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)
AuthorsS Fernández-Gallardo, M P Ortega, J G Priego, M F de Casa-Juana, C Sunkel, M Sánchez Crespo
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 255 Issue 1 Pg. 34-9 (Oct 1990) ISSN: 0022-3565 [Print] UNITED STATES
PMID2170626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Dihydropyridines
  • Endotoxins
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Tumor Necrosis Factor-alpha
  • platelet activating factor receptor
  • PCA 4248
  • Animals
  • Blood Pressure (drug effects)
  • Capillary Permeability (drug effects)
  • Dihydropyridines (pharmacology)
  • Endotoxins (toxicity)
  • Male
  • Mice
  • Platelet Activating Factor (antagonists & inhibitors)
  • Platelet Membrane Glycoproteins
  • Rats
  • Rats, Inbred Strains
  • Receptors, Cell Surface (drug effects)
  • Receptors, G-Protein-Coupled
  • Tumor Necrosis Factor-alpha (pharmacology)

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