title: Changes in cytosolic free calcium induced by platelet-activating factor in rabbit platelets: specific inhibition by BN 52021 and structurally related compounds.
abstract: Increases in cytosolic free Ca2+ concentration induced by PAF-acether in rabbit washed platelets were recorded by using the fluorescent Ca2+ indicator Quin 2. In the presence of 1 mM external Ca2+, PAF-acether 2 X 10(-9) M has been found to increase the intracellular level of free calcium from a basal level of 135.0 +/- 26.9 nM to 2.0 +/- 0.7 microM. Pretreatment of platelets with the PAF-acether receptor antagonists BN 52020, BN 52021 or BN 52022 inhibited dose-dependently the PAF-acether-induced fluorescence signal. This activity was specific for PAF-acether, as shown with BN 52021, the most active derivative, which at 3 X 10(-6) M totally abolished PAF-acether effect without modifying thrombin - or calcium ionophore-induced signal. Kadsurenone, another PAF-acether receptor antagonist exhibited similar efficiency as BN 52021 against PAF-acether stimulation. Studied on PAF-induced aggregation of washed rabbit platelets: BN 52020, BN 52021 and BN 52022 exhibited the same potencies for inhibition as on the Quin 2 signal induced by PAF-acether; their activities were BN 52021 greater than BN 52020 greater than BN 52022. The results confirm that these derivatives, which are structurally closely related act at receptor level. The difference in their efficiencies seem to prove that the binding on its receptor site needs a highly defined chemical structure. They could be useful tools for structure-activity relationship studies in order to elucidate the conformation of the PAF-acether binding site.
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002118:Calcium / Q000097:blood*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C045856:ginkgolide B; C035739:Quin2; D002118:Calcium