Summary
Systemic administration of synthetic PAF produces a number of dose-dependent circulatory
effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441,
for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate.
In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean ± 1 S.D.) 39 ± 5% decrease in carotid blood pressure.
Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent
manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 ± 8% increase in hematocrit and a 50 ± 11% elevation in bronchial resistance.
The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012
mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 μg kg-1 PAF i.v. exhibited 28.7 ±6.5% increase in hematocrit 10 min after injection. The
ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to
3.5 pg kg-1 i.v. PAF with a 30 ± 6% increase in hematocrit. Using the primates in a cross-over
design, the ED50 OF SRI 63-441 WAS 0.11 MG KG 1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is ∼1:25. The effectiveness of SRI 63-441 in these models suggest potential
clinical applications in disease states involving hyperpermeability and pulmonary
dysfunction.
Keywords
Platelet - activating factor - Guinea pig - Rat - Dog - Primate - Hemoconcentration
- Vascular permeability - Receptor antagonist
