Effects of the methyl xanthine S 9795 on isolated bronchi of the dog

Abstract

The xanthine derivative 1-methyl 3-isobutyl 8-{2-ethyl[1-(4-diphenylmethyl piperazinyl)]}3, 7-dihydro (1H) purine 2, 6-dione (S 9795) is a potent inhibitor of bronchoconstriction in vivo. The aim of the present study was to analyze the effects of S 9795 in vitro and determine whether S 9795 affects the autonomic nerves, the epithelium or the smooth muscle of the bronchial wall. S 9795 had an inhibitory effect on the contractile responses evoked by acetylcholine and by electrical stimulation of the cholinergic nerves. S 9795 appeared more potent against contractions evoked by nerve stimulation. In addition, S 9795 caused the release of [ 3H]norepinephrine from the adrenergic nerve endings but did not affect neuronal uptake of the catecholamine. At low concentrations, S 9795 acted as a competitive serotonergic antagonist; at higher concentrations, the compound inhibited noncompetitively the contractions evoked by histamine and acetylcholine. In both second and fourth order bronchi, S 9795 (and theophylline) produced concentration-dependent relaxations that were significantly greater in rings with, compared with rings without, epithelium. The compound also facilitated the epithelium-dependent component of the relaxation response to beta-adrenergic activation. These results suggest that S 9795: 1) causes prejunctional inhibition of the release of acetylcholine, 2) evokes the displacement of stored norepinephrine, 3) exerts a differential inhibitory effect on airway contractions induced by various bronchoconstrictors and 4) augments the release or facilitates the effect of the epithelium-derived relaxing factor. These effects could contribute to the bronchodilator effect of the drug.