Treatment of portal hypertension with NCX-1000, a liver-specific NO donor. A review of its current status.
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.
Fiorucci
Stefano
S
Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Universita degli Studi di Perugia, Via E dal Pozzo, 06122, Perugia, Italy. fiorucci@unipg.it.
Antonelli
Elisabetta
E
Tocchetti
Paola
P
Morelli
Antonio
A
D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D009566:Nitrates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014580:Ursodeoxycholic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid