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标题：Trachea Relaxing Effects and β2-Selectivity of SPFF, a Newly Developed Bronchodilating Agent, in Guinea Pigs and Rabbits
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作者：Le-Ling Gan ; Min-Wei Wang ; Mao-Sheng Cheng 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2003
卷号：26
期号：3
页码：323-328
DOI：10.1248/bpb.26.323
出版社：The Pharmaceutical Society of Japan
摘要：In this paper we evaluated the bronchodilator effects of SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2- tert -butylamino-ethanol chloride], a newly synthesized β₂ adrenergic agonist in guinea pigs and rabbits, in comparison with other β₂ adrenergic agonists, isoprenaline or salbutamol. We studied in vitro the bronchodilator effects of SPFF and isoprenaline on isolated guinea pig trachea strips with or without the precontraction of bronchocontractors (acetylcholine and histamie). The positive chronotropic effects of SPFF and isoprenaline on isolated guinea pig left atria were also tested in vitro . Potency values (pD₂, pA₂ or ED₅₀) were determined from the cumulative concentration–response curves. The results showed that SPFF and isoprenaline dose-dependently relaxed the isolated guinea pig trachea strips and the pD₂ values of both drugs were 7.66±0.68 and 8.79±0.19, respectively. Moreover, we confirmed that the bronchodilator effect of SPFF was due to the activation of β₂ adrenoceptor because this effect was easily antagonized by ICI-118551 (pA₂ 8.90±0.01), a specific β₂ adrenoceptor antagonist. SPFF also dose-dependently relaxed the isolated guinea pig trachea strip precontraction with acetylcholine or histamine with ED₅₀ values of 10.2±0.7 μ M and 550±38.2 n M , respectively. Furthermore, the positive chronotropic effect of SPFF on isolated guinea pig left atria (pD₂ 5.41±0.38) was much weaker than that of isoprenaline (pD₂ 8.75±0.24), which implied that SPFF was more selective to airway β₂ adrenoceptor than isoprenaline; the β₁/β₂ selectivity assay also showed that SPFF was about 162 times more selective to β₂ adrenoceptor than isoprenaline. A radioligand binding experiment using guinea pig lung and cardiac ventricle as β₂ and β₁ adrenoceptor sources, respectively, also demonstrated that SPFF possesses high affinity (27.3 n M ) and selectivity (4.6 fold) to β₂ adrenoceptors. The protective effects of SPFF and salbutamol on bronchospasm induced by bronchoconstrictor aerosol in guinea pigs in vivo were investigated, and the Konzett and Rössler experiment in rabbits in vivo was also carried out. SPFF significantly prolonged the latency time of histamine and acetylcholine induced asphyxiation collapse in guinea pigs: the ED₅₀ value of SPFF i.g. was 0.32±0.05 mg·kg⁻¹ in this experiment. Meanwhile, the ED₅₀ values of salbutamol was 2.37±0.22, which meant that the bronchorelaxation effect of salbutamol was about 6 times less potent than that of SPFF. The Konzett and Rössler experiment performed in anesthetized rabbit showed that intraduodenal administration of SPFF exerted action of longer duration than salbutamol. From the results above we suggested that SPFF was a potent, long-acting bronchodilator with relatively higher β₂ adrenoceptor selectivity.
关键词：β2 adrenergic agonist;bronchodilator effect;receptor selectivity;2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol chloride (SPFF)