Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury

Akar, Fatma; Uydeş-Doğan, B. Sönmez; Buharalioğlu, C. Kemal; Abban, Gülçin; Heinemann, Ákos; Holzer, Peter; Voorde, Johan Van de

doi:10.1016/s0014-2999(99)00277-0

Cited by 25 publications

(19 citation statements)

References 39 publications

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“…Our results show that glibenclamide, an ATP-sensitive potassium channel blocker [26,27], did not have any antiproliferative action on these two cell lines. However, low doses of TEA, a non-specific BK channel blocker, significantly reduced the proliferation of HeLa and A2780 cells, indicative of involvement of BK channels in the tumor cell growth progression.…”

Section: Discussionmentioning

confidence: 72%

Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

et al. 2007

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Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90alpha, hsp90beta, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.

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Section: Discussionmentioning

confidence: 72%

Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

et al. 2007

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“…We also examined the effects of tertiapin-Q (TPNQ), an inhibitor of Kir1.1 and Kir3.x channels (25), or glybenclamide (Glyb), an inhibitor of ATP-activated K ϩ channels (26,27), which exist as heteromultimers of sulfonylurea receptor subunits and Kir6.1 or Kir6.2 subunits (28). For each inhibitor, concentrations were chosen that were substantially (Ͼ10 times) higher than the IC 50 described for the relevant targets (25,29).…”

Section: Inward Rectifier Potassium Channel Function Is Important For ␣9mentioning

confidence: 99%

The α9β1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

deHart¹,

Jin

McCloskey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The ␣9␤1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the ␣9 cytoplasmic domain. We now show that SSAT enhances ␣9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K ؉ ion efflux through inward-rectifier K ؉ (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited ␣9-dependent cell migration. ␣9␤1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an ␣9␤1 ligand. These results identify a pathway through which the ␣9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.T he ␣9␤1 integrin is widely expressed and binds to a number of ligands, including the extracellular matrix protein tenascin-C, the vascular cell adhesion molecule, VCAM-1, and several members of the ADAM family (1-3). ␣9␤1 mediates enhanced cell migration, an effect that specifically depends on the ␣9 cytoplasmic domain (4, 5). The closely related integrin ␣4 subunit also accelerates cell migration, through reversible interaction with the scaffolding protein, paxillin (6, 7). The mechanism by which the ␣9 subunit cytoplasmic domain accelerates cell migration is completely different (4, 5), and requires binding of the enzyme, spermidine/ spermine-N 1 -acetyltransferase (SSAT) (5). The mechanisms by which SSAT binding modulates migration were until now unknown. SSAT specifically catalyzes catabolism of the higher order polyamines, spermidine and spermine, to the lower order polyamine, putrescine (8), thereby increasing intracellular levels of putrescine, and decreasing those of spermidine and spermine (9, 10).Spermine and spermidine are potent blockers of outward potassium (K ϩ ) currents from inward rectifier K ϩ (Kir) channels (11-13). These channels conduct larger inward currents at membrane voltages below the resting potential than outward currents at more positive voltages. The long, positively charged polyamines, spermine (ϩ4) or spermidine (ϩ3), mediate rectification by binding to negatively charged residues in the channel pore (12,14). The catabolized polyamine putrescine (ϩ2) is less effective at blocking outward flow of K ϩ ions (11, 12). Although Kir channels have been implicated in the regulation of many different physiological processes, including heart rate and membrane excitability (15), there are currently no reports suggesting their involvement in the regulation of cell migration. However, numerous studies have suggested that K ϩ efflux is a critical factor in modulating cell migration (16)(17)(18)(19). In this study, we show that both the catalytic activity of SSAT and the downstream catabolism of polyamines are specifically required for ␣9...

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“…From these observations, it was suggested that gastric PGI2 reduces gastric mucosal lesions primarily by inhibiting leukocyte accumulation. Akar et al [1999] used an indomethacin-induced gastric injury model to evaluate the pharmacological action of K + channel-opening drugs, monitored gastric mucosal blood flow, myeloperoxidase activity, and neutrophil accumulation, and suggested that the action of the drugs involved the modulation of neutrophil function. These side effects of NSAIDs may be strongly related to the pathology shown in this study where the microbial translocation as well as absorption of endotoxin from the gut is likely induced during treatment.…”

Section: Discussionmentioning

confidence: 99%

Septic shock induced by microbial products and indomethacin

Moriya

Ohno

Miura

et al. 2002

Drug Development Research

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Lethal toxicity was induced in mice by sequential administration of β-glucan and indomethacin. Whole cell preparations of Gram-positive bacteria, Gram-negative bacteria, and fungi also showed a similar toxicity. However, bacterial lipopolysaccharides (LPS) alone were not toxic. After the indomethacin administration, the sensitivity of mice to LPS was significantly elevated and the animals died following only a 0.1-µg intravenous administration. An accumulation of leukocytes in the liver and enhancement of TNF, IL-6, and MIP-2 concentrations were noted. Antibiotic treatment prolonged the survival of mice. The toxicity resembles septic shock, and is strongly related to microbial translocation and endotoxin absorption from the gut. Drug Dev. Abbreviations used: BRM = biological response modifier; CA = Candida albicans; CAWS = Candida water soluble polysaccharide fraction; COX = cyclooxygenase; CSBG = Candida solubilized cell wall β-glucan; CSF = colony stimulating factor; DB = degree of branching; DMSO = dimethylsulfoxide; IFN = interferon; IL-6 = interleukin-6; LPS = lipopolysaccharide; MW = molecular weight; NaClO = sodium hypochlorite; NK= natural killer; NSAIDs = nonsteroidal anti-inflammatory drugs; OX-CA = NaClO oxidized Candida albicans; PG= prostaglandin; SPG = sonifillan (schizophyllan); SSG = soluble β-glucan of Sclerotinia sclerotiorum IFO9395; YPG = culture medium containing yeast ext., polypeptone, and glucose; Z-CA= zymolyase solubilized CA; ZYC= zymocel; ZYM = zymosan A.

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Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury

Cited by 25 publications

References 39 publications

Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

The α9β1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

Septic shock induced by microbial products and indomethacin

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