The effect of Ro 21-7634 on the antigen-induced production of bronchoconstrictive arachidonic acid metabolites in the guinea pig lung.
Ro 21-7634 has previously been shown to inhibit histamine and SRS-A release from actively-sensitized guinea pig lung fragments upon antigen challenge. In the studies described herein, it was observed that Ro 21-7634 does not decrease SRS-A release but instead acts to inhibit the synthesis of this mediator. This was confirmed by studying SRS-A synthesis in vitro in rat peritoneal cells after challenge with ionophore A23187. In the peritoneal cell system, Ro 21-7634 exhibited an IC50 of 500 microM, in comparison with 5.8,11,14-eicosatetraynoic acid, phenidone and BW755C (IC50's of 2, 100, and 100 microM, respectively). When studied at 10(-4) and 10(-3) M in perfused guinea pig lung, Ro 21-7634 inhibited antigen-induced thromboxane A2 production by 68 and 96%, respectively. In this system, antigen is believed to induce thromboxane A2 production through the release of histamine and SRS-A from lung tissue. These mediators then interact at receptor sites in the lung parenchyma to induce thromboxane A2 synthesis. Ro 21-7634 could thus be inhibiting thromboxane A2 production by preventing the release of histamine and synthesis of SRS-A in the perfused lung system. Such a mechanism is suggested by the fact that although Ro 21-7634 was effective in inhibiting antigen-induced thromboxane production, it was ineffective in inhibiting thromboxane A2 production induced in the guinea pig lung system by the direct perfusion of histamine or SRS-A through the lung.
D000403:Airway Resistance; D000707:Anaphylaxis / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001202:Ascitic Fluid / Q000166:cytology; D000001:Calcimycin / Q000494:pharmacology; D006168:Guinea Pigs; D008168:Lung / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D013189:SRS-A / Q000096:biosynthesis*; D013931:Thromboxanes / Q000096:biosynthesis
D001095:Arachidonic Acids; D011799:Quinazolines; D013189:SRS-A; D013931:Thromboxanes; D016718:Arachidonic Acid; D000001:Calcimycin; C023625:2-methoxy-11-oxo-11H-pyrido(2,1-b)quinazoline-8-carboxylic acid