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噻嗪类利尿剂引起高血压治疗的机制：恶性卒中倾向自发性高血压大鼠基因表达和组织学分析的见解。

Mechanisms of thiazide-induced hypertension treatment: insights from gene expression and histological analysis in malignant stroke-prone spontaneously hypertensive rats.

机构信息

Department of Social and Environmental Medicine, Faculty of Medicine, Saga University, Saga.

Department of Pharmacology, Kindai University School of Medicine, Osaka-Sayama-city, Osaka.

出版信息

J Hypertens. 2024 Dec 1;42(12):2084-2093. doi: 10.1097/HJH.0000000000003837. Epub 2024 Aug 21.

DOI:10.1097/HJH.0000000000003837
PMID:39206783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11556871/
Abstract

OBJECTIVE

Diuretics, including thiazides and thiazide-like drugs, are commonly recommended for treating hypertension, though their precise mechanism of action is not fully understood. This study aimed to investigate the pharmacological effects of trichloromethiazide (TCM) in malignant stroke-prone spontaneously hypertensive rats (M-SHRSP).

METHODS

M-SHRSPs were treated with varying doses of TCM. Prognosis, histological changes, and mRNA expression related to hypertension and stroke were assessed.

RESULTS

The high-dose TCM group (3%) exhibited significantly lower SBP compared with the untreated group, whereas the low-dose group (0.3%) did not show a significant reduction in SBP. The survival rate was 54% in the low-dose group, whereas all rats in the high-dose group survived without experiencing a stroke by 16 weeks of age. Organ weights in both TCM-treated groups were lower than those in the control group, without severe histological abnormalities, including stroke and sclerosis. Plasma levels of thiobarbituric acid-reactive substances (TBARS) were significantly reduced in both TCM-treated groups. Additionally, 20 genes related to tissue protection, repair, proliferation, maintenance, and function were significantly expressed.

CONCLUSION

TCM administration in M-SHRSPs significantly modulated the expression of 20 genes associated with tissue protection and maintenance, and reduced plasma TBARS levels. These findings suggest that TCM, a thiazide diuretic, may protect against tissue impairment in hypertension by modulating gene expression and exhibiting antioxidant activity.

摘要

目的

利尿剂，包括噻嗪类和噻嗪样药物，常用于治疗高血压，但它们的确切作用机制尚未完全了解。本研究旨在研究三氯甲噻嗪（TCM）在恶性卒中易发性自发性高血压大鼠（M-SHRSP）中的药理作用。

方法

用不同剂量的 TCM 处理 M-SHRSP。评估预后、与高血压和中风相关的组织学变化和 mRNA 表达。

结果

高剂量 TCM 组（3%）的 SBP 明显低于未治疗组，而低剂量组（0.3%）的 SBP 没有明显降低。低剂量组的存活率为 54%，而高剂量组的所有大鼠在 16 周龄时均未发生中风而存活。两个 TCM 治疗组的器官重量均低于对照组，没有严重的组织学异常，包括中风和硬化。两个 TCM 治疗组的血浆硫代巴比妥酸反应物质（TBARS）水平均显著降低。此外，20 个与组织保护、修复、增殖、维持和功能相关的基因显著表达。

结论

TCM 给药可显著调节与组织保护和维持相关的 20 个基因的表达，并降低血浆 TBARS 水平。这些发现表明，噻嗪类利尿剂 TCM 通过调节基因表达和表现出抗氧化活性来预防高血压中的组织损伤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/df06435082e3/jhype-42-2084-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/af391eb6d561/jhype-42-2084-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/63e14183f589/jhype-42-2084-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/ee937d00f114/jhype-42-2084-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/7f05b0b0e156/jhype-42-2084-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/df06435082e3/jhype-42-2084-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/af391eb6d561/jhype-42-2084-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/63e14183f589/jhype-42-2084-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/ee937d00f114/jhype-42-2084-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/7f05b0b0e156/jhype-42-2084-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f2e/11556871/df06435082e3/jhype-42-2084-g005.jpg

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本文引用的文献

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First-line diuretics versus other classes of antihypertensive drugs for hypertension.一线利尿剂与其他类别降压药治疗高血压的比较。
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Hypertension-Associated Genes in the Mesenteric Artery of Three Spontaneously Hypertensive Rat Substrains Identified Using a DNA Array Method.
采用 DNA 芯片方法鉴定三种自发性高血压大鼠亚系肠系膜动脉中与高血压相关的基因。
Front Biosci (Landmark Ed). 2022 Jun 15;27(6):191. doi: 10.31083/j.fbl2706191.
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Thiazide Use and Decreased Risk of Heart Failure in Nondiabetic Patients Receiving Intensive Blood Pressure Treatment.噻嗪类利尿剂的使用与强化降压治疗的非糖尿病患者心力衰竭风险降低有关。
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Mechanism of Thiazide Diuretic Arterial Pressure Reduction: The Search Continues.噻嗪类利尿剂降低动脉压的机制：探索仍在继续。
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Redefining diuretics use in hypertension: why select a thiazide-like diuretic?重新定义高血压治疗中的利尿剂使用：为何选择噻嗪样利尿剂？
J Hypertens. 2019 Aug;37(8):1574-1586. doi: 10.1097/HJH.0000000000002088.
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Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms.原发性高血压的遗传学研究：聚焦于激素机制。
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Thiazide Therapy in Chronic Kidney Disease: Renal and Extra Renal Targets.慢性肾脏病中的噻嗪类药物治疗：肾脏及肾外靶点
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