Platelet activating factor-induced ischemic bowel necrosis: The effect of PAF antagonists

We have reported a model of ischemic bowel necrosis produced in the rat by injecting platelet activating factor (PAF) or PAF with bacterial endotoxin (LPS) into the mesenteric vasculature. In the present study, we examined the protecting effects of three PAF antagonists, i.e. (R,S)-3-[2-[(2-octadecylaminocarbonyloxymethyltetrahydro-2-furanylmethoxy)-hydroxyphosphinyloxyl]-ethyl--thiazolium hydroxide inner salt 4-oxide (SRI 63-072), (±)-3-[4-[3- octadecylaminocarbonyloxy-2- methoxy)- propoxy]- butyl-]thiazolium bromide (SRI 63-119) and 1-O-hexadecyl-2RS-O-ethyl-3-O-(7-thiazolinoheptyl)-glycerol-methanesulfonate (ONO-6240), on PAF-induced bowel necrosis. The antagonists were injected into the vein 10 min before PAF. Two microgram of PAF or 20 μg LPS with 1 μg of PAF were injected into the aorta above the renal arteries. The parameters assessed included blood pressure, hematocrit, white blood cell count, extent of bowel perfusion and microscopic changes of the bowel. We found that SRI 63-072 (3 mg/kg), SRI 63-119 (3 mg/kg) and ONO-6240 (2 mg/kg) significantly improved the initial hypotension, hemoconcentration and leukopenia caused by PAF. All three drugs also corrected the sustained hypotension and hypoperfusion and gross lesions of the bowel, although microscopic examination still revealed focal mild lesions. SRI 63-072 was also active at a much lower dose (0.3 mg/kg).