On the inhibition of prostanoid formation by SK&F 96365, a blocker of receptor-operated calcium entry.
1. The proposed blocker of receptor-operated calcium channels, SK&F 96365 was shown to inhibit formation of prostaglandin E2 in two osteoblast-like cell lines, MC3T3-E1 and UMR-106 in a dose-dependent manner at an IC50 of 3-4 microM. Inhibition was observed with various stimuli (arachidonic acid, bradykinin and calcium ionophore A23187). 2. This effect was also observed in human platelets, where SK&F 96365 dose-dependently blocked thromboxane biosynthesis and formation of 12-hydroxy-heptadecatrienoic acid after stimulation with arachidonic acid (IC50 = 4 microM). 3. The compound had no effect on 12-hydroxy-eicosatetraenoic acid production by human platelets. Additionally, linoleic acid oxidation by soybean 15-lipoxidase was not impaired by SK&F 96365. The results thus provide evidence for cyclo-oxygenase inhibition by SK&F 96365 at concentrations used to block receptor-operated calcium influx.
Leis
H J
HJ
Dept. of Biochemical Analysis, Univ. Childrens Hospital, Graz, Austria.
Zach
D
D
Huber
E
E
Ziermann
L
L
Gleispach
H
H
Windischhofer
W
W
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology*; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D013931:Thromboxanes / Q000037:antagonists & inhibitors
D002121:Calcium Channel Blockers; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D008041:Linoleic Acids; D013931:Thromboxanes; D016718:Arachidonic Acid; D000001:Calcimycin; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D019787:Linoleic Acid; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D015232:Dinoprostone; D001920:Bradykinin