Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits

Non-alcoholic fatty liver disease (NAFLD) is considered as the most frequent cause of chronic hepatic disease in adults. It is strictly correlated with insulin resistance, frequently associated with components of metabolic syndrome, and, similarly to the latter, it has been correlated with high risk of developing type 2 diabetes and cardiovascular diseases. Systemic arterial hypertension has been suggested to be associated with NAFLD in approximately 40% of the cases, and NAFLD has been independently associated with an increased risk of arterial hypertension in observational studies. Therefore, we can infer that treating arterial hypertension in NAFLD carriers will be often necessary and that the potential beneficial effects of the antihypertensive might, in this context, influence the choice of the respective drug. The renin-angiotensin system has been correlated to the whole basic physiopathogenic mechanism of NAFLD in experimental models. Based on these findings, we conducted this study to evaluate the effects of the ACE-inhibitor ramipril, used preventively, in NAFLD induced in rabbits fed hyperlipidaemic diet.

Twenty-nine rabbits were divided into three groups (normal, placebo, and ramipril). The placebo and ramipril groups were fed a ration containing 0.925% cholesterol. The groups were orally administered 0.35 mg/kg/day of ramipril, and an equivalent volume of vehicle was administered to the placebo group. At the end of the 8th week, all rabbits underwent segmental hepatic resection and were euthanized. Blood samples were collected to determine glucose, insulin, creatinine, total cholesterol, triglycerides, HDL-C, and aminotransferase levels at baseline and euthanasia. Haematoxylin and eosin and Gomori trichrome-stained slides were analysed based on the histological scoring system for NAFLD. Sudan III-stained slides were analysed by morphometry and immunostained based on the Allred scoring system.

When compared with placebo, ramipril significantly diminished the development of steatosis (P=0.032), lobular inflammation (P=0.006), hepatocellular ballooning (P=0.023), and fibrosis (P=0.02). Based on the NAFLD activity score (NAS), ramipril significantly reduced the development of non-alcoholic steatohepatitis (NASH) (P=0.003).

The preventive use of ramipril in rabbits fed hyperlipidaemic diet, attenuates the development of the whole NAFLD histopathological spectrum and based on NAS, ramipril significantly reduced the development of NASH.