Trachea Relaxing Effects and β_2-Selectivity of SPFF, a Newly Developed Bronchodilating Agent, in Guinea Pigs and Rabbits

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概要

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• In this paper we evaluated the bronchodilator effects of SPFF |2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-fert-butylamino-ethanol chloride|, a newly synthesized β_2 adrenergic agonist in guinea pigs and rabbits, in comparison with other β_2 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 preeontraction 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 (Pd_2, Pa_2 or ED_50) 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 Pd_2 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 β_2 adrenoceptor because this effect was easily antagonized by IC'I-118551 (Pa_2 8.90±0.01), a specific β_2 adrenoceptor antagonist. SPFF also dose-dependently relaxed the isolated guinea pig trachea strip preeontraction with acetycholinc or histaminc with ED_50 values of 10.2±0.7μM and 550±38.2 Nm, respectively. Furthermore, the positive chronotropic effect of SPFF on isolated guinea pig left atria (Pd_2 5.41±0.38) was much weaker than that of isoprenaline (Pd_2 8.75±0.24), which implied that SPFF was more selective to airway β_2 adrenoceptor than isoprenaline ; the β_1β_2 selectivity assay also showed that SPFF was about 162 times more selective to β_2 adrenoceptor than isoprenaline. A radioligand binding experiment using guinea pig lung and cardiac ventricle as β_2 and β_1 adrenoceptor sources, respectively, also demonstrated that SPFF possesses high affinity (27.3 Nm) and selectivity (4.6 fold) to β_2 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 Rossler 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 ED_50 value of SPFF I. G. was 0.32±0.05 mg・kg^1 in this experiment. Meanwhile, the ED_50 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 Rossler 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 β_2 adrenoceptor selectivity.

• 公益社団法人日本薬学会の論文
• 2003-03-01

著者

• Wang Min-wei

  Department Of Pharmacology Shenyang Pharmaceutical University School Of Pharmacy

• Wang M‐w

  Shenyang Pharmaceutical Univ. Liaoning Province Chn

• GAN Le-Ling

  Department of Pharmacology, Shenyang Pharmaceutical University

• CHENG Mao-Sheng

  Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University

• PAN Li

  Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University

• Pan Li

  Department Of Pharmaceutical Engineering Shenyang Pharmaceutical University

• Gan Le-ling

  Department Of Pharmacology Shenyang Pharmaceutical University

• Cheng Mao-sheng

  Department Of Pharmaceutical Engineering Shenyang Pharmaceutical University

• Wang Min-wei

  Department Of Pharmacology Shen Yang Pharmaceutic University

• Cheng Mao-sheng

  Dep. Of Pharmaceutical Engineering Shenyang Pharmaceutical Univ.

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