The effects of methoxamine on increased intrahepatic vascular resistance in a rat model of non-alcoholic fatty liver disease

Affiliations 1 Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium 2 Department of Gastroenterology and Hepatology, Antwerp... [ view full abstract ]

Affiliations

1 Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium

2 Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem (Antwerp), Belgium

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Before the development of advanced disease (inflammation/fibrosis), portal pressure is already increased due to an increased intrahepatic vascular resistance, impairing hepatic blood flow and potentially causing disease progression. Intrahepatic endothelial dysfunction and altered reactivity to α1-adrenergic stimulation are potential mechanisms.

Aim: To study the effects of α1-adrenergic stimulation on the transhepatic pressure gradient (THPG) in NAFLD.

Methods: Male Wistar rats (n≥6/group) on a methionine-choline-deficient diet (MCDD), inducing severe steatosis after 4 weeks, were compared to controls. Dose-response curves to α1-adrenergic agonist methoxamine (Mx; 10-6-3*10-4 M) were constructed with in situ ex vivo perfusion-experiments, where the liver is isolated and perfused by Krebs with or without Mx. A dose of 10-5 M (EC50 in controls) was subsequently used in flow-pressure curves, increasing flow with 5mL/min every 5 minutes. Ultimately, livers were perfused at a constant flow during 60 minutes to study time-dependent effects.

Results: Dose-response curves show an increased vascular reactivity of steatotic livers to Mx compared to controls. Flow-pressure curves demonstrate a significantly higher baseline THPG and a larger increase in THPG after the addition of Mx in steatosis compared to controls (Fig. 1). Time-dependent effects were similar in both groups.  

Conclusion: THPG was increased in steatotis compared to controls, confirming previous reports. Reactivity to Mx in control and steatotic livers show significant differences, with a higher reactivity in steatotic livers, pointing towards a role of altered α1-adrenergic mechanisms in the increased THPG observed in NAFLD.

Key words: NAFLD, endothelial dysfunction, methoxamine, transhepatic pressure gradient, vascular resistance