Effects of the methyl xanthine S 9795 on isolated bronchi of the dog.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Busk
M F
MF
Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
Flavahan
N A
NA
Vanhoutte
P M
PM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology*; D046508:Culture Techniques; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D008297:Male; D009411:Nerve Endings / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
D001993:Bronchodilator Agents; D014970:Xanthines; C055633:S 9795; D009569:Nitric Oxide; D000109:Acetylcholine; D009638:Norepinephrine