Ishikawa H, Miller D D, Patil P N
College of Pharmacy, Division of Pharmacology, Ohio State University, Columbus 43210-1291, USA.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Dec;354(6):765-72. doi: 10.1007/BF00166903.
The relative potency of alpha-adrenoceptor agonists and the dissociation constants of competitive antagonists were studied to characterize the post-junctional alpha-adrenoceptor of the human iris dilator muscle. The data obtained from human iris dilator tissue was compared to that from rabbit. The iris dilator muscle was mounted in an organ bath and tension changes were recorded. (-)-Norepinephrine, (-)-phenylephrine (PE), oxymetazoline and p-aminoclonidine caused contractile responses in albino rabbit, pigmented rabbit and human iris dilator muscle in a concentration-dependent manner. The imidazoline molecules were partial agonists. In rabbit iris dilator, desensitization occurred to repeated oxymetazoline application at an interval of 1 h but recovery to the agonist activity was complete in about 3 h. Exposure to cocaine (10 mumol/l), hydrocortisone (100 mumol/l) and U-0521, a catechol-O-methyltransferase inhibitor (100 mumol/l), significantly potentiated the response to norepinephrine by 92-, 32- and 7 fold in iris dilator tissue of albino rabbit, pigmented rabbit and human, respectively. After block of "uptake1" and "uptake2", the EC50 values of norepinephrine in the albino rabbit, pigmented rabbit and human iris dilator did not differ and ranged from 99 to 195 nmol/l. Small but significant potentiation by uptake blockers was also observed in the responses to PE in the albino rabbit or pigmented rabbit iris dilator. The average maximum tension induced by 100 mumol/l PE was 96 +/- 11 mg (n = 10), 197 +/- 11 mg (n = 11), 45 +/- 5 mg (n = 27) in albino rabbit, pigmented rabbit and human iris dilator, respectively. In human iris dilator, the responses to PE were competitively antagonized by prazosin, 5-methylurapidil and phentolamine with apparent pKB values of 7.3, 6.6 and 7.5, respectively. The pKB values of the prazosin-PE interaction in iris dilator of albino and pigmented rabbit were 8.6 and 6.4, respectively. These results suggest that the post-junctional alpha-adrenoceptors in iris dilator may be similar to that in pigmented rabbit iris. The alpha-adrenoceptor of the human or pigmented rabbit iris dilator may be characterized as alpha 1L-adrenoceptor subtype. The alpha-adrenoceptor of albino rabbit iris dilator appears to be a high affinity subtype. Furthermore, albino rabbit may not be the best strain for the drug research which is relevant to human ocular therapeutics.
研究α-肾上腺素能受体激动剂的相对效价和竞争性拮抗剂的解离常数，以表征人虹膜开大肌的节后α-肾上腺素能受体。将从人虹膜开大肌组织获得的数据与从兔获得的数据进行比较。将虹膜开大肌安装在器官浴槽中并记录张力变化。（-）-去甲肾上腺素、（-）-去氧肾上腺素（PE）、氧甲唑啉和对氨基可乐定在白化兔、有色兔和人虹膜开大肌中引起浓度依赖性的收缩反应。咪唑啉分子为部分激动剂。在兔虹膜开大肌中，每隔1小时重复应用氧甲唑啉会发生脱敏，但约3小时后激动剂活性完全恢复。暴露于可卡因（10μmol/L）、氢化可的松（100μmol/L）和儿茶酚-O-甲基转移酶抑制剂U-0521（100μmol/L）后，白化兔、有色兔和人虹膜开大肌组织中对去甲肾上腺素的反应分别显著增强92倍、32倍和7倍。阻断“摄取1”和“摄取2”后，白化兔、有色兔和人虹膜开大肌中去甲肾上腺素的EC50值无差异，范围为99至195nmol/L。在白化兔或有色兔虹膜开大肌中对PE的反应中也观察到摄取阻滞剂有小但显著的增强作用。100μmol/L PE诱导的平均最大张力在白化兔、有色兔和人虹膜开大肌中分别为96±11mg（n = 10）、197±11mg（n = 11）、45±5mg（n = 27）。在人虹膜开大肌中，对PE的反应被哌唑嗪、5-甲基乌拉地尔和酚妥拉明竞争性拮抗，表观pKB值分别为7.3、6.6和7.5。哌唑嗪-PE在白化兔和有色兔虹膜开大肌中的相互作用的pKB值分别为8.6和6.4。这些结果表明，虹膜开大肌中的节后α-肾上腺素能受体可能与有色兔虹膜中的相似。人或有色兔虹膜开大肌的α-肾上腺素能受体可能被表征为α1L-肾上腺素能受体亚型。白化兔虹膜开大肌的α-肾上腺素能受体似乎是高亲和力亚型。此外，白化兔可能不是与人类眼部治疗相关的药物研究的最佳品系。
