科研之友
微信
新浪微博
Facebook
分享链接
摘要
Abnormalities of the D2R 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-2(-/-)) in mice increases blood pressure. The hypertension of D-2(-/-) mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D-2(-/-) mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-beta-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D-2(-/-) mice treated with etamicastat by gavage, (10 mg/kg), conscious D-2(-/-) mice, and D-2(+/+) littermates, and mice with the D2R 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-2(-/-) mice and mice with renal-selective silencing of D2R to levels similar or close to those measured in D-2(+/+) littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D-2(-/-) 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 D1R but not D5R in D-2(-/-) mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D-2(-/-) mice.
- 出版日期2018-7
