Protective Effects And Its Mechanism Of Verapamil On Acute Liver Failure

ObjectiveTo evaluate the therapeutic effect and mechanism of verapamil on the acute liver failure (ALF) induced with D-galactosamine/lipopolysachide (D-GlaN/LPS) in mice.Methods1. Mice were treated with D-GlaN and LPS to induce ALF.1 mg/kg verapamil was administered intravenously (i.v.) before D-GlaN/LPS injection. The mortality, serum levels of alanine aminotransferase(ALT), aspartate transaminase(AST), total bilirubin (TBIL), malonaldehyde(MDA), superoxide dismutase (SOD)were measured to detect the liver function. Hematoxylin and eosin (HE) was used to evaluate pathologic changes;2. The expression of TNF-a and activaty of Cathepsin B were detected by enzyme linked immunosorbent assay (ELISA). Real-time fluorescence quantitative PCR were used to evaluate the Bax gene and Bcl-2 gene expression.3.The mean arterial pressure (MAP), heart rate (HR), blood flow, blood flow velocity were measured to evaluate the influence of VER on cardiovascular system.Results1. Administrated via i.v. at 1 h before induction of ALF, VER significantly decreased mice mortality rate and levels of ALT, AST, TBIL, MDA, also improve the activity of SOD. VER can also alleviate D-GlaN/LPS induced severe injury of hepatic tissue:prevent the liver cell from necrosis.2. The expression of TNF-a and Cath B activaty were increased in ALF mice, and the highest expression occurred at 1 h and 4h after D-GlaN/LPS injection. VER could extremely significantly curb the increase, either TNF-a or Cath B. Also, VER could inhibit Bax gene expression, increase Bcl-2 gene expression, and result in the Bax/Bcl-2 ratio.3. VER may lower the MAP, increase HR, and also improve the liver microcirculation, it may cause unwelcome reactions like hypotension, bradycardia.ConclusionVER has very good therapeutic effect against ALF. It can alleviate the severe injury of hepatic tissue:improve the liver function and the liver microcirculation. VER could effectively eliminate the [Ca2+]i overload, and by the mechanism, inhibit the increase of the expression of TNF-α、Bax, depress the activation of Cath B, all of them lead to strong suppression of apoptosis and cell necrosis.