Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, 08035, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.
Sci Rep. 2017 Jan 13;7:40461. doi: 10.1038/srep40461.
Statins present many beneficial effects in chronic liver disease, but concerns about safety exist. We evaluated the hepatic effects of a nitric oxide-releasing atorvastatin (NCX 6560) compared to conventional statins. Simvastatin, atorvastatin and NCX 6560 were evaluated in four-week bile duct-ligated rats (BDL) simulating decompensated cirrhosis and in thirteen-week carbon tetrachloride (CCl) intoxicated rats, a model of early cirrhosis. In the BDL model, simvastatin treated rats showed high mortality and the remaining animals presented muscular and hepatic toxicity. At equivalent doses, NCX 6560 eliminated hepatic toxicity and reduced muscular toxicity (60-74%) caused by atorvastatin in the more advanced BDL model; toxicity was minimal in the CCl model. Atorvastatin and NCX 6560 similarly reduced portal pressure without changing systemic hemodynamics in both models. Atorvastatin and NCX 6560 caused a mild decrease in liver fibrosis and inflammation and a significant increase in intrahepatic cyclic guanosine monophosphate. NCX 6560 induced a higher intrahepatic vasoprotective profile (activated endothelial nitric oxide synthase and decreased platelet/endothelial cell adhesion molecule-1), especially in the CCl model, suggesting a higher benefit in early cirrhosis. In conclusion, NCX 6560 improves the liver profile and portal hypertension of cirrhotic rats similarly to conventional statins, but with a much better safety profile.
他汀类药物在慢性肝病中有许多有益的作用，但存在安全性方面的担忧。我们评估了一种释放一氧化氮的阿托伐他汀（NCX 6560）与传统他汀类药物相比对肝脏的影响。我们在模拟失代偿性肝硬化的四周胆管结扎大鼠（BDL）和十三周四氯化碳（CCl）中毒大鼠（早期肝硬化模型）中评估了辛伐他汀、阿托伐他汀和 NCX 6560。在 BDL 模型中，辛伐他汀治疗的大鼠死亡率很高，其余动物表现出肌肉和肝脏毒性。在等效剂量下，NCX 6560 消除了阿托伐他汀在更晚期 BDL 模型中引起的肝毒性和肌肉毒性（60-74%）；在 CCl 模型中，毒性最小。阿托伐他汀和 NCX 6560 同样降低了门静脉压力，而不改变两种模型的全身血液动力学。阿托伐他汀和 NCX 6560 导致肝纤维化和炎症轻度减少，肝内环鸟苷单磷酸显著增加。NCX 6560 诱导了更高的肝内血管保护谱（激活内皮型一氧化氮合酶，降低血小板/内皮细胞黏附分子-1），特别是在 CCl 模型中，这表明在早期肝硬化中具有更高的益处。总之，NCX 6560 改善了肝硬化大鼠的肝脏状况和门静脉高压，与传统的他汀类药物相似，但安全性更好。
