Inhibition of the Platelet Activating Factor Mediated Component of Guinea Pig Anaphylaxis by Receptor Antagonists

Abstract

The role of platelet activating factor (PAF) and its inhibition by specific receptor antagonists was studied in hypersensitivity reactions in guinea pig lung parenchymal strips and in guinea pigs in vivo. Immunological challenge of isolated lung parenchymal strips with ovalbumin resulted in a contractile response of 184 ± 16 mg (n = 38). Pretreatment of the strips with a combination of the antihistamine diphenhydramine, the dual lipoxygenase and cyclooxygenase product synthesis inhibitor BW-755C, and the PAF receptor antagonist kadsurenone totally inhibited the increase in tension. The bronchoconstrictor effects induced by immunological challenge were also totally inhibited when the leukotriene receptor antagonist FPL-55,712 was used to replace BW-755C or another PAF receptor antagonist, alprazolam was used to replace kadsurenone. Ovalbumin challenge in sensitized guinea pigs in vivo resulted in airway constriction, circulatory failure and an abrupt fall in continuously measured platelet count by 75 ± 12%, followed by death of all animals within 5–8 min. Pretreatment with diphenhydramine, BW-755C and kadsurenone (or alprazolam) improved survival to 64% (i.e., 7 of 11 animals) compared to a survival rate of 0% (i.e., 0 of 8 vehicle treated controls). Despite the improved survival, the severe thrombocytopenia was unaltered with the combined therapy. PAF, histamine and peptide leukotrienes appear to act in concert in mediating the anaphylaxis-induced airway constriction and circulatory failure in guinea pigs, but are not apparently responsible for the accompanying thrombocytopenia.

Hetrazepines as antagonists of platelet activating factor

“…However, PAF is not the only mediator involved as the PAF antagonist alprazolam when given alone failed to block the anaphylactic response; histamine seems to be the predominant mediator of the very early phase [110,111].…”

“…HETRAZEPINES AS PAF ANTAGONISTS were immunologically challenged with ovalbumin, the hetrazepine-related PAF antagonist alprazolam was reported by Darius et al [110,111] to antagonize the contractile response to ovalbumin in the presence of an antihistamine and the dual lipoxygenase and cyclooxygenase inhibitor BW 755C or the leukotriene receptor antagonist FPL 55712. However, PAF is not the only mediator involved as the PAF antagonist alprazolam when given alone failed to block the anaphylactic response; histamine seems to be the predominant mediator of the very early phase [110,111].…”

Anaphylactic shock depends on PI3K and eNOS-derived NO

“…Although PAF was originally named after its ability to induce platelet aggregation, it stimulates a broad range of cell types and tissues by binding to a unique G protein-coupled 7 transmembrane receptor (PAF-R), activating a number of signaling pathways, including those that elevate intracellular calcium content and activate phospholipase A2 (PLA2) and PI3K (4). As PAF antagonists or PAF-R deficiency can prevent fatal anaphylaxis in animal models, PAF is thought to be a critical factor in the development of anaphylactic shock (5)(6)(7)(8)(9). In addition, PAF is known to contribute to hypotension and cardiac dysfunctions during hemorrhagic, traumatic, or septic shock (4).…”

Anaphylactic death: the effect of aminoguanidine and heparin on histamine and stress hormones in guinea pigs

“…The survival rate for guinea pigs immunized and challenged with ovalbumin was improved from 0 to 64% by pretreatment with a combination of diphenhydramine, BW-755C (a cyclo-oxygenase and lipoxygenase synthesis inhibitor) and a PAF receptor antagonist, either kadsurerone or alphrazolam [13], which support the role of several mediators in the mechanism of anaphylactic shock.…”