The relaxing effects of the nitric oxide (NO) donors 1,2,3,4-oxatriazolium,3-(3-chloro-2-methylphenyl-5-[[(4-methoxyphe nyl) sulfonyl]amino]-,hydroxide inner salt (GEA 3268) 1,2,3,4-oxatriazolium,3-(3-chloro-2-methyphenyl-5-[methys ulfonyl)amino]- hydroxide inner salt (GEA 5145), 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) were inhibited in vitro by iberiotoxin (IbTX) and charybdotoxin (ChTX), the two selective inhibitors of Ca(++)-activated K+ channels (KCa) in guinea pig trachea. When studied in cumulative concentrations in metacholine constriction, the relaxing effects of the NO donors were inhibited by at least 70% in the presence of the toxins, with the exception of SIN-1 in the presence of ChTX. The inhibitory effect of ChTX was less marked than that of IbTX. This suggests that the relaxing effects of the structurally different NO donors are mediated through KCa channels and that IbTX is more potent than ChTX. A selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one (ODQ), significantly inhibited the relaxing effects of GEA 3268 and GEA 5145 on metacholine and KCl constriction and almost totally inhibited the relaxing effects of SIN-1 and SNAP. The inhibitor of the delayed rectifier K+ channel current 4-aminopyridine did not influence the relaxations of the NO donors, and under the experimental conditions of this study, the ATP-sensitive K+ channel inhibitor glibenclamide had no effect. In conclusion, the relaxing effects of the structurally different NO-releasing compounds are mediated via KCa channels. However, the significance of some other possible mechanisms unrelated to K+ channels cannot be excluded.

1996-12-01·Journal of Pharmacy and Pharmacology3区 · 医学

In-vitro Bronchorelaxing Effects of Novel Nitric Oxide Donors GEA 3268 and GEA 5145 in Guinea-pigs and Rats

3区 · 医学

Article

作者: Vapaatalo, Heikki ; Li, Liang ; Redemann, Beatrix ; Vaali, Kirsi ; Paakkari, Ilari

AbstractEndogenously released nitric oxide (NO) in airways might contribute to physiological bronchodilation; induced production of NO might play a role in the pathogenesis of asthma, although it could also be a compensatory mechanism to other factors that cause bronchoconstriction or inflammation. To investigate the efficacy of NO donors on bronchial tone, the bronchorelaxing efficacies of NO donors, new experimental GEA compounds 3268 and 5145 (oxatriazole sulphonylamides) were compared with those of sodium nitroprusside and SIN-1 (3-morpholinosydnonimine) and to the standard β2-adrenergic agonist, salbutamol, in bronchi of guinea-pigs and rats in-vitro. Their relaxing effects were also studied in rat mesentery arteries to compare the selectivity for airways. The capacity of the NO donors to produce nitrites and nitrates was assayed by the Griess reaction.The novel NO donors GEA 3268 and GEA 5145 were more potent bronchorelaxing agents than the old NO donors sodium nitroprusside and SIN-1. In guinea-pig bronchi, however, salbutamol was most potent. In rat bronchi the GEA compounds induced the strongest relaxation effect when compared with the old NO donors or with salbutamol. The airway selectivity of the drugs studied decreased in the order of salbutamol, SIN-1, GEA 5145, GEA 3268, sodium nitroprusside. The nitrites and nitrates produced spontaneously did not correlate with the efficacy of the relaxantsThe results obtained suggest that NO is only partly responsible for the relaxation and the potency is dependent on the animal species and constricting agents used.

100 项与 GEA-5145 相关的药物交易

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