Illustration of a dam obstructing a river of blood cells, symbolizing portal hypertension, with NADPH oxidase molecules acting as keys.

Unlocking Hypertension: How NADPH Oxidase Inhibition Could Revolutionize Treatment

Soraya Malik in Health & Wellness November 2025 • 4 min read.

"New research illuminates the role of NADPH oxidase in portal hypertension, offering hope for targeted therapies to modulate angiogenesis and arterial reactivity."

Portal hypertension (PHT) is a severe complication arising from chronic liver diseases, marked by an increase in portal pressure, splanchnic blood flow, and the formation of portal-systemic collaterals. This syndrome leads to critical conditions such as esophageal varices, hepatic encephalopathy, and ascites, significantly impacting patient well-being and outcomes.

A key characteristic of PHT is the hyperdynamic circulation, influenced by reduced responsiveness to vasoconstrictors and vascular remodeling. Nitric oxide (NO), a potent vasodilator produced by endothelial cells, plays a central role in this process. Additionally, the development of splanchnic hemodynamic dysfunction involves active angiogenic processes driven by factors like vascular endothelial growth factor (VEGF), further complicating the condition.

Recent research has focused on NADPH oxidase (NOX) as a major source of reactive oxygen species (ROS), which are crucial in the redox state of vessels. During PHT, inhibiting NADPH oxidase has shown promise in attenuating endothelial dysfunction and reducing the formation of portal-systemic collaterals. A specific NOX inhibitor, GKT137831, has emerged as a potential therapeutic agent, superior to non-specific inhibitors due to its targeted action.

How Does NADPH Oxidase Contribute to Portal Hypertension?

Illustration of a dam obstructing a river of blood cells, symbolizing portal hypertension, with NADPH oxidase molecules acting as keys.

The study by Deng et al. (2018) investigates the role of NADPH oxidase (NOX)-derived reactive oxygen species (ROS) in portal hypertension (PHT) and explores the therapeutic potential of NOX inhibition. The research focuses on whether inhibiting NADPH oxidase activity can alleviate PHT in rats, providing insights into new treatment strategies.

To examine the impact of NADPH oxidase inhibition, the study employed partial portal vein ligation (PPVL) to establish a PHT model in rats. These rats were then treated with GKT137831, a specific Nox1/4 inhibitor, and various parameters were assessed. Here’s a breakdown of what was measured:

Hemodynamics: Monitored to understand changes in blood flow and pressure.
Severity of Portal-Systemic Shunting: Evaluated to determine the extent of blood flow bypassing the liver.
Vascular Contractility: Assessed to measure the responsiveness of blood vessels.
Expression of VEGF, VEGFR-2, CD31, AKT, and phospho-AKT: These markers are involved in angiogenesis and vascular function.
eNOS and phospho-eNOS Expression: Evaluated to assess nitric oxide production.
Nitric Oxide (NO) Production and Oxidative Stress: Measured in mesenteric arteries to determine the balance of vasodilation and constriction.
Hydrogen Peroxide (H2O2) Levels: Measured in mesenteric tissues and arteries to assess oxidative stress.

The study revealed that inhibiting NOX1/4 with GKT137831 significantly reduced cardiac index, increased portal flow resistance, and decreased portal pressure and blood flow in PPVL rats. GKT137831 also reduced H2O2 production and down-regulated mesenteric angiogenesis markers, indicating its potential in mitigating PHT.

Future Implications for Portal Hypertension Treatment

The findings from Deng et al. (2018) suggest that pharmacological inhibition of NOX1/4 activity could be a promising treatment for PHT-related complications. By decreasing portal pressure, ameliorating hyperdynamic circulation, and reducing mesenteric angiogenesis and arterial hyperresponsiveness, NOX1/4 inhibitors like GKT137831 offer a novel therapeutic avenue for managing portal hypertension.

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This article is based on research published under:

DOI-LINK: 10.1016/j.clinre.2018.10.004, Alternate LINK

Title: Nadph Oxidase 1/4 Inhibition Attenuates The Portal Hypertensive Syndrome Via Modulation Of Mesenteric Angiogenesis And Arterial Hyporeactivity In Rats

Subject: Gastroenterology

Journal: Clinics and Research in Hepatology and Gastroenterology

Publisher: Elsevier BV

Authors: Wensheng Deng, Ming Duan, Binbin Qian, Yiming Zhu, Jiayun Lin, Lei Zheng, Chihao Zhang, Xiaoliang Qi, Meng Luo

Published: 2019-06-01

Everything You Need To Know

What is portal hypertension, and why is it a concern for patients with chronic liver diseases?

Portal hypertension (PHT) is a serious complication of chronic liver diseases. It's characterized by increased portal pressure, splanchnic blood flow, and the development of portal-systemic collaterals. This condition can lead to esophageal varices, hepatic encephalopathy, and ascites, significantly impacting patient well-being and outcomes. The hyperdynamic circulation, influenced by reduced responsiveness to vasoconstrictors and vascular remodeling further complicates PHT. Factors like vascular endothelial growth factor (VEGF) also drive active angiogenic processes.

How does NADPH oxidase (NOX) contribute to the development and progression of portal hypertension?

NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) that are vital in the redox state of vessels. During portal hypertension, NOX activity contributes to endothelial dysfunction and the formation of portal-systemic collaterals. Specifically, inhibiting NADPH oxidase can attenuate these effects, suggesting its role in the pathophysiology of PHT. Studies like the one by Deng et al. (2018) have shown that inhibiting NOX activity can alleviate PHT in rats, highlighting the therapeutic potential of targeting this enzyme. Specifically NOX 1/4 contributes to PHT.

What is GKT137831, and how does it differ from non-specific NADPH oxidase inhibitors in the treatment of portal hypertension?

GKT137831 is a specific inhibitor of Nox1/4. It has emerged as a potential therapeutic agent for portal hypertension because of its targeted action. Unlike non-specific NADPH oxidase inhibitors, GKT137831 selectively inhibits Nox1/4. This targeted approach is superior because it reduces the potential for off-target effects, making it a more precise and potentially safer treatment option for managing portal hypertension-related complications. Deng et al. (2018) used GKT137831 in studies.

According to the research, what specific effects does inhibiting NOX1/4 with GKT137831 have on hemodynamics and vascular function in rats with portal hypertension?

In rats with portal hypertension induced by partial portal vein ligation (PPVL), inhibiting NOX1/4 with GKT137831 significantly reduced cardiac index, increased portal flow resistance, and decreased portal pressure and blood flow. Furthermore, GKT137831 reduced hydrogen peroxide (H2O2) production and down-regulated mesenteric angiogenesis markers, indicating its potential in mitigating PHT. The treatment also affects the expression of VEGF, VEGFR-2, CD31, AKT, and phospho-AKT, which are involved in angiogenesis and vascular function, as well as eNOS and phospho-eNOS expression, which is important for nitric oxide production.

What are the potential future implications of using NADPH oxidase inhibitors, such as GKT137831, in the clinical management of portal hypertension and its associated complications?

The findings suggest that pharmacological inhibition of NOX1/4 activity could offer a promising treatment for PHT-related complications. By decreasing portal pressure, ameliorating hyperdynamic circulation, and reducing mesenteric angiogenesis and arterial hyperresponsiveness, NOX1/4 inhibitors like GKT137831 offer a novel therapeutic avenue for managing portal hypertension. Future clinical applications could involve using these inhibitors to prevent or manage conditions such as esophageal varices, hepatic encephalopathy, and ascites, ultimately improving patient outcomes. Further research and clinical trials are needed to fully validate these findings and determine the optimal use of NOX1/4 inhibitors in treating portal hypertension in humans. Also, NOX inhibition can modulate angiogenesis and arterial reactivity offering hope.