Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats

Abstract

Increased superoxide in cirrhotic livers, by reducing nitric oxide bioavailability, contributes to increase intrahepatic vascular resistance to portal blood flow and as a consequence portal pressure. We aimed to evaluate whether a strategy directed to reduce superoxide using tempol, a small membrane permeable SOD-mimetic, is able to modulate intrahepatic nitric oxide content and reduce portal pressure in cirrhotic rats. Superoxide and nitric oxide were evaluated in control sinusoidal endothelial cells (SEC) pre-treated with the pro-oxidant diethyldithiocarbamate (DDC) and in CCl(4)-cirrhotic rat livers treated with tempol or vehicle. Mean arterial pressure, portal pressure, and portal blood flow were measured in control and cirrhotic rats treated with tempol (180μmol/kg/h; via ileocholic vein) or vehicle. In a subset of animals, hemodynamic measurements were performed after NO-inhibition with l-NAME. Tempol reduced superoxide content and increased NO both in SEC and cirrhotic livers. In cirrhotic rats, but not in controls, tempol significantly reduced portal pressure, and increased portal blood flow, which most likely reflects a reduction in intrahepatic vascular resistance. Tempol significantly reduced mean arterial pressure. l-NAME prevented all these effects. Tempol reduces superoxide, increases nitric oxide, and reduces portal pressure in sinusoidal endothelial cells and in cirrhotic livers. These results confirm that oxidative stress has a role in the pathogenesis of portal hypertension and supports the use of antioxidants in its treatment. However, when considering the use of antioxidants as additional therapy to treat portal hypertension, the potential to produce deleterious effects on systemic hemodynamics needs to be carefully evaluated.