Berkowitz B A, Arleth A J, Sung C P, Kruse L I, DeWolf W E, Ohlstein E H
Smith Kline and French Laboratories, Philadelphia, Pennsylvania.
J Pharmacol Exp Ther. 1988 Jun;245(3):850-7.
The novel dopamine beta-hydroxylase (D beta H) inhibitor SK&F 102698 was characterized in vitro with soluble enzyme from bovine adrenal medulla and in vivo by measuring the dopamine/norepinephrine (DA/NE) ratio in the mesenteric artery, heart and brains of spontaneously hypertensive rats (SHR). SK&F 102698 was a potent D beta H inhibitor with an IC50 of 1.2 microM on crude enzyme and had a Ki value of 40 nM on purified enzyme. SK&F 102698 produced a dose-dependent fall in NE and a dose-dependent increase in DA in the vasculature of SHR after p.o. administration. Elevation of the vascular DA/NE ratio was observed within 0.5 hr after administration. Peak effects were observed at 12 hr and values were still significantly increased at 18 hr. The rise in the DA/NE ratio of the blood vessels correlated with the fall in blood pressure following the first 4 hr after SK&F 102698. SK&F 102698 inhibited SHR heart D beta H and elevated the myocardial DA/NE ratio approximately 2.4-fold. SK&F 102698 also caused a dose-dependent increase in the whole brain DA/NE ratio of SHR. Catecholamine levels were also studied in six discrete brain regions and SK&F 102698 produced the greatest increase in the DA/NE ratio in the cerebellum, brain stem and midbrain regions, whereas the striatum was the region least affected. No overt sedation was observed in the rats. Further study with SK&F 102698 is warranted to better explore the role of DA and D beta H in pathophysiology, and to determine whether this drug or a congener D beta H inhibitor will be a useful therapeutic agent in humans.
新型多巴胺β-羟化酶（DβH）抑制剂SK&F 102698在体外使用来自牛肾上腺髓质的可溶性酶进行了特性研究，并在体内通过测量自发性高血压大鼠（SHR）肠系膜动脉、心脏和大脑中的多巴胺/去甲肾上腺素（DA/NE）比值进行了研究。SK&F 102698是一种强效DβH抑制剂，对粗酶的IC50为1.2微摩尔，对纯化酶的Ki值为40纳摩尔。口服给药后，SK&F 102698使SHR血管中的NE呈剂量依赖性下降，DA呈剂量依赖性增加。给药后0.5小时内观察到血管DA/NE比值升高。在12小时观察到峰值效应，18小时时数值仍显著升高。SK&F 102698给药后头4小时内血管DA/NE比值的升高与血压下降相关。SK&F 102698抑制SHR心脏DβH并使心肌DA/NE比值升高约2.4倍。SK&F 102698还使SHR全脑DA/NE比值呈剂量依赖性增加。还对六个离散脑区的儿茶酚胺水平进行了研究，SK&F 102698在小脑、脑干和中脑区域使DA/NE比值增加最大，而纹状体是受影响最小的区域。在大鼠中未观察到明显的镇静作用。有必要对SK&F 102698进行进一步研究，以更好地探索DA和DβH在病理生理学中的作用，并确定这种药物或同类DβH抑制剂是否将成为人类有用的治疗剂。
