Inhibition of leukotriene B4-INDUCED increase in intracellular calcium ion level of human peripheral blood polymorphonuclear leukocytes by Y-24180, an antagonist of platelet-activating factor receptor |
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| Affiliation: | 1. Pharmaceutical Research, Yoshitomi Pharmaceutical Industries, Ltd, 955 Koiwai, Yoshitomi-cho, Chikujo-gun, Fukuoka 871-8550, Japan;1. Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, UKM Bangi, Selangor Darul Ehsan, Malaysia;2. Nuclear Science Program, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia;3. Material Technology Group, Industrial Technology Division, Malaysian Nuclear Agency, Bangi, 43000, Kajang, Selangor, Malaysia;4. Fuel Cell Institute, University Kebangsaan Malaysia, 43600, UKM Bangi, Selangor, Malaysia;1. Department of Chemical Engineering, School of Chemical and Energy Engineering, Universiti Teknologi Malaysia, 81310, UTM, Johor Bahru, Johor, Malaysia;2. Chemical and Petroleum Engineering Department, UAE University, P.O. Box 15551, Al Ain, United Arab Emirates;1. Department of Mechanical and Aerospace Engineering, The Hong Kong University of Science and Technology, Hong Kong, China;2. Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China;1. School of Safety Science and Engineering, Xi''an University of Science and Technology, 58, Yanta Mid. Rd., Xi''an 710054, Shaanxi, PR China;2. Chongqing Wanzhou Gas Co., LTD. 1, Wangpai Rd., Chongqing 404000, PR China;1. Human Systems Engineering Laboratory, Department of Industrial and Systems Engineering, Mississippi State University, Mississippi State, MS 39762, USA;2. Applied Biomechanics Laboratory, Department of Health, Exercise Science, and Recreation Management, The University of Mississippi, University, MS 38677, USA;3. Neuromechanics Laboratory, Department of Kinesiology, Mississippi State University, Mississippi State, MS 39762, USA |
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| Abstract: | Y - 24180 ( (±) - 4 - (2-chlorophenyl ) - 2 - [2 - (4-isobutylphenyl ) ethyl] - 6,9 - dimethyl - 6H - thieno [3,2 - f ] [1,2,4] triazolo [4,3-a] [1,4] diazepine) , an antagonist of platelet-activating factor (PAF) receptor, has already been reported to inhibit leukotriene B4 (LTB4) -induced activation of polymorphonuclear leukocytes. In this article, to clarify the mechanism of inhibition of LTB4-induced activation by Y-24180, we examined the effect of Y-24180 on LTB4-induced increase in intracellular calcium ion ( [Ca2] i) level of human polymorphonuclear leukocytes at a single cell level using a laser scanning confocal microscope. Preincubation with Y-24180 significantly inhibited the increase in [Ca2] i level at 0.3–3 μM, while WEB 2086 (4- [3- [4- (2-chlorophenyl ) -9-methyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] propionyl] morpholine) , another PAF receptor antagonist, did not show the inhibitory effect at 3–30 μM, indicating that the difference in potency between these compounds was more than 100-fold. The LTB4-induced increase in [Ca2] i level was suppressed by microinjection of anti-PAF antibody, but not control antibody, into leukocytes. Microinjection of Y-24180 at 0.003–0.03 μM or WEB 2086 at 0.03–0.3 μM into leukocytes also inhibited the LTB4-induced increase. The microinjection of WEB 2086 at the 10-fold greater concentrations than those of Y-24180 inhibited to the almost equal level to that obtained by Y-24180. In addition, microinjection of PAF into leukocytes induced the increase in [Ca2] i level. Preincubation with Y-24180 at 1 or 3 μM significantly attenuated the PAF microinjection-induced increase, but WEB 2086 showed little effect at 3–30 μM. These results indicate that Y-24180 inhibits LTB4-induced activation of leukocytes by suppressing the increase in [Ca2] i level and the inhibitory effect is mediated by antagonistic action against intracellular PAF-induced up-regulation of [Ca2] i level. The difference in inhibitory activity for the increase in [Ca2] i level between Y-24180 and WEB 2086 when these are added in the culture medium may depend upon their aptitude for the transmembrane influx. |
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