Rho 激酶抑制剂 SAR407899 能强力抑制内皮素-1 引起的肾血管阻力增加。

The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries.

机构信息

Institute of Physiology, University of Greifswald, Karlsburg, Germany.

出版信息

J Hypertens. 2012 May;30(5):980-9. doi: 10.1097/HJH.0b013e328351d459.

DOI:10.1097/HJH.0b013e328351d459

PMID:22388233

Abstract

OBJECTIVES

Increased renal vascular resistance contributes to the pathogenesis of hypertension. The new Rho kinase (ROCK) inhibitor SAR407899 more potently lowers arterial pressure than the commercially available ROCK inhibitor Y27623. We tested whether ROCK inhibition more effectively reduced agonist-induced vasoconstriction in renal than in nonrenal resistance arteries and if SAR407899 more potently inhibits agonist-induced vasoconstriction than Y27632.

METHODS

The effects of the ROCK inhibitors on endothelin-1 (ET-1) induced vasoconstriction were investigated in isolated renal and coronary arteries from lean, normotensive Dark Agouti and obese, type 2 diabetic Zucker diabetic fatty (ZDF) rats as well as in isolated human resistance arteries from the kidney and thymus. Vascular ROCK mRNA abundance was studied by real-time PCR (RT-PCR).

RESULTS

ET-1-induced constriction depended more on ROCK in rat and human renal resistance arteries than in rat coronary or human thymic arteries, respectively. SAR407899 was more effective than Y27632 in reducing ET-1-induced vasoconstriction in ZDF rat renal resistance arteries. Maximum ET-1-induced vasoconstriction in SAR407899-treated and Y27632-treated human renal resistance arteries was 23 ± 5 and 48 ± 6% of control values, respectively. Transcripts of both ROCK isoforms were detected in rat and human renal resistance arteries. In human thymic arteries, only the ROCK2 transcript was found.

CONCLUSION

ET-1-induced vasoconstriction is more ROCK-dependent in renal than in nonrenal resistance arteries. SAR407899 causes a greater inhibition of ET-1-induced vasoconstriction in renal resistance arteries from ZDF rats and patients than Y27632. The greater efficacy in renal vessels may contribute to the higher antihypertensive potency of SAR407899 compared with Y27632.

摘要

目的

肾血管阻力增加是高血压发病机制之一。新型 Rho 激酶（ROCK）抑制剂 SAR407899 比市售的 ROCK 抑制剂 Y27623 更有效地降低动脉血压。我们测试了 ROCK 抑制是否更有效地降低肾阻力血管而非非肾阻力血管中激动剂诱导的血管收缩，以及 SAR407899 是否比 Y27632 更有效地抑制激动剂诱导的血管收缩。

方法

在来自瘦型、正常血压的 Dark Agouti 和肥胖、2 型糖尿病 Zucker 糖尿病肥胖（ZDF）大鼠的分离肾和冠状动脉以及来自肾脏和胸腺的分离人阻力血管中，研究了 ROCK 抑制剂对内皮素-1（ET-1）诱导的血管收缩的影响。通过实时 PCR（RT-PCR）研究血管 ROCK mRNA 丰度。

结果

ET-1 诱导的收缩在大鼠和人肾阻力血管中对 ROCK 的依赖性大于在大鼠冠状动脉或人胸腺血管中。SAR407899 在降低 ZDF 大鼠肾阻力血管中 ET-1 诱导的血管收缩方面比 Y27632 更有效。SAR407899 和 Y27632 处理的人肾阻力动脉中最大 ET-1 诱导的血管收缩分别为对照值的 23±5%和 48±6%。在大鼠和人肾阻力血管中均检测到两种 ROCK 同工型的转录本。在人胸腺血管中，仅发现 ROCK2 转录本。