Platelet-activating factor (PAF) inhibitory profile of KO-286011 on blood platelets in vitro and in vivo.
A newly synthesised structural analogue of PAF, coded KO-286011 (1-O-hexadecyl-2-O-ethyl-rac-glycero-3-phosphoric acid 4-(N,N-dimethylamino)pyridinium butylester), was proved for its ability to inhibit PAF-mediated platelet responses in vitro and in vivo. The compound inhibited effectively the PAF-induced aggregation and secretion of human and rabbit platelets. In contrast, there was little influence on ADP-, collagen-, and arachidonic acid-triggered platelet responses. Schild-analysis of aggregation data ascertained in human platelet-rich plasma was consistent with a simple competitive antagonism and yielded a pA2 of 6.44. Proaggregatory activity of KO-286011 was excluded turbidimetrically as well as by means of a single cell counting technique. [3H]PAF binding studies provided evidence that KO-286011 exerts its inhibitory action at the PAF-receptor level. A significant inhibition of the ex vivo PAF-induced platelet aggregation was found after i.v. administration of 0.5 mg/kg KO-286011 to rabbits. The effect was most pronounced 5 min after dosing the inhibitor and detectable over a period of 30 min. Intravenous administration of 10 and 25 micrograms/kg KO-286011 to guinea pigs prevented dose-dependently the PAF-induced formation of thromboxane A2. The PAF-inhibitory action of KO-286011 was more potent than that of the ginkgolide BN 52021.
Ostermann
G
G
Institute für Pathologische Biochemie, Medizinische Akademie Erfurt, Federal Republic of Germany.
Hofmann
B
B
Kertscher
H P
HP
Till
U
U
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D046934:Ginkgolides; D006168:Guinea Pigs; D006801:Humans; D007275:Injections, Intravenous; D007783:Lactones / Q000494:pharmacology; D008297:Male; D010742:Phospholipid Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; C069064:KO 286011; D012701:Serotonin; D013929:Thromboxane B2; C045856:ginkgolide B