Inhibition by ibudilast of leukotriene D<sub>4</sub>‐induced formation of inositol phosphates in guinea‐pig lung

Etoh, Susumu; Ohashi, Mitsuo; Baba, Akemichi; Iwata, Heitaroh

doi:10.1111/j.1476-5381.1990.tb15847.x

Cited by 14 publications

(13 citation statements)

References 12 publications

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“…In spite of this, our results add to the growing list of biological effects in vitro and in vivo which ibudilast shares with this class of compound. The inhibitory effect of ibudilast on inositol phosphate formation in guineapig lung (Etoh et al, 1990) may be due to cyclic AMP elevation as a result of PDE inhibition -rolipram inhibits histamine-stimulated inositol phospholipid hydrolysis in bovine tracheal smooth muscle (Hall et al, 1989). The inhibitory effect of ibudilast on eicosanoid mediator release ) from leukocytes is a property shared with PDE IV inhibitors .…”

Section: Discussionmentioning

confidence: 99%

“…This conclusion is reinforced by the finding that ibudilast can inhibit histamine, platelet activating factor as well as LTD4-induced inositol phosphate formation in guineapig lung slices (Etoh et al, 1990). …”

Section: Introductionmentioning

confidence: 89%

“…['H]-LTD4 from guinea-pig lung membranes (Etoh et al, 1990) suggest that ibudilast is not a specific LTD4 receptor antagonist. This conclusion is reinforced by the finding that ibudilast can inhibit histamine, platelet activating factor as well as LTD4-induced inositol phosphate formation in guineapig lung slices (Etoh et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Souness¹,

Villamil²,

Scott³

et al. 1994

British J Pharmacology

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1 The possible role of cyclic AMP phosphodiesterase (PDE) in the inhibitory actions of ibudilast on tracheal smooth muscle contractility and eosinophil thromboxane generation was investigated. 2 Ibudilast was a non-selective inhibitor of partially purified cyclic nucleotide PDE isoenzymes from pig aorta and bovine tracheal smooth muscle, exhibiting only moderate potency against bovine tracheal PDE IV (IC0 = 12 ± 4 AM, n = 3). Similar or slightly lower potencies were displayed against PDEs I, II, III and V. In contrast, rolipram exhibited selectivity for PDE IV (3 0.5 AM, n = 3).3 Ibudilast (IC50 = 0.87 ± 0.37 AM, n = 3), like rolipram (IC = 0.20 0.04 AM, n = 3), was a more potent inhibitor of membrane-bound PDE IV from guinea-pig eosinophils than of partially purified PDE IV from bovine tracheal smooth muscle. The potency of ibudilast increased when the eosinophil enzyme was solubilised with deoxycholate and NaCl (IC50 = 0.11 ± 0.05 JAM, n = 3) or exposed to vanadate/glutathione complex (V/GSH) (ICo=0.11 ± 0.02 JM, n = 3). The potency of rolipram was also increased by solubilization (IC50 = 0.012 0.003, n = 3) or V/GSH (IC,0 = 0.012 ± 0.003, n = 3). 4 In intact eosinophils, ibudilast (0.032 jiM-20 JM) potentiated isoprenaline-induced cyclic AMP accumulation in a concentration-dependent manner, being approximately 20 fold less potent than rolipram. Little or no effect on basal cyclic AMP levels was observed with either compound. The cyclic AMP-dependent protein kinase activity ratio was significantly increased following incubation of eosinophils with either ibudilast (20 AM) or rolipram (20 gM) in the absence or presence of isoprenaline. 5Leukotriene B4 (300 nM)-induced thromboxane generation from guinea-pig eosinophils was inhibited by ibudilast (IC50 = 11.3 ± 3.7 AM, n = 5) and rolipram (IC,0 = 0.280 ± 0.067 AM, n = 5) in a concentration-dependent manner. 6 Ibudilast (10 nM-I AM), whilst generally less potent than rolipram (1 nM-AM), produced concentration-dependent relaxation of spasmogen (methacholine, histamine, LTD4)-induced tone in the guineapig isolated tracheal strip. Ibudilast was less potent in reversing the methacholine (IC50 = 1.95 ± 0.40 JM, n = 6)-induced contraction than those of histamine (IC50 = 0.18 ± 0.70 AM, n =6) or leukotriene D4 (LTD4, IC50 = 0.12 ± 0.05 JM, n = 6). Rolipram also exhibited a similar pattern of activity, although the difference in potency against methacholine (IC50 = 0.1 ± 0.01 JAM, n = 6) compared with the other two spasmogens, histamine (IC50 = 0.034 ± 0.017 JM, n = 7) and LTD4 (IC50 = 0.026 ± 0.008 AM, n = 7), was not as great.7 These results demonstrate that ibudilast, like rolipram, has several biological actions on the eosinophil and airways smooth muscle which may be attributed to inhibition of cyclic AMP PDE. These actions may account, at least in part, for the recently reported anti-asthma effects of ibudilast.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

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Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Souness¹,

Villamil²,

Scott³

et al. 1994

British J Pharmacology

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“…The aliquots of KRB (300 izl) containing three to four slices were replaced into 10 ml tubes and sonicated. Extraction, chromatographic separation, and measurement of [3H]inositol phosphates were carried out as described previusty (16).…”

Section: Preparations Of Prelabeled Iiippocampal Slices and Membranesmentioning

confidence: 99%

Cytochalasin B inhibits phosphoinositide hydrolysis in rat hippocampal slices

1993

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The effect of cytochalasin B on phosphoinositide (PI) hydrolysis was examined in rat hippocampal slices. Pretreatment of the slices with cytochalasin B caused a significant decrease in PI hydrolysis elicited by carbachol, norepinephrine, or by high K+. This effect was cytochalasin B dose- and time-dependent and was not mimicked by cytochalasin D, vinblastine, colchicine, or phloretin. In contrast, in [3H]inositol-prelabeled hippocampal membranes, cytochalasin B did not affect PI hydrolysis elicited by GTP gamma S and GTP gamma S plus carbachol. Similar result was obtained using the membranes prepared from the slices pretreated with cytochalasin B. The inhibitory effect of cytochalasin B on the carbachol-response was observed in SK-N-SH human neuroblastoma cells, but not in cultured rat astrocytes. These results indicate that cytochalasin B inhibits PI hydrolysis in neuron-specific manner and that its action may be an indirect cellular mechanism other than interaction with cytoskeleton elements.

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“…The plates were washed with 0.66 ml of water and the aqueous solution was added to the cell suspension. Extraction, chromatographic separation, and measurement of 'Hlabeled inositol phosphates (3H-IPs) were performed as described previously (Etoh et al, 1990) and expressed as the percentage of total incorporated counts (Garg and Kapturczak, 1990) using the following formula: 3H-IPs released (% total amount of [3H]inositol incorporated into the cells) = (dpm in IPS X 100)/(dpm in IPS + dpm in organic fraction).…”

Section: Pi Hydrolysis Assaymentioning

confidence: 99%

Phloretin as an Antagonist of Prostaglandin F_2α Receptor in Cultured Rat Astrocytes

Kitanaka

Ishibashi

Baba

1993

Journal of Neurochemistry

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Abstract:The effect of phloretin on prostaglandin (PG) F,*-induced phosphoinositide hydrolysis and elevation of intracellular CaZf concentration was examined in cultured rat astrocytes. Phloretin inhibited PGF,, ( I pLM)-induced phosphoinositide hydrolysis in a concentration-dependent manner with an ICs0 value of 16 p M . The inhibitory action of phloretin was specific for PGs. The addition of increasing concentrations of phloretin caused progressive shifts of the dose-response curves of PGF,, to the right. In digitoninpermeabilized astrocytes, phloretin ( 100 pLIz/J) inhibited the stimulation induced by PGF,,, ( I pA.4) plus GTPyS (50 &f) without affecting that induced by CTPyS alone. PGF2, at 1 p M transiently increased astrocytic intracellular Ca2' concentration in 39% of the cells tested. The response was completely blocked by 100 pM phloretin and the calcium response recovered again after washing out phloretin. These results suggest that phloretin is an antagonist of PGF,, receptor linked to phospholipase C in astrocytes.

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Inhibition by ibudilast of leukotriene D₄‐induced formation of inositol phosphates in guinea‐pig lung

Cited by 14 publications

References 12 publications

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Cytochalasin B inhibits phosphoinositide hydrolysis in rat hippocampal slices

Phloretin as an Antagonist of Prostaglandin F_2α Receptor in Cultured Rat Astrocytes

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Inhibition by ibudilast of leukotriene D4‐induced formation of inositol phosphates in guinea‐pig lung

Cited by 14 publications

References 12 publications

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Cytochalasin B inhibits phosphoinositide hydrolysis in rat hippocampal slices

Phloretin as an Antagonist of Prostaglandin F2α Receptor in Cultured Rat Astrocytes

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Product

Resources

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Inhibition by ibudilast of leukotriene D₄‐induced formation of inositol phosphates in guinea‐pig lung

Phloretin as an Antagonist of Prostaglandin F_2α Receptor in Cultured Rat Astrocytes