Antagonistic effect of KC-404, a new anti-asthmatic agent, on leukotriene D4-induced contractile responses in isolated guinea pig smooth muscles

Ohashi, Mitsuo; Kanai, Riho; Nishino, Koichiro; Sato, Takahiro; Takayanagi, Issei

doi:10.1016/0090-6980(86)90096-1

Cited by 23 publications

(12 citation statements)

References 28 publications

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“…The studies of Ohashi et al (1986a) suggested that low concentrations (less than 1.3 AM) of ibudilast inhibited leukotriene D4 (LTD4)-induced contraction of guinea-pig lung strips in an apparently competitive manner; however, the deviation from competitive inhibition observed at higher concentrations of ibudilast coupled with its inability to displace…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…KC-404 is shown to be a potent inhibitor of SRS-A released from guinea pig lung fragments [6] and a se lective antagonist of LTD4 [7], In addition to these anti-allergic actions, KC-404 has cerebrovasodilating activity and selectively increases vertebral blood flow when compared with femoral blood flow in anesthe tized dogs [12]. But there are no reports about the ef fect of KC-404 to the release of LTs.…”

Section: Discussionmentioning

confidence: 99%

“…According to reports, KC-404 prefe rentially inhibited SRS-A-induced contraction of isolated guinea pig ileum, SRS-A-induced bronchoconstriction in anesthetized guinea pig and SRS-A-induced increase in cutaneous vascular permeability in rats and guinea pigs [6]. Later it was suggested that KC-404 is a selective antagonist of LTD4 and that it interacts with LTD4 receptor in airway smooth mus cles but not in ileum [7,8]. KC-404 also inhibited the antigen-induced SRS-A release of lung and perito neal mast cells [6).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Effect of KC-404 on Leukotriene Release from Human Leukocytes Induced by Ionophore A23187

Ohtsu

Fujimoto

Yamauchi

et al. 1989

Int Arch Allergy Immunol

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Release of leukotriene (LT) B₄, LTC₄ and histamine from human peripheral mixed leukocytes stimulated with calcium ionophore A23187 was evaluated. The amounts of LTB₄ and LTC₄ in supernatants were analyzed by high performance liquid chromatography and histamine was measured by an automated fluorometric technique. A time-course study demonstrated the characteristic patterns of the release of these mediators. LTB₄ and LTC₄ were more slowly released than histamine and the release of these LTs was inhibited by KC-404, a novel anti-asthmatic drug which has no effect on histamine release.

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“…Ibudilast [3-isobutyryl-2-isopropylpyrazolo-(1,5a)-pyridine] is an orally active compound produced as a pyrazopyridine derivative in Japan, which suppresses tracheal constriction and inflammation [1, 2]. This compound also demonstrates vasodilatory action [3, 4]and platelet aggregation inhibitory action [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Ibudilast on Urinary Albumin Excretion in Type 2 Diabetes mellitus with Microalbuminuria

Hoshino

Ikeda

2002

Nephron

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To evaluate the clinical effect of ibudilast, a prostacyclin-mediated vasodilator and antiplatelet agent, on diabetic nephropathy, 8 nonhypertensive patients with type 2 diabetes mellitus (DM; 4 men and 4 women, mean age: 58.9 ± 11.4 years, duration of diabetes: 16.9 ± 3.2 years) with microalbuminuria [20–200 mg/g creatinine (Cr)] were administered ibudilast (30 mg/day) for 18 months (ibudilast group). The urinary albumin excretion index (UAE, mg albumin/g Cr) was compared with 8 age-matched type 2 DM with microalbuminuria (control group). During the study, the UAE significantly decreased in the ibudilast group, while it significantly increased in the control group. After 18 months, the UAE (52 ± 19 mg/g Cr) in the ibudilast group was significantly (p < 0.05) lower than that (99 ± 46 mg/g Cr) in the control group. These results suggest that ibudilast may inhibit the progression of early diabetic nephropathy in type 2 DM.

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Antagonistic effect of KC-404, a new anti-asthmatic agent, on leukotriene D4-induced contractile responses in isolated guinea pig smooth muscles

Cited by 23 publications

References 28 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

Pharmacological Effect of KC-404 on Leukotriene Release from Human Leukocytes Induced by Ionophore A23187

Inhibitory Effect of Ibudilast on Urinary Albumin Excretion in Type 2 Diabetes mellitus with Microalbuminuria

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