Background:

Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling.

Methods:

The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague–Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined.

Results:

Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels.

Conclusions:

HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.

中文翻译：

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氢氯噻嗪可减少 DOCA 盐诱导的高血压中的心脏肥大、纤维化和 Rho 激酶活化

背景：

噻嗪类是治疗高血压最常用的抗高血压药物之一，氢氯噻嗪（HCTZ）是治疗高血压最常用的利尿剂。Rho/Rho 激酶 (ROCK) 路径在心血管重塑中起关键作用。我们假设在临床前高血压中，HCTZ 可减少心肌 ROCK 激活和随之而来的心肌重塑。

方法：

使用脱氧皮质酮（DOCA）-盐高血压的临床前模型（Sprague-Dawley 雄性大鼠）。3 周后，在 3 个不同的组中：HCTZ，加入 ROCK 抑制剂法舒地尔或螺内酯（3 周）。在心肌肥大和纤维化 6 周后，测定心脏促纤维化蛋白水平、促重构和促氧化分子的 mRNA 水平 (RT PCR) 和 ROCK 活性。

结果：

HCTZ、法舒地尔和螺内酯显着降低了血压、心肌肥大和纤维化。在心脏中，促纤维化蛋白 Col-I、Col-III 和 TGF-β1 的水平增加，促重塑分子 TGF-β1、CTGF、MCP-1 和 PAI-1 和促氧化分子的基因表达增加HCTZ、法舒地尔和螺内酯显着降低了 gp91phox 和 p22phox。与假手术组和 HCTZ、螺内酯和法舒地尔相关，心肌中的 ROCK 活性增加了 54% ( P < 0.05)，将 ROCK 活化降低至控制水平。

结论：

HCTZ 通过控制血压、肥大和心肌纤维化以及通过降低心肌 ROCK 活化、促重塑、促纤维化和促氧化基因的表达来降低病理性 LVH。在高血压中，观察到的 HCTZ 对心肌的影响可能解释了噻嗪类药物在高血压中的预防效果，特别是对 LVH 消退和心力衰竭事件的预防效果。