Regulation of canine mucus secretion by a novel leukotriene synthesis inhibitor (U-60,257).

A novel leukotriene synthesis inhibitor, piriprost (U-60,257) was characterized in three quantitated assays of secretion in the canine in vivo trachea. The normal baseline secretion rate was inhibited in a dose-related fashion when the inhibitor was given via the cranial thyroid artery (decrease compared to control dogs: 27 +/- 3.11% at 0.1 mg, n = 3, p less than 0.05; 56 +/- 4.85% at 0.5 mg, n = 3, p less than 0.01; 61.5 +/- 6.8% at 1.0 mg, n = 14, p less than 0.001). Hypoxia gas mixtures (8% O2 and 92% N2 4 min) delivered into the lung caused a mean increase in secretion of 160 +/- 11.2% (p less than 0.05). When the leukotriene inhibitor (1.0 mg) was given into the close arterial segment before hypoxia, this increased secretion response was blocked (160 +/- 11.2 to 40 +/- 16.7%; p less than 0.05). Finally, arachidonic acid caused a potent and long-lasting enhancement in secretion (179 +/- 9.0% of control; p less than 0.01) that was partially blocked by 5 mg/kg indomethacin 30 min before (90 +/- 12.7% of arachidonic acid; p less than 0.01), and when 1.0 mg U-60,257 preceded the arachidonic acid, an additional inhibition of 50% of the indomethacin inhibition was seen (p less than 0.01; n = 14). These findings are consistent with the hypothesis that canine secretion is modulated by arachidonic acid metabolites that act as agonists for secretion both by the cyclooxygenase and lipoxygenase pathways.