Antagonism of platelet activating factor-induced chemiluminescence in guinea-pig peritoneal macrophages in differing states of activation.
1. The effects of the platelet activating factor (Paf) antagonists alprazolam, BN 52021, kadsurenone, L 652,731 and SRI 63119 have been studied on Paf-induced chemiluminescence (CL) of guinea-pig, C. parvum-activated peritoneal macrophages in vitro. 2. All antagonists produced a shift to the right in the dose-response curve to Paf (0.001-10 mumol l-1). Schild plots for BN 52021, L 652,731, kadsurenone and SRI 63119 were linear, but only for BN 52021 and kadsurenone did the mean slope not differ significantly from unity. Mean pA2 values for BN 52021 and kadsurenone were 6.60 +/- 0.05 and 6.41 +/- 0.14 (mean + s.e.mean) respectively. Calculation of IC50 values for all antagonists (at 0.1 mumol l-1 Paf) gave an order of potency: L 652731 greater than kadsurenone greater than or equal to BN 52021 greater than alprazolam greater than SRI 63119. 3. When individual pA2 values for BN 52021 and kadsurenone were plotted against the maximal CL response to Paf of cell suspensions in the absence of antagonist (reflecting the degree of activation of the macrophages by the C. parvum), it was found that the affinity of both antagonists for macrophage Paf receptors remained relatively constant irrespective of the activation state of the cells. 4. We conclude that activation of guinea-pig peritoneal macrophages does not account for the increased affinity for macrophage Paf receptors previously observed for kadsurenone. Kadsurenone and BN 52021 presumably bind to a site on Paf receptors which is not affected by the activation process, while alprazolam and SRI 63119 are non-specific antagonists. The reason for the difference between the competitive nature of kadsurenone and its structural analogue L 652,731 is unclear.
Parnham
M J
MJ
Rhône-Poulenc/Nattermann, Cologne Research Centre, F.R.G.
Bittner
C
C
Lambrecht
G
G
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D004224:Diterpenes; D005663:Furans / Q000494:pharmacology; D046934:Ginkgolides; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D017705:Lignans; D008163:Luminescent Measurements; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology
D001572:Benzofurans; D004224:Diterpenes; D005663:Furans; D046934:Ginkgolides; D007783:Lactones; D017705:Lignans; D010972:Platelet Activating Factor; D013844:Thiazoles; C049821:SRI 63119; C044540:kadsurenone; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; C045856:ginkgolide B; D000525:Alprazolam