induced hyperpolarization, with an IC 50 value of 455, 34, and 3.2 nM, respectively. 3) Among other L-type Ca 2ϩ channel (I L ) blockers, 10 M verapamil exerted a 20% inhibition on ACh-induced hyperpolarization, whereas diltiazem and the metal ion Ca 2ϩ channel blockers Cd 2ϩ and Ni 2ϩ had no effect. 4) Nitrendipine and charybdotoxin abolished ACh-induced dilation in the SMA. We conclude that ACh-induced hyperpolarization in the SMA is generated mainly by activation of the IK in the ECs, and dihydropyridines suppress the EDHF-mediated hyperpolarization by blocking the IK channel, not the I L channel. The clinical relevance of this dihydropyridine action is discussed.Several vasoactive agents, such as acetylcholine (ACh), substance P, and bradykinin, cause robust hyperpolarization and vasodilation when the endothelium is intact. The hyperpolarization and vasodilation have been attributed to endothelium-derived hyperpolarization factor (EDHF) or endothelium-derived relaxation factor (Faraci and Heistad, 1998;Busse et al., 2002). The EDHF is an important mechanism regulating blood flow to organs and tissues and is implicated in vascular pathology, such as ischemia, hypertension, atherosclerosis, diabetic and aging vascular malfunction (Faraci and Heistad, 1998), and coronary vascular spasms (Konidala and Gutterman, 2004).The EDHF seems to be a variable combination of gap junction coupling, endothelial release of K ϩ , NO, epoxyeicosatrienoic acids, and prostanoid in various vascular beds and in different animal species (Busse et al., 2002). We reported recently that ACh induced hyperpolarization and dilation in the cochlear spiral modiolar artery (SMA) via the EDHF (Jiang et al., 2005) and found that ACh-induced EDHF in the SMA was a complex. The induced hyperpolarization originated in the endothelial cell (EC) by activating Ca 2ϩ -acti-

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Section: Discussionsupporting

confidence: 51%

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Jiang

Shi²,

Guan

et al. 2006

J Pharmacol Exp Ther

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“…In contrast, the DCEBIO ϩ ionomycin-activated K ϩ current was markedly inhibited by CTX (200 nM), CTL (2 M), and the newly identified IK Ca channel antagonist NPPB (300 M; see Ref. 4), suggesting that it was sustained by IK Ca channels. Figure 2C shows that the ionomycin-activated current block by both CTL and CTX was (Fig.…”

Section: Intracellularmentioning

confidence: 86%

Intermediate-conductance Ca²⁺-activated K⁺ channel is expressed in C₂C₁₂ myoblasts and is downregulated during myogenesis

Fioretti¹,

Pietrangelo²,

Catacuzzeno³

et al. 2005

American Journal of Physiology-Cell Physiology

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“…For whole-cell perforated-patch recordings the bathing Physiological Salt Solution (PSS) consisted of (in mM): NaCl 106.5, KCl 5, CaCl 2 2, MgCl 2 2, MOPS 5, glucose 20, Na·Gluconate 30, octanol 1 (to block gap-junctions; [34,35] Ionomycin and EBIO (1-ethyl-2-benzimidazolinone) were from Tocris Cookson Ltd. (Bristol, UK). Stock solutions were obtained by dissolving CTL, EBIO, ionomycin and amphotericin B in DMSO to concentrations of 20, 100, 1 and 500 mM respectively.…”

Section: Solutions and Drugsmentioning

confidence: 99%

Expression and Modulation of the Intermediate- Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel in Glioblastoma GL-15 Cells

Fioretti

Castigli

Micheli

et al. 2006

Cell Physiol Biochem

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We report here the expression and properties of the intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca) channel in the GL-15 human glioblastoma cell line. Macroscopic IK_Ca currents on GL-15 cells displayed a mean amplitude of 7.2±0.8 pA/pF at 0 mV, at day 1 after plating. The current was inhibited by clotrimazole (CTL, IC₅₀=257 nM), TRAM-34 (IC₅₀=55 nM), and charybdotoxin (CTX, IC₅₀=10.3 nM). RT-PCR analysis demonstrated the expression of mRNA encoding the IK_Ca channel in GL-15 cells. Unitary currents recorded using the inside-out configuration had a conductance of 25 pS, a K_D for Ca²⁺ of 188 nM at -100 mV, and no voltage dependence. We tested whether the IKCa channel expression in GL-15 cells could be the result of an increased ERK activity. Inhibition of the ERK pathway with the MEK antagonist PD98059 (25 µM, for 5 days) virtually suppressed the IK_Ca current in GL-15 cells. PD98059 treatment also increased the length of cellular processes and up-regulated the astrocytic differentiative marker GFAP. A significant reduction of the IKCa current amplitude was also observed with time in culture, with mean currents of 7.17±0.75 pA/pF at 1-2 days, and 3.11±1.35 pA/pF at 5-6 days after plating. This time-dependent downregulation of the IK_Ca current was not accompanied by changes in the ERK activity, as assessed by immunoblot analysis. Semiquantitative RT-PCR analysis demonstrated a ~35% reduction of the IK_Ca channel mRNA resulting from ERK inhibition and a ~50% reduction with time in culture.

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NPPB block of the intermediate-conductance Ca2+-activated K+ channel

Cited by 42 publications

References 21 publications

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Intermediate-conductance Ca²⁺-activated K⁺ channel is expressed in C₂C₁₂ myoblasts and is downregulated during myogenesis

Expression and Modulation of the Intermediate- Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel in Glioblastoma GL-15 Cells

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NPPB block of the intermediate-conductance Ca2+-activated K+ channel

Cited by 42 publications

References 21 publications

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Dihydropyridines Inhibit Acetylcholine-Induced Hyperpolarization in Cochlear Artery via Blockade of Intermediate-Conductance Calcium-Activated Potassium Channels

Intermediate-conductance Ca2+-activated K+ channel is expressed in C2C12 myoblasts and is downregulated during myogenesis

Expression and Modulation of the Intermediate- Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel in Glioblastoma GL-15 Cells

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Intermediate-conductance Ca²⁺-activated K⁺ channel is expressed in C₂C₁₂ myoblasts and is downregulated during myogenesis