Biological properties of the antagonist SRI 63-441 in the PAF and endotoxin models of hypotension in the rat and dog.

Abstract

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.

• Authors: D A Handley, R G Van Valen, J C Tomesch, M K Melden, J M Jaffe, F H Ballard, R N Saunders
• Journal: Immunopharmacology (Immunopharmacology) Vol. 13 Issue 2 Pg. 125-32 (Apr 1987) ISSN: 0162-3109 [Print] Netherlands
• PMID: 3597060 (Publication Type: Journal Article)

Chemical References

• Endotoxins
• Platelet Activating Factor
• Quinolinium Compounds
• SRI 63-441

Topics

• Animals
• Blood Pressure (drug effects)
• Dogs
• Endotoxins (antagonists & inhibitors)
• Feces (analysis)
• Male
• Platelet Activating Factor (antagonists & inhibitors)
• Quinolinium Compounds (metabolism, pharmacology)
• Rats
• Rats, Inbred Strains