title: Trachea relaxing effects and beta2-selectivity of SPFF, a newly developed bronchodilating agent, in guinea pigs and rabbits.
abstract: 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 beta(2) adrenergic agonist in guinea pigs and rabbits, in comparison with other beta(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 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 (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 beta(2) adrenoceptor because this effect was easily antagonized by ICI-118551 (pA(2) 8.90+/-0.01), a specific beta(2) adrenoceptor antagonist. SPFF also dose-dependently relaxed the isolated guinea pig trachea strip precontraction with acetylcholine or histamine with ED(50) values of 10.2+/-0.7 microM 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 beta(2) adrenoceptor than isoprenaline; the beta(1)/beta(2) selectivity assay also showed that SPFF was about 162 times more selective to beta(2) adrenoceptor than isoprenaline. A radioligand binding experiment using guinea pig lung and cardiac ventricle as beta(2) and beta(1) adrenoceptor sources, respectively, also demonstrated that SPFF possesses high affinity (27.3 nM) and selectivity (4.6 fold) to beta(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 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 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 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 beta(2) adrenoceptor selectivity.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, China. gll206@sina.com
authors.forename: Le-Ling
authors.initials: LL
authors.lastname: Gan
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Wang
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Cheng
authors.forename: Li
authors.initials: L
authors.lastname: Pan
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000737:chemistry / Q000494:pharmacology*; D002082:Butylamines / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay / Q000379:methods; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: C477926:2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol chloride; D000085:Acetates; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001993:Bronchodilator Agents; D002082:Butylamines; D002712:Chlorides; D011412:Propanolamines; C026777:ICI 118551; D006632:Histamine; D007545:Isoproterenol; C081124:acetyl chloride; D000420:Albuterol