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.