Antagonism of Antigen-Induced Contraction of Isolated Guinea-Pig Trachea by 5-Lipoxygenase Inhibitors

Abstract

Tracheal strips were obtained from guinea pigs actively sensitized to chicken ovaibumin (OA). OA-induced contractile responses, obtained by cumulative log addition, were found to be comparable both temporally and in magnitude with responses obtained by single addition of OA. The concentration-response curve obtained by cumulative addition of OA was partially inhibited by pretreatment of tissues with chlorpheniramine. On tracheal spirals treated with chlorpheniramine, indomethacin enhanced OA-induced contractile responses. In the presence of chlorpheniramine and indomethacin, pretreatment with one of the reference 5-lipoxygenase inhibitors (ETYA, NDGA, phenidone or BW-755C) both reduced the maximum contractile response and produced a rightward shift of the OA concentration-response curve. The data suggest that cumulative log addition of OA, on the indomethacin- and chlorpheniramine-treated guinea-pig trachea, is a useful model for evaluating compounds active as either inhibitors of 5-lipoxygenase or antagonists of the products of this pathway.

Antigen‐induced contraction of guinea‐pig isolated trachea: studies with novel inhibitors and antagonists of arachidonic acid metabolites

“…It is known from previous studies that multiple mediators are released following antigen challenge of this tissue (Adams & Lichtenstein, 1979;Hand & Buckner, 1979). Moreover, the method of sensitization (Andersson, 1980), the type of immunological response (Regal, 1984), the dose of antigen (Hand et al, 1986), the presence or absence of additional blocking drugs (Hand et al, 1986) can influence the relative contributions made by these various mediators. Our assay conditions were standardized in terms of the sensitization procedure, the dose of antigen in vivo and in vitro and the inclusion of additional pharmacological blocking drugs.…”

“…Most studies concur that contractile responses are the result of the collective actions and interactions of released histamine and arachidonic acid metabolites generated via the 5-lipoxygenase (leukotrienes C4, D4 and E4) and cyclo-oxygenase (prostaglandins, endoperoxide and thromboxane) enzyme systems (Adams & Lichtenstein, 1979;Hand & Buckner, 1979;Burka & Paterson, 1980;Burka & Paterson, 1981b;Hand et al, 1986). A major role for 5lipoxygenase products in the mediation of the response has been postulated based on pharmacological studies with FPL-55712 and some relatively weak 5-lipoxygenase inhibitors (Adams & Lichtenstein, 1979;Hand & Buckner, 1979;Burka & Paterson, 1980;Hand et al, 1986). Moreover, this component of the response in central airway preparations is potentiated by cyclo-oxygenase inhibitors, suggesting an interaction between prostanoids and leukotriene production and/or actions.…”

“…this response have been the subject of extensive biochemical and pharmacological investigation over the years (Chand & Eyre, 1978;Adams & Lichtenstein, 1979;Hand & Buckner, 1979;Burka & Paterson, 1980;1981ab;Saad et al, 1983;De Nucci et al, 1986). Conclusions about the precise contribution of various mediators to the contractile response vary depending on the species studied (Dunlop & Smith, 1975;Dunlop et al, 1977;Dahlen et al, 1983;Jones et al, 1987), the type of antibody mediating the response (Andersson, 1980;Regal, 1984;Undem et al, 1985) the nature of the experiment (biochemical or functional response) and the experimental conditions such as the presence or absence of additional blocking drugs (Hand et al, 1986).…”

“…A major role for 5-lipoxygenase products in the mediation of the response has been postulated based on pharmacological studies with FPL-55712 and some relatively weak 5-lipoxygenase inhibitors (Adams & Lichtenstein, 1979;Hand & Buckner, 1979;Burka & Paterson, 1980;Hand et al, 1986). Moreover, this component of the response in central airway preparations is potentiated by cyclo-oxygenase inhibitors, suggesting an interaction between prostanoids and leukotriene production and/or actions.…”

The inhibition of 5-lipoxygenase by RG 6866

“…The pretreatment pharmacology was designed to eliminate the deleterious effects of histamine as well as to potentiate the de novo production ofleukotrienes in this species. In both models, the inclusion of indomethacin is thought to shunt the metabolism of arachidonic acid from the cyclooxygenase to the 5-LOX pathways [18]. The administration of an H a blocker in both models is necessitated by the extreme sensitivity of guinea pigs to histamine [19,20].…”