Activity of the new and specific PAF-antagonists WEB 2170 and STY 2108 on PAF-induced bronchoconstriction and intrathoracic accumulation of platelets in the guinea-pig

Hetrazepines as antagonists of platelet activating factor

“…prevents immediate death (early histamine-predominated component) thereby disclosing the following (PAF predominated) component characterized by a remaining severe anaphylactic bronchoconstriction which can be attenuated by WEB 2086 in a dose-dependent manner [110,111]. In line with these results is the action of another hetrazepine, WEB 2170 [68], to counteract antigen-induced anaphylactic bronchoconstriction in actively sensitized guinea pigs [ 1181. When actively sensitized guinea pigs (sensitized by a modification of the method described by Andersson) were challenged by 100 mg/kg ovalbumin i.v.…”

“…On the other hand, WEB 2086 has been shown to counteract PAF-induced platelet aggregation competitively, since Schild plot slopes were not significantly different from unity and WEB 2086 shifted PAF-induced aggregation to the right in a parallel and concentration-dependent manner using platelets from various sources [51, 61,63,66]. Also for WEB 2170 (Ida), specific inhibition of PAF-induced platelet aggregation, at least at the same magnitude as for WEB 2086 has been shown (ICso values 0.3 and 0.03 pM, respectively) [39,68,69]. The same is true for the competition of…”

“…Because, particularly in the latter study, decrease of mean arterial pressure (MAP) was also slowed by WEB 2086, this points to a good systemic absorption from the lung when this antagonist was inhaled When bronchoconstriction in the guinea pig is caused by a bolus of PAF at 100 ng/kg intravenously, all the changes in pulmonary function associated with severe bronchoconstriction occur. Oral (60 min before PAF) and intravenous (10 min before PAF) pretreatment with PAF antagonists WEB 2086, WEB 2170 [68,90], and STY 2108 [68,90] opposed the bronchoconstriction as [361.…”

“…Peroral (60 min prior to PAF) or intravenous (10 min prior to PAF) pretreatment with the hetrazepine-related triazolam [25,26] [68], and other hetrazepines prevented these effects in a dose-dependent manner. In Figure 5, the results are exemplified by the PAF antagonist STY 2108 [68].…”

“…Continuous intravenous administrution of PAF at 30 ng x kg-l x min-' in guinea pigs prepared as described in Ref. 36 produced a continuous decrease of respiratory flow, mean arterial blood pressure, and intrathoracic accumulation of '"Indium-labeled platelets which ended with death at about 15-20 rnin after the start of PAF infusion [ 25, 26,36,68,90].…”