Department of Medicine, Division of Renal Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20057, USA.
MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319, Porto, Portugal.
Hypertens Res. 2018 Jul;41(7):489-498. doi: 10.1038/s41440-018-0041-5. Epub 2018 Apr 13.
Abnormalities of the DR gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D) in mice increases blood pressure. The hypertension of D mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-β-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D mice treated with etamicastat by gavage, (10 mg/kg), conscious D mice, and D littermates, and mice with the DR selectively silenced in the kidney, treated with etamicastat in the drinking water (10 mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D mice and mice with renal-selective silencing of DR to levels similar or close to those measured in D littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of DR but not DR in D mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D mice.
DR 基因（DRD2）的异常在人类原发性高血压的发病机制中起作用；已有报道称，DRD2 的变体与高血压有关。小鼠 Drd2（D）的破坏会增加血压。D 小鼠的高血压部分与交感神经活动增加、肾氧化应激和肾内皮素 B 受体（ETBR）表达增加有关。我们在 D 小鼠中测试了 etamicastat 的效果，etamicastat 是一种可逆的多巴胺-β-羟化酶外周抑制剂，可减少多巴胺转化为去甲肾上腺素，从而降低交感神经活性。通过灌胃给予 etamicastat（10mg/kg），在麻醉的 D 小鼠、清醒的 D 小鼠和 D 同窝仔鼠中测量血压，并在肾脏中选择性沉默 DR 的小鼠以及在饮用水中给予 etamicastat（每天 10mg/kg）的小鼠中测量血压。还测量了组织和尿液儿茶酚胺以及选定的 G 蛋白偶联受体、与活性氧产生相关的酶和钠转运体在肾脏中的表达。Etamicastat 降低了麻醉和清醒的 D 小鼠以及肾脏选择性沉默 DR 的小鼠的血压，使其降低到与 D 同窝仔鼠相似或接近的水平。Etamicastat 降低了 D 小鼠的心脏和肾脏去甲肾上腺素水平，增加了心脏和尿液多巴胺水平。它还使 D 小鼠的 ETBR、NADPH 氧化酶同工酶和尿液 8-异前列腺素的增加的肾蛋白表达正常化，以及增加了肾 NHE3 和 NCC 的表达，并增加了肾 DR 的表达，但不增加 DR。总之，etamicastat 可有效降低 D 小鼠的血压升高和部分异常的肾脏生化改变。
