Treatment of Portal Hypertension with NCX‐1000, a Liver‐Specific NO donor. A Review of Its Current Status

Abstract

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.

Recent Advances on the Roles of NO in Cancer and Chronic Inflammatory Disorders

“…Inflammatory stimuli, such as endotoxin and cytokines, can induce iNOS in a variety of inflammatory cells including macrophages, and neutrophils, as well as in vascular endothelium and smooth muscle. Generation and secretion of high NO concentrations by these cells may lead to perpetuation of local tissue damage, irrespective of the cause of the inflammatory response [219][220][221][222][223]. Endothelial cells, fibroblasts, or mast cells, or all three are also thought to contribute to NO generation in inflamed tissues although via calcium dependent activity.…”

“…Both Crohn's disease and ulcerative colitis are characterised by an abundance of activated macrophages and granulocytes in the inflamed tissue [219,220]. Inflammatory stimuli, such as endotoxin and cytokines, can induce iNOS in a variety of inflammatory cells including macrophages, and neutrophils, as well as in vascular endothelium and smooth muscle.…”

“…Conversely, IBD pathogenesis relies on irregular interactions of the host mucosal intestinal immunity with the huge antigenic load represented by the microorganisms present in the gut lumen [1]. A major mechanism underlying the deleterious effects of cytokines in IBD is represented by the induction of iNOS and subsequent overproduction of NO in the injured intestine [1,22,[215][216][217][218][219][220]. This is represented by studies of ulcerative colitis in rhesus monkeys, which have histopathological features and spontaneous developing symptoms close to those of humans that indicated high expression of iNOS and high NO production in the colic mucosa [221].…”

Alteration of intrahepatic microcirculation in cirrhotic livers

“…66 It has been reported that chronic administration of thalidomide, through inhibition of endotoxin-related acceleration of hepatic fibrogenesis, significantly decreased portal pressure and IHR in cirrhotic animals ( Figure 3). 67 It is well-established that endotoxemia will stimulate macrophage and platelet activity associated with the release of inflammatory cytokines, tumor necrosis factor (TNF)a, and thromboxane A 2 in cirrhosis. 59,68e70 Further studies have shown that endotoxin-induced TNFa production is the key factor to induce liver injury and promote hepatic fibrogenesis.…”

Albumin as a Nitric Oxide-Traffic Protein: Characterization, Biochemistry and Possible Future Therapeutic Applications

“…By a NOtraffic protein is meant a protein with i) high efficiency of S-nitrosylation, ii) high stability of the S-nitroso form in the circulation and iii) high efficiency of S-transnitrosation into cells which need NO. As a candidate in this respect we focus on human serum albumin (HSA), because HSA is the most abundant plasma protein (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) g/L) and because endogenous S-nitrosothiols in human plasma is largely associated with HSA. 49) S-nitrosylated HSA (SNO-HSA) is significantly more stable than low molecular weight S-nitrosothiols.…”