Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University.
Biol Pharm Bull. 2020;43(3):493-502. doi: 10.1248/bpb.b19-00865.
The β-adrenoceptor (β-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (β-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (β-AR dominant), normetadrenaline (NMA) and MA (10 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10 M) significantly suppressed ISO-induced relaxation. DHPG (10 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10 M) significantly suppressed relaxation induced by CGP-12177 A (a β-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β-AR agonistic action; 2) NMA and MA augment β-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β-, β-AR antagonistic action (β > β); 3) DHPG exhibits β-, β-, β-AR antagonistic action, and this is particularly marked for β-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.
儿茶酚胺（CA）代谢物的β-肾上腺素能受体（β-AR）介导的药理学作用尚不清楚。我们研究了七种 CA 代谢物对小鼠和豚鼠（GP）气管以及大鼠胸主动脉平滑肌松弛的影响。其中，间肾上腺素（MA）可显著松弛 GP 气管（β-AR 占优势），即使存在单胺氧化酶-A 抑制剂氯丙嗪。在小鼠气管（β-AR 占优势）中，去甲肾上腺素（NMA）和 MA（各 10 μM）显然不会影响异丙肾上腺素（ISO）诱导的松弛，但在氯丙嗪存在下会显著抑制。ISO 诱导的松弛也不受 3,4-二羟苯乙二醇（DHPG）（10 μM）的影响，但当加入儿茶酚-O-甲基转移酶抑制剂 3,5-二硝基儿茶酚时，观察到明显的抑制作用。在 GP 气管中，NMA、MA、3,4-二羟扁桃酸（DOMA）和 DHPG（各 10 μM）均可显著增强 ISO 诱导的松弛。然而，在氯丙嗪加 3,5-二硝基儿茶酚存在下，NMA 和 MA（各 10 μM）均显著抑制 ISO 诱导的松弛。DHPG（10 μM）在 3,5-二硝基儿茶酚存在下也显著抑制 ISO 诱导的松弛。在大鼠胸主动脉中，DHPG（10 μM）在 3,5-二硝基儿茶酚加普萘洛尔存在下可显著抑制 CGP-12177A（β-AR 部分激动剂）诱导的松弛。我们的研究结果表明：1）MA 可能具有β-AR 激动作用；2）在没有 CA 代谢抑制剂的情况下，NMA 和 MA 增强β-AR 介导的气管松弛，尽管它们本身具有β-、β-AR 拮抗作用（β＞β）；3）DHPG 表现出β-、β-、β-AR 拮抗作用，特别是对β-AR 的拮抗作用更为明显。我们的观察结果可能有助于解释一些与嗜铬细胞瘤相关的病理，嗜铬细胞瘤的特点是 CA 代谢物水平升高。
