Yoshiki Hatsumi, Uwada Junsuke, Umada Hidenori, Kobayashi Tadashi, Takahashi Toshihiro, Yamakawa Tomio, Yamaguchi Akio, Yokoyama Osamu, Muramatsu Ikunobu
Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Fukui, Japan.
Br J Pharmacol. 2013 Nov;170(6):1242-52. doi: 10.1111/bph.12403.
Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors.
A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery.
All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery.
The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy.
最近已证实两种不同的α1 -肾上腺素能受体表型（α1A和α1L）源自单一的α1A -肾上腺素能受体基因。在此，我们研究了重组α1A和α1L表型以及下尿路（LUT）α1 -肾上腺素能受体的激动剂谱。
一系列最初开发用于治疗压力性尿失禁（SUI）的药物（A61603、Ro 115 - 1240、NS - 49、MK017和ESR1150）被用于刺激重组α1A -和α1L -肾上腺素能受体表型，并根据Ca(2+)反应估计它们的效价和内在活性。还在大鼠和人类的LUT组织以及人类肠系膜动脉和大鼠尾动脉中检测了激动剂诱导的收缩。
与α1L -肾上腺素能受体表型相比，所有药物都是α1A -肾上腺素能受体的强效激动剂。其中，Ro 115 - 1240被证明是一种α1A特异性部分激动剂，它通过α1A -肾上腺素能受体在大鼠前列腺和尾动脉中产生部分收缩，但在其他LUT组织和人类肠系膜动脉中则不然。相比之下，P - come 102在α1A -和α1L -肾上腺素能受体上表现出完全激动剂活性，但对α1A -肾上腺素能受体的选择性低于去甲肾上腺素。与去甲肾上腺素一样，P - come 102在所有测试的LUT组织中诱导收缩的效力都很高。然而，P - come 102在人类肠系膜动脉中的效价和内在活性明显低于去甲肾上腺素。
α1A -和α1L -肾上腺素能受体表型以及LUTα1 -肾上腺素能受体具有不同的激动剂谱。由于LUT中的肾上腺素能收缩主要通过α1L -肾上腺素能受体介导，开发α1L选择性激动剂可能为SUI治疗提供临床上有用的药物。
