Article date: July 1996
By: Marta Giral, Dolors Balsa, Rosa Ferrando, Manuel Merlos, Julian Garcia‐Rafanell, Javier Forn, in Volume 118, Issue 5, pages 1223-1231
The effects of the selective and potent novel platelet‐activating factor (PAF) antagonist, UR‐12633 (1‐(3,3‐diphenylpropionyl)‐4‐(3‐pyridylcyanomethyl)piperidine) on several markers of endotoxic shock syndrome were evaluated in rats and mice.
UR‐12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS‐induced sustained hypotension in rats at doses of 0.01 to 1 mg kg−1, i.v. The reference compound WEB‐2086 (1 mg kg−1) also reversed the LPS‐induced hypotension. UR‐12633 (1 mg kg−1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR‐12633 or WEB‐2086.
Pretreatment with 10 mg kg−1, i.v. of either UR‐12633 or WEB‐2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition, respectively), and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition).
Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg−1, i.v. of either UR‐12633 or WEB‐2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited.
UR‐12633, but not WEB‐2086, inhibited the LPS‐induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation.
In a series of nine reference compounds and UR‐12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF‐induced rabbit platelet aggregation or PAF‐induced mortality in mice and the inhibition of LPS‐induced mortality.
In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR‐12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.
The effects of the selective and potent novel platelet‐activating factor (PAF) antagonist, UR‐12633 (1‐(3,3‐diphenylpropionyl)‐4‐(3‐pyridylcyanomethyl)piperidine) on several markers of endotoxic shock syndrome were evaluated in rats and mice.
UR‐12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS‐induced sustained hypotension in rats at doses of 0.01 to 1 mg kg−1, i.v. The reference compound WEB‐2086 (1 mg kg−1) also reversed the LPS‐induced hypotension. UR‐12633 (1 mg kg−1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR‐12633 or WEB‐2086.
Pretreatment with 10 mg kg−1, i.v. of either UR‐12633 or WEB‐2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition, respectively), and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition).
Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg−1, i.v. of either UR‐12633 or WEB‐2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited.
UR‐12633, but not WEB‐2086, inhibited the LPS‐induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation.
In a series of nine reference compounds and UR‐12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF‐induced rabbit platelet aggregation or PAF‐induced mortality in mice and the inhibition of LPS‐induced mortality.
In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR‐12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.
DOI: 10.1111/j.1476-5381.1996.tb15527.x
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