Aims

Dipeptidyl peptidase-4 inhibitor (DPP4i), a new antidiabetic agent, is reported to affect the progression of chronic liver diseases. The study aims to investigate the effects of DPP4i on contractile response, splanchnic hemodynamics, and portal pressure in cirrhotic rats.

Materials and methods

A rat model of carbon tetrachloride-induced cirrhosis was used in this study. Sixteen rats with cirrhosis were treated with DDP4i sitagliptin for 5 consecutive days. Portal and systemic pressures and portal blood flow were measured. Mesenteric arterioles were isolated, and concentration-response curves to norepinephrine (NE) were evaluated. The expression of NADPH oxidase (Nox)1, Nox2, Nox4, and soluble epoxide hydrolase (sEH) were detected. Reactive oxygen species (ROS) and epoxyeicosatrienoic acid (EET) levels in mesenteric arteries were also measured.

Key findings

In cirrhotic rats, sitagliptin significantly reduced portal blood flow and portal pressure without effects on systemic pressure and reversed the decreased response of mesenteric arterioles to NE in an endothelium-dependent manner. Sitagliptin suppressed the increased Nox4 expression and ROS production. In vitro studies showed that Nox4 inhibitor enhanced arteriolar response to NE and reduced hydrogen peroxide (H₂O₂) level in cirrhotic rats. Sitagliptin also reduced EET levels and increased sEH expression of mesenteric vessels. Pre-incubation with sEH inhibitor in vitro reversed sitagliptin-induced augmentation of response to NE in cirrhotic rats.

Significance

DPP4 inhibition by sitagliptin in vivo has beneficial effects on portal hypertension in cirrhotic rats through normalizing arterial hypocontractility. DDP4 inhibitor may be a novel strategy in the treatment of patients with cirrhosis and portal hypertension.

中文翻译：

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DPP4抑制剂通过使动脉收缩功能正常化来降低肝硬化大鼠的门静脉高压

宗旨

据报道，二肽基肽酶 4 抑制剂 (DPP4i) 是一种新型抗糖尿病药物，可影响慢性肝病的进展。该研究旨在研究 DPP4i 对肝硬化大鼠收缩反应、内脏血流动力学和门静脉压力的影响。

材料和方法

本研究使用四氯化碳诱导的肝硬化大鼠模型。16 只肝硬化大鼠连续 5 天接受 DDP4i 西格列汀治疗。测量门静脉和全身压力以及门静脉血流量。分离肠系膜小动脉，并评估对去甲肾上腺素 (NE) 的浓度-反应曲线。检测 NADPH 氧化酶 (Nox)1、Nox2、Nox4 和可溶性环氧化物水解酶 (sEH) 的表达。还测量了肠系膜动脉中的活性氧 (ROS) 和环氧二十碳三烯酸 (EET) 水平。

主要发现

在肝硬化大鼠中，西格列汀显着降低门静脉血流量和门静脉压力，而不影响全身压力，并以内皮依赖性方式逆转肠系膜小动脉对 NE 的反应降低。西格列汀抑制了 Nox4 表达和 ROS 产生的增加。体外研究表明，Nox4 抑制剂增强了对 NE 的小动脉反应并降低了肝硬化大鼠的过氧化氢 (H ₂ O ₂ ) 水平。西格列汀还降低 EET 水平并增加肠系膜血管的 sEH 表达。在体外与 sEH 抑制剂预孵育逆转了西格列汀诱导的肝硬化大鼠对 NE 反应的增强。

意义

西格列汀在体内抑制 DPP4 对肝硬化大鼠的门静脉高压有有益作用，可通过使动脉收缩不足正常化。DDP4抑制剂可能是治疗肝硬化和门静脉高压症患者的一种新策略。