# Carvedilol decreases hepatic vascular resistance by reducing fibrogenesis and reversing endothelial dysfunction in cirrhotic rats

## TL;DR

Carvedilol reduces liver vascular resistance and fibrosis in cirrhotic rats more effectively than propranolol, offering potential benefits for treating portal hypertension.

## Contribution

This study reveals carvedilol's novel ability to reverse hepatic endothelial dysfunction and reduce fibrosis in cirrhosis, beyond its β-blocking effects.

## Key findings

- Carvedilol significantly reduced portal pressure and liver fibrosis in both early and advanced cirrhosis in rats.
- Carvedilol improved endothelial dysfunction and reduced oxidative stress and inflammation in cirrhotic liver cells.
- Propranolol had minimal effect on portal pressure and lacked the fibrosis-reducing benefits of carvedilol.

## Abstract

Cirrhosis increases hepatic vascular resistance (IHVR) by disrupting liver architecture due to fibrosis, and by elevating hepatic vascular tone due to hepatic endothelial dysfunction. IHVR increases portal pressure (PP), later aggravated by increased portal blood inflow. Carvedilol, a third-generation non-selective β-blocker with anti-α1-adrenergic activity, reduces PP more than propranolol, likely decreasing IHVR. However, its intrahepatic effects remain largely unexplored. This study aimed to address these issues.

Human cell lines (LX2 and HUVECs) and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) isolated from cirrhotic rats (12-week thioacetamide [TAA] model) were treated with vehicle, carvedilol (10 μM), or propranolol (10 μM). Nitric oxide release, oxidative stress, and cell contraction were assessed. Cirrhotic rats were treated with vehicle, carvedilol (10 mg/kg/day for 2 weeks), or propranolol (30 mg/kg/day for 2 weeks) at early and advanced stages of cirrhosis (9 and 12 weeks of TAA). Hepatic hemodynamics, liver fibrosis, antioxidant activity, and inflammatory biomarkers were evaluated.

Carvedilol increased nitric oxide release in LSECs and HUVECs and significantly reduced contraction of HSCs and LX2 cells in cirrhotic conditions. In vivo, carvedilol significantly reduced PP in both early and advanced cirrhosis (12-week TAA: −22%, p = 0.0008; 9-week TAA: −17%, p = 0.0038), decreased liver fibrosis area (−26.8%, p = 0.0013 vs. −23.1%, p = 0.0047), and reduced α-SMA expression (−22.7%, p = 0.0018 vs. −17.4%, p = 0.0455). Additionally, carvedilol improved endothelial dysfunction and reduced oxidative stress and inflammation. Propranolol did not exert these beneficial effects and produced a smaller, non-significant reduction in PP (−7%, p = 0.4029).

The greater reduction in PP achieved with carvedilol is mediated not only by its non-selective β-blocker effects but, more importantly, by its ability to reverse hepatic endothelial dysfunction, reduce fibrosis, enhance antioxidant activity, and exert moderate anti-inflammatory effects. These findings support extending the use of carvedilol even to patients without overt signs of portal hypertension.

Carvedilol is considered the best β-blocker for treating portal hypertension. In this study we show that carvedilol, unlike traditional β-blockers such as propranolol, downregulates the factors that lead to increased portal pressure in cirrhosis: it lowers the hepatic vascular tone by counteracting hepatic sinusoidal endothelial dysfunction, and decreases liver fibrosis by deactivating hepatic stellate cells and inhibiting their proliferation. On top of decreasing portal vein inflow via its non-selective β-blocker effect. Moreover, through its antioxidant and anti-inflammatory activity, it may contribute to improving liver function. These effects are noted both in early and in advanced cirrhosis, suggesting that it can be effective in slowing/reversing disease progression when associated with etiological therapy.

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•Propranolol decreases portal pressure in cirrhosis by decreasing portal blood flow.•In addition, carvedilol decreases hepatic vascular tone and reduces liver fibrosis.•Rat and human cell studies suggest that these effects are linked to its antioxidant activity and HSC deactivation.•These effects are seen in early and advanced cirrhosis, so carvedilol might help prevent disease progression.

Propranolol decreases portal pressure in cirrhosis by decreasing portal blood flow.

In addition, carvedilol decreases hepatic vascular tone and reduces liver fibrosis.

Rat and human cell studies suggest that these effects are linked to its antioxidant activity and HSC deactivation.

These effects are seen in early and advanced cirrhosis, so carvedilol might help prevent disease progression.