PAF, rather than Histamine, Participates in Mouse Anaphylactic Hypotension

Abstract

We determined the roles of platelet-activating factor (PAF) and histamine in anaphylactic hypotension in ovalbumin-sensitized anesthetized BALB/c mice. The effects of PAF and histamine on hemodynamic variables were studied by measuring the systemic arterial (Psa), portal venous (Ppv) and central venous (Pcv) pressures. Intravenous PAF evoked a biphasic Psa response, an initial rapid and transient drop followed by marked hypotension, accompanied by a decrease in Pcv. Histamine caused only mild systemic hypotension. Both agents similarly increased Ppv by approximately 4 cm H₂O at high doses. After an injection of antigen, Psa initially increased slightly and then decreased from the baseline of 94 ± 1 mm Hg to 46 ± 1 mm Hg at 10 min after antigen administration, with Pcv decreasing by 2.5 cm H₂O. Ppv increased by 3.5 cm H₂O at 5 min after antigen injection. Pretreatment with either CV-6209 (PAF receptor antagonist, 1 mg/kg) or diphenhydramine (histamine H₁ receptor antagonist, 20 mg/kg) significantly attenuated an antigen-induced decrease in Psa. The inhibitory action of CV-6209 was greater than that of diphenhydramine, and the combination of these 2 antagonists almost completely inhibited the anaphylactic hypotension. In contrast, the antigen-induced increase in Ppv was attenuated by CV-6209 alone but augmented by diphenhydramine. It is concluded that anaphylactic hypotension is mainly mediated by PAF and, to a lesser extent, by histamine in anesthetized BALB/c mice.

Effects of Antihistamines on Innate Immune Responses to Severe Bacterial Infection in Mice

“…For oral treatment with antihistamines, mice received diphenhydramine (first-generation H1R antagonist, 20 mg/kg body weight per day; Sigma), desloratadine (second-generation H1R antagonist 20 mg/kg body weight per day; Essex Pharma, Munich, Germany), cimetidine (H2R antagonist, 100 mg/kg; Sigma), thioperamide (H3R/H4R antagonist, 20 mg/kg; Sigma) or vehicle based on previously reported doses [8,9,10] 10 days before and for 5 days after cecal ligation and puncture (CLP). All drugs were dispersed in 200-ml water bottles, and mice were allowed to drink freely.…”

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

“…28,31,39,40 Serum PAF levels correlate with the severity of anaphylaxis in human subjects and mouse models. 31,41 It is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, Kupffer cells, endothelial cells, neutrophils, and spermatozoa, 31,39,42,43 and has been found to be active at concentrations as low as 10 212 mol/L, 5 despite its short half-life.…”

“…39,41,42 In mice PAF has been shown to activate and induce degranulation of mouse eosinophils. 44 PAF signaling results from its binding to the PAFR rather than to direct physicochemical effects on the target cell.…”

Mast cell modulation of the vascular and lymphatic endothelium

“…In another example of interaction between multiple MC mediators, combined PAF and H1 inhibition almost completely abolished the hypotension seen in passive systemic anaphylaxis. 100 Recent evidence that PAF also can induce MC degranulation has suggested that PAF may act in an autocrine fashion to augment local or systemic MC degranulation responses. 101 MCs are an important source of cytokines during inflammatory responses.…”