Effects of the nitric oxide-donor, GEA 3175, on guinea-pig airways.

This investigation characterized the smooth muscle relaxing effect of a novel nitric oxide (NO)-releasing substance, GEA 3175 (1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino], hydroxide inner salt) on guinea-pig trachea. GEA 3175 caused a concentration-dependent relaxation of tracheal smooth muscle precontracted with acetylcholine. This effect was reversed by both okadaic acid, an inhibitor of serine/threonine-specific phosphatases, and iberiotoxin, an inhibitor of Ca2+-activated K+ channels. Furthermore, GEA 3175 had a relaxation potency similar to that of the commonly used NO-donor, S-nitroso-N-acetyl-penicillamine. On the contractile response provoked by electrical field stimulation, GEA 3175 induced a long-lasting relaxation which persisted even after repeated washing. The relaxing effect of GEA 3175 was associated with rises in guanosine 3':5'-cyclic monophosphate (cGMP). In time course studies, cGMP continued to increase with incubation time after stimulation with GEA 3175 and there was a significant elevation of cGMP even after washing. In contrast, incubation with S-nitroso-N-acetyl-penicillamine caused a transient rise in cGMP. The present investigation showed that GEA 3175 evokes long-lasting effects on contractile responses and cGMP levels in guinea-pig trachea. Our results indicate that the relaxing effect of GEA 3175 occurs through a mechanism involving phosphatases and iberiotoxin-sensitive K+ channels.

Influence of tolfenamic acid on airway contractility in guinea pigs.

The effect of the NSAIDs tolfenamic acid and indomethacin was tested on acetylcholine-induced and antigen-induced contractions in guinea pig airways. Indomethacin potentiated antigen-induced contractions while tolfenamic acid showed dilatory properties. The effects of the drugs on acetylcholine-induced contractions showed no significant differences; indomethacin had a slightly increasing tendency while tolfenamic acid reduced the contractile response. These results indicate that tolfenamic acid does not have bronchoconstrictive properties, which is a common side effect of other NSAIDs in asthmatics.

Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers.

Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng x mL(-1). The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.

Pertussis toxin attenuates presynaptic inhibition of cholinergic but not nonadrenergic noncholinergic contraction in guinea pig airways.

Several alpha-2- and opioid receptors exert their intracellular effects via a pertussis toxin-sensitive G protein. Both cholinergic and nonadrenergic noncholinergic nerve-mediated contractions of airways can be reduced by stimulation of presynaptic alpha-2- and opioid receptors. Using guinea pig trachea and bronchi, pretreated with pertussis toxin 100 micrograms/kg or 0.9% NaCl, we investigated whether these inhibitory effects on airway contractions, evoked by electrical field stimulation, are mediated via a pertussis toxin-sensitive G protein. The results indicate a difference between cholinergic and excitatory nonadrenergic non-cholinergic neurotransmission. Inhibition of cholinergic contraction via presynaptic alpha-2- and opioid receptors seems to be mediated via a pertussis toxin-sensitive G protein, whereas inhibition of nonadrenergic noncholinergic contraction is not affected by pertussis toxin.

The modulatory effects of prostaglandins on both excitatory and inhibitory non-adrenergic non-cholinergic neurotransmission in guinea-pig airways.

Guinea-pig trachea and bronchi were used to investigate the effects of indomethacin and prostaglandin E2 (PGE2) on non-adrenergic non-cholinergic excitatory (e-NANC) and inhibitory (i-NANC) neurotransmission evoked by electrical field stimulation. Indomethacin potentiated e-NANC responses in bronchi with intact epithelium but had no effect on epithelium-denuded preparations. Inhibitory NANC responses were increased by indomethacin independent of the epithelium. Both i-NANC and e-NANC neurotransmission were suppressed by PGE2 in a dose-dependent manner. These results indicate that endogenous prostaglandins (e.g. PGE2) generated from the epithelium have an inhibitory effect on i-NANC and e-NANC nerve responses in airways. The epithelium is presumably not the only source for generation of prostaglandins that are involved in i-NANC neurotransmission.