RESUMO
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.
Assuntos
Músculo Liso/efeitos dos fármacos , Óxido Nítrico/biossíntese , Traqueia/efeitos dos fármacos , Triazóis/farmacologia , Acetilcolina/farmacologia , Animais , GMP Cíclico/metabolismo , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Cobaias , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Ácido Okadáico/farmacologia , Peptídeos/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Bloqueadores dos Canais de Potássio , Traqueia/fisiologiaRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Broncoconstrição/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Adolescente , Animais , Cricetinae , Cobaias , Humanos , Indometacina/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
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.
Assuntos
Dinoprostona/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Acetilcolina/fisiologia , Animais , Brônquios/efeitos dos fármacos , Brônquios/inervação , Estimulação Elétrica , Cobaias , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/inervação , Transmissão Sináptica/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/inervaçãoRESUMO
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.