新型异喹啉衍生的β2肾上腺素能受体激动剂BDTI在犬气管和大鼠心脏中的药理学特性

Pharmacological characteristics of BDTI, a new isoquinoline-derived beta 2-adrenoceptor agonist, in canine trachea and rat heart.

作者信息

Lin C H, Yang C M, Chen C M, Ko F N, Teng C M

机构信息

Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, ROC.

出版信息

Pharmacology. 1996 Jul;53(1):19-27. doi: 10.1159/000139411.

DOI:10.1159/000139411

PMID:8875598

Abstract

The tracheal relaxing effects and beta 2-selectivity of BDTI (1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline HBr) were investigated in canine trachea and rat heart by radioligand binding assay and pharmacological experiments in comparison with those of other beta-adrenoceptor agonists, salbutamol and isoprenaline. The potency of relaxing effect on carbachol-induced contraction in isolated canine trachea was in the order of isoprenaline (pD2 = 6.70 +/- 0.08) > BDTI (6.11 +/- 0.06) approximately salbutamol (6.14 +/- 0.08). ICI-118,551 (a selective beta 2-antagonist) and atenolol (a selective beta 1-antagonist) inhibited the relaxant action of BDTI with pKB values of 8.4 and 5.3, respectively, corresponding to high affinity for ICI-118,551 and low affinity for atenolol in antagonizing this response. The Kd values of radioligand ([3H]-CGP12177) were 453.3 +/- 30.8 and 563.4 +/- 96.7 pmol/l in cultured canine tracheal smooth muscle cells (TSMCs) and rat cardiomyocytes, respectively, and the Bmax values were 64.6 +/- 10.7 and 245.7 +/- 44.5 fmol/mg protein, respectively. BDTI, salbutamol and isoprenaline inhibited the binding of [3H]-CGP12177 in a concentration-dependent manner in cultured canine TSMCs (Ki 0.73 +/- 0.15, 0.75 +/- 0.21 and 0.24 +/- 0.05 mumol/l, respectively) and rat cardiomyocytes (Ki 2.76 +/- 0.36, 2.31 +/- 0.26 and 0.22 +/- 0.03 mumol/l, respectively). These results demonstrated that BDTI possessed moderate selectivity (3.8-fold) to beta 2-adrenoceptors as judged from the Ki (heart)/Ki (trachea) value (salbutamol 3.1-fold, isoprenaline 0.92-fold). BDTI and salbutamol also stimulated cAMP formation in a concentration-dependent manner in cultured canine TSMCs (EC50 0.5 +/- 0.2 and 0.4 +/- 0.1 mumol/l, respectively) and rat cardiomyocytes (EC50 6.2 +/- 0.5 and 5.7 +/- 0.6 mumol/l, respectively). The selectivity of BDTI and salbutamol for beta 2-adrenoceptors on the cAMP response were 12.4 and 14.3 times, respectively. It is concluded that BDTI is a beta 2-selective adrenoceptor agonist.

摘要

通过放射性配体结合试验和药理学实验，在犬气管和大鼠心脏中研究了BDTI（1-苄基-6,7-二羟基-1,2,3,4-四氢异喹啉溴化氢）的气管舒张作用和β2选择性，并与其他β肾上腺素能受体激动剂沙丁胺醇和异丙肾上腺素进行比较。在离体犬气管中，BDTI对卡巴胆碱诱导的收缩的舒张作用强度顺序为：异丙肾上腺素（pD2 = 6.70±0.08）> BDTI（6.11±0.06）≈沙丁胺醇（6.14±0.08）。ICI-118,551（一种选择性β2拮抗剂）和阿替洛尔（一种选择性β1拮抗剂）分别以pKB值8.4和5.3抑制BDTI的舒张作用，这对应于在拮抗该反应时对ICI-118,551的高亲和力和对阿替洛尔的低亲和力。放射性配体（[3H]-CGP12177）在培养的犬气管平滑肌细胞（TSMCs）和大鼠心肌细胞中的Kd值分别为453.3±30.8和563.4±96.7 pmol/L，Bmax值分别为64.6±10.7和245.7±44.5 fmol/mg蛋白质。BDTI、沙丁胺醇和异丙肾上腺素在培养的犬TSMCs（Ki分别为0.73±0.15、0.75±0.21和0.24±0.05 μmol/L）和大鼠心肌细胞（Ki分别为2.76±0.36、2.31±0.26和0.22±0.03 μmol/L）中以浓度依赖性方式抑制[3H]-CGP12177的结合。从Ki（心脏）/Ki（气管）值判断，这些结果表明BDTI对β2肾上腺素能受体具有中等选择性（3.8倍）（沙丁胺醇为3.1倍，异丙肾上腺素为0.92倍）。BDTI和沙丁胺醇在培养的犬TSMCs（EC50分别为0.5±0.2和0.4±0.1 μmol/L）和大鼠心肌细胞（EC50分别为6.2±0.5和5.7±0.6 μmol/L）中也以浓度依赖性方式刺激cAMP形成。BDTI和沙丁胺醇对cAMP反应中β2肾上腺素能受体的选择性分别为12.4倍和14.3倍。结论是BDTI是一种β2选择性肾上腺素能受体激动剂。