Pharmacological actions of PCA 4248, a new platelet-activating factor receptor antagonist: in vivo studies.
The ability of PCA 4248 [2-(phenylthio)ethyl-5-methoxycarbonyl- 2,4,6-trimethyl-1,4-dihydropyridine-3-carboxylate] to block PAF-induced systemic hypotension and protein-rich plasma extravasation in rats, and PAF-induced death in mice, was tested. These studies were complemented with experiments using soluble aggregates of immunoglobulin G (A-IgG), bacterial endotoxin and the cytokine tumor necrosis factor as putative inducers of the generation of endogenous PAF. Significant inhibition of PAF-induced systemic hypotension was observed with i.v. PCA 4248 at doses of 0.3 to 1 mg/kg (IC50 value, 0.45 mg/kg, with PAF 0.33 micrograms/kg). Reversal of the hypotension was rapidly observed when PCA 4248 was administered after PAF. The extravasation induced by 1 microgram/kg PAF was also blocked by PCA 4248 (IC50 value, 0.36 mg/kg). Inhibition of the extravasation induced by A-IgG and endotoxin was also provided by PCA 4248 at the dose of 1 mg/kg, and lasted for at least 1 hr in the experiments carried out with endotoxin, which caused extravasation with a temporal pattern more protracted than that of PAF and A-IgG. Intradermal extravasation induced by PAF reached a maximum at 30 min after injection, and was also inhibited by PCA 4248. In contrast, PCA 4248 caused a less remarkable, but statistically significant reduction of the intradermal extravasation caused by tumor necrosis factor. Pretreatment of mice with an oral dose of 30 mg/kg PCA 4248, 5 min before challenge with PAF (LD84 = 80 micrograms/kg PAF, i.v.) increased the survival rate from 16% to 68%. These data indicate that compounds containing a 1,4-dihydropyridine structure can antagonize PAF effects on experimental animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Fernández-Gallardo
S
S
Instituto de Investigaciones Médicas de la Fundación Jiménez Diaz, Centro Asociado al CSIC, Madrid, Spain.
Ortega
M P
MP
Priego
J G
JG
de Casa-Juana
M F
MF
Sunkel
C
C
Sánchez Crespo
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity; D008297:Male; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004095:Dihydropyridines; D004731:Endotoxins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; C066024:PCA 4248