Hosohata Y, Sasaki K, Shen Y, Hattori K, Suzuki J, Nagatomo T
Department of Pharmacology, Niigata College of Pharmacy, Japan.
Biol Pharm Bull. 1995 Aug;18(8):1066-71. doi: 10.1248/bpb.18.1066.
This study used radioligand binding assay methods and pharmacological experiments to examine whether bopindolol, possessing a long-lasting action in addition to potent beta-adrenoceptor antagonistic effects, is a slowly dissociating antagonist. In addition, the slow dissociation of two of its metabolites, 18-502 (4-(3-tert-butylamino-2-hydroxypropoxy)-2-methyl indole) and 20-785 (4-(3-tert-butylaminopropoxy)-2-carboxyl indole), which have potent beta-blocking activities, was also assessed. The blockade of 3H-CGP12177 binding sites in rat heart and brain induced by pindolol was readily reversed by washing, whereas this inhibition by bopindolol and 18-502 was not easily reversed by washing. In addition, specific bindings of the hearts of the treatment animals with 20-785, atenolol, (+/-)propranolol, nadolol and celiprolol and of washout were 86.7, 78.8, 77.5, 82.3 and 79.9% of the control, respectively. These blockades by the treatment of each drug and washout in the brain were, however, lower than those in the hearts. On the other hand, when the left and right atria were pretreated with propranolol, bopindolol and 18-502, the inotropic and chronotropic actions of isoprenaline were inhibited by these drugs even though they were not present in the extracellular medium. Pretreatment with 20-785, atenolol and nadolol was readily reversed for both inotropic action and chronotropic rate, and inhibition by celiprolol and pindolol remained at 25% of the control at 240 min after treatment with these drugs. A good correlation between inhibitory binding percentage in the hearts and inhibitory inotropic or chronotropic actions were observed, although it was not observed in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
本研究采用放射性配体结合测定法和药理学实验，以检验除具有强效β-肾上腺素能受体拮抗作用外还具有长效作用的波吲洛尔是否为一种解离缓慢的拮抗剂。此外，还评估了其两种具有强效β-阻滞活性的代谢产物18 - 502（4-(3-叔丁基氨基-2-羟基丙氧基)-2-甲基吲哚）和20 - 785（4-(3-叔丁基氨基丙氧基)-2-羧基吲哚）的缓慢解离情况。吲哚洛尔对大鼠心脏和大脑中3H-CGP12177结合位点的阻断作用经冲洗后很容易逆转，而波吲洛尔和18 - 502所致的这种抑制作用经冲洗不易逆转。此外，用20 - 785、阿替洛尔、(±)普萘洛尔、纳多洛尔和塞利洛尔处理动物心脏和冲洗后的特异性结合率分别为对照组的86.7%、78.8%、77.5%、82.3%和79.9%。然而，这些药物处理及冲洗后在大脑中的阻断率低于心脏中的阻断率。另一方面，当左、右心房用普萘洛尔、波吲洛尔和18 - 502预处理时，即使细胞外介质中不存在这些药物，它们也能抑制异丙肾上腺素的变力性和变时性作用。用20 - 785、阿替洛尔和纳多洛尔预处理后，变力性作用和变时性心率很容易逆转，而用塞利洛尔和吲哚洛尔处理后240分钟，其抑制作用仍维持在对照组的25%。尽管在大脑中未观察到，但在心脏中观察到了结合抑制百分比与变力性或变时性抑制作用之间的良好相关性。（摘要截短至250字）
