Introduction Inflammation plays a pivotal role in modulating the severity of intrahepatic resistance in cirrhosis. Our studies have shown a close relationship between the activation of the sympathetic nervous system, inflammatory response and severity of portal hypertension. Stimulation of alpha 2a adrenergic (ADRA2a) receptors results in inflammation and vasodilation in resistance vasculature, and its antagonism has shown benefit in models of sepsis.
Aim The aim of the study was to test the hypothesis that treating bile duct ligated rats (BDL) with an ADRA2a antagonist reduces hepatic inflammation and improves the haemodynamic abnormalities associated with cirrhosis.
Method Male Sprague-Dawley rats (N=46) were studied 4-weeks after BDL surgery (N=29) or sham operation (N=17) and randomised to two doses of placebo or ADRA2a antagonist (BRL 44408, Sigma, UK, 10mg/kg s.c 24 hours prior to study). Portal vein and hepatic arterial blood flow, mean arterial (MAP) and portal pressure were measured directly. Plasma biochemistry was measured by colorimetry. ADRA2a and NFkB protein expression were determined by western blotting and immunohistochemistry (ADRA2a).
Results BDL rats had significantly increased hepatic protein expression of ADRA2a compared with sham operated rats and this was mostly shown to be located on hepatocytes by immunohistochemistry. Following treatment with ADRA2a antagonist there was a significant increase in the MAP (p<0.05) and a significant reduction in portal pressure as compared to the placebo treated group (11.4±3.4 vs. 18.0±3.7 mmHg, p<0.001). The hepatic arterial blood flow was markedly increased in the treated group without significant change in the portal venous blood flow resulting in a significant reduction in intrahepatic resistance post treatment (1.1±0.2 vs. 0.5±0.1 mmHg/ml/min, p<0.05). Biochemical analysis showed a significant reduction in plasma lactate (p<0.05), AST (p<0.05) and a trend towards reduction in creatinine in treated animals. Hepatic phosphorylated NFκB expression was increased in BDL animals and this reduced significantly with ADRA2a antagonist treatment (p<0.05).
Conclusion The results of this study show for the first time that modulating ADRA2a-mediated sympathetic tone and hepatic inflammation with an ADRA2a antagonist significantly improves systemic haemodynamics and reduces portal pressure, whilst also increasing hepatic blood flow. Our data provide the rationale for evaluating an ADRA2a antagonist in the treatment of portal hypertension.
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