Portal hypertension, a life threatening complication of
liver cirrhosis, results from increased intrahepatic resistance and increased portal blood inflow through a hyperdynamic splanchnic system. The increased intrahepatic vascular tone is the result of an enhanced activity of endogenous
vasoconstrictors and a deficiency of
nitric oxide (NO) release by sinusoidal endothelial cells. These pathophysiological events provide the rational basis for using NO-based
therapies for the treatment of
portal hypertension. Clinical studies have demonstrated that
nitrate therapy results in a significant reduction of portal pressure as assessed by hepatic venous portal gradient but causes vasodilation in both systemic arterial and venous vascular beds, aggravating the progression of the vasodilatory syndrome of cirrhotic patients. For this reason, the ideal
drug for the treatment of
portal hypertension should act by decreasing intrahepatic vascular resistance, without worsening the splanchnic/systemic vasodilatation.
NCX-1000 is the prototype of a family of NO-releasing derivatives of
ursodeoxycholic acid (UDCA). These compounds are releasing selectively, from parenchymal and non-parenchymal hepatic cells, biologically active NO into the liver microcirculation with no detectable effect on systemic circulation. Preclinical studies have shown that long- and short-term administration of
NCX-1000 to rodents with chronic liver injury protects against the development of
portal hypertension and reduces the intrahepatic hyperreactivity to alpha1-adrenoceptor agonists. The finding of increased liver
nitrite/
nitrate content in NCX-1000-treated animals together with an increase in cGMP levels in their liver homogenates suggests that this nitro-compound behaves as a liver-selective NO donor. In contrast to conventional NO-donors such as
isosorbide mono- and di-
nitrate, which are also used for primary and
secondary prevention of gastrointestinal
bleeding,
NCX-1000 has no effect on mean arterial pressure in either normal or cirrhotic animals indicating the absence of adverse systemic effect. In summary, these data suggest that
NCX-1000 may provide a novel
therapy for the treatment of patients with
portal hypertension.