PAF-Induced Human Platelet Aggregation is Selectivley Inhibited by Class II and Class III But Not Class I Calcium “Antagonists”
PAF-Induced Human Platelet Aggregation is Selectivley Inhibited by Class II and Class III But Not...
Shaw,, A.M.;Brydon,, L.J.;Maclntyre,, D.E
1983-04-01 00:00:00
Downloaded from https://academic.oup.com/eurheartj/article/4/suppl_B/4/541980 by DeepDyve user on 18 September 2020 4 Abstracts THE ROLE OF PI TURNOVER IN TxA -INDUCED PLATELET ACTIVATION : EFFECTS OF TxA ANTAGONISTS. W.K. Pollock, D.E. Maclntyre. Department of Pharmacology, University of Glasgow. Receptor mediated human platelet activation id dependent upon a rise in the concentration of intracellular free calcium. It has been proposed that the mechanism by which Ca is mobilised from intracellular or extracellular sources, is receptor mediated stimulation of phosphatidyl-inositol, (PI) metabolism. We used the stable TxA - mimetic [9,ll-epoxymethano-PGH2, (U44069)] and selective TxA antagonists, 2 2 EP045 and trimethoquinol, to examine the role of PI turnover in TxA -induced platelet activation. Plasma free suspensions of washed human platelets were prelabelled with [ P]- orthophosphate and resuspended in fresh buffer. Aliguots (0.4 ml) plus or minus antagonist were then stimulated with U44069. Phospholipids were extracted and analysed by two dimensional thin layer chromatography. U44069 (10 nM - 3 uM) markedly stimulates PI turnover as indicated by the formation of [ p]-phosphatidic acid (PA). The TxA receptor antagonists EP045 (0.3 - 3 uM) and trimethoquinol (1 - 30 uM) inhibit U44069-induced formation of [ P]-PA. These results indicate that TxA receptor occupancy is coupled to stimulation of PI metabolism in human platelets. The interrelationships between receptor occupancy, PI turnover and Ca availability are currently being investigated. PAF-INDUCED HUMAN PLATELET AGGREGATION IS SELECTIVLEY INHIBITED BY 008 CLASS II AND CLASS III BUT NOT CLASS I CALCIUM "ANTAGONISTS". A.M. Shaw, L.J. Brydon, D.E. Maclntyre. Dept. of Pharmacology, University of Glasgow. Cytosolic free Ca is considered to be the final mediator of platelet functional change. We have shown, using the calcium indicator dye Quin 2, that PAF mobilises 2 2 intracellular Ca ans stimulates an influx of Ca in human platelets. Using citrate PRP prepared from aspirin-treated donors, we examined the effects of calcium "antagonists" on human platelet aggregation (40-70% of maximum) induced by PAF, ADP and lysophosphatidic acid (LPA). Aggregation induced by PAF was inhibited by Verapamil, (class II), (I50 - 25pM) and by Diltiazem (class III), (I50 ~ 5uM). Verapamil and Diltiazem inhibited platelet aggregation induced by ADP and LPA but at higher concen- trations (Verapamil I v ADP = 150 yM ; I v LPA = 150 uM ; Dilthiazem 5 0 5 0 I50 v ADP = 150 yM ; I50 v LPA = 55 viM). Nicardipine (class I) , exhibited no selective inhibition of PAF-induced aggregation and was the least potent inhibitor of aggregation induced by all agonists (I50 > 170 pM in all cases). The selective inhibition by Verapamil and Diltiazem of PAF-induced aggregation could not be attributed to phospho- diesterase inhibition, a-adrenoceptor antagonism or Na channel blockade. These results suggest that PAF-induced platelet activation involves a calcium translocation mechanism sensitive to class II and class III but not class I calcium "antagonists".
http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.pngEuropean Heart JournalOxford University Presshttp://www.deepdyve.com/lp/oxford-university-press/paf-induced-human-platelet-aggregation-is-selectivley-inhibited-by-isowiBi2Oy
PAF-Induced Human Platelet Aggregation is Selectivley Inhibited by Class II and Class III But Not Class I Calcium “Antagonists”
Downloaded from https://academic.oup.com/eurheartj/article/4/suppl_B/4/541980 by DeepDyve user on 18 September 2020 4 Abstracts THE ROLE OF PI TURNOVER IN TxA -INDUCED PLATELET ACTIVATION : EFFECTS OF TxA ANTAGONISTS. W.K. Pollock, D.E. Maclntyre. Department of Pharmacology, University of Glasgow. Receptor mediated human platelet activation id dependent upon a rise in the concentration of intracellular free calcium. It has been proposed that the mechanism by which Ca is mobilised from intracellular or extracellular sources, is receptor mediated stimulation of phosphatidyl-inositol, (PI) metabolism. We used the stable TxA - mimetic [9,ll-epoxymethano-PGH2, (U44069)] and selective TxA antagonists, 2 2 EP045 and trimethoquinol, to examine the role of PI turnover in TxA -induced platelet activation. Plasma free suspensions of washed human platelets were prelabelled with [ P]- orthophosphate and resuspended in fresh buffer. Aliguots (0.4 ml) plus or minus antagonist were then stimulated with U44069. Phospholipids were extracted and analysed by two dimensional thin layer chromatography. U44069 (10 nM - 3 uM) markedly stimulates PI turnover as indicated by the formation of [ p]-phosphatidic acid (PA). The TxA receptor antagonists EP045 (0.3 - 3 uM) and trimethoquinol (1 - 30 uM) inhibit U44069-induced formation of [ P]-PA. These results indicate that TxA receptor occupancy is coupled to stimulation of PI metabolism in human platelets. The interrelationships between receptor occupancy, PI turnover and Ca availability are currently being investigated. PAF-INDUCED HUMAN PLATELET AGGREGATION IS SELECTIVLEY INHIBITED BY 008 CLASS II AND CLASS III BUT NOT CLASS I CALCIUM "ANTAGONISTS". A.M. Shaw, L.J. Brydon, D.E. Maclntyre. Dept. of Pharmacology, University of Glasgow. Cytosolic free Ca is considered to be the final mediator of platelet functional change. We have shown, using the calcium indicator dye Quin 2, that PAF mobilises 2 2 intracellular Ca ans stimulates an influx of Ca in human platelets. Using citrate PRP prepared from aspirin-treated donors, we examined the effects of calcium "antagonists" on human platelet aggregation (40-70% of maximum) induced by PAF, ADP and lysophosphatidic acid (LPA). Aggregation induced by PAF was inhibited by Verapamil, (class II), (I50 - 25pM) and by Diltiazem (class III), (I50 ~ 5uM). Verapamil and Diltiazem inhibited platelet aggregation induced by ADP and LPA but at higher concen- trations (Verapamil I v ADP = 150 yM ; I v LPA = 150 uM ; Dilthiazem 5 0 5 0 I50 v ADP = 150 yM ; I50 v LPA = 55 viM). Nicardipine (class I) , exhibited no selective inhibition of PAF-induced aggregation and was the least potent inhibitor of aggregation induced by all agonists (I50 > 170 pM in all cases). The selective inhibition by Verapamil and Diltiazem of PAF-induced aggregation could not be attributed to phospho- diesterase inhibition, a-adrenoceptor antagonism or Na channel blockade. These results suggest that PAF-induced platelet activation involves a calcium translocation mechanism sensitive to class II and class III but not class I calcium "antagonists".
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