Platelet-activating factor receptor antagonist attenuates endotoxin-induced vascular hyporeactivity in the pithed rat.
The role of platelet activating factor (PAF) and nitric oxide (NO) in the endotoxin-induced hyporeactivity to noradrenaline was studied in the pithed rat. Pressor dose-response curves to noradrenaline (0.01-10 microg/kg, i.v.) were made starting 1 h after the administration of endotoxin (0.5 mg/kg, i.v.) to the rats. Saline was administered to the control rats. The PAF receptor antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbon yloxy)ethyl]carbamoyl]ethy]carbamoyl]-1-propylpyridinium nitrate, 100 microg/kg, i.v.), or the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 30 mg/kg, i.v.), was administered to the endotoxin-treated rats 20 or 10 min before the noradrenaline challenge. L-NMMA reversed endotoxin-induced hyporeactivity completely. TCV-309 produced a significant, but partial attenuation of the hyporeactivity to noradrenaline (P < 0.01). There was still significant hyporeactivity when compared with the control rats (P < 0.01) and the L-NMMA-treated endotoxin-administered rats (P < 0.05). These data suggest that endogenous PAF contributes to the vascular hyporeactivity to noradrenaline induced by endotoxin and that NO plays a major role in the endotoxin-induced hyporeactivity.
Yoshikawa
D
D
Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, Maebashi, Japan.
Shiga
T
T
Saito
S
S
Morita
T
T
Imai
T
T
Goto
F
F
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D003655:Decerebrate State; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D044005:Tetrahydroisoquinolines; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004731:Endotoxins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D044005:Tetrahydroisoquinolines; D014662:Vasoconstrictor Agents; C039351:platelet activating factor receptor; D019323:omega-N-Methylarginine; C044101:endotoxin, Escherichia coli; D019001:Nitric Oxide Synthase; C067430:TCV 309; D009638:Norepinephrine