Evidence against a role for NADPH oxidase modulating hepatic vascular tone in cirrhosis.

Abstract

BACKGROUND & AIMS:

Increased hepatic vascular resistance in cirrhosis is in part due to reduced nitric oxide (NO) bioavailability. This is related to insufficient NO synthesis from endothelial nitric oxide synthase and to enhanced NO scavenging by superoxide radicals (O(2)(-)). Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is an important source of O(2)(-) that increases vascular tone in different cardiovascular disorders. Thus, our aims were to study the molecular and biochemical state of NADPH-oxidase in cirrhotic livers and to investigate its possible role in modulating hepatic vascular tone in cirrhosis.

METHODS:

NADPH-oxidase expression and enzymatic activity were determined in control (n = 8) and CCl(4)-cirrhotic (n = 8) rat livers. Additional control (n = 6) and CCl(4)-cirrhotic (n = 10) rats were treated with apocynin (a selective NADPH-oxidase inhibitor) or its vehicle. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow were measured in vivo. Moreover, hepatic endothelial function was evaluated in isolated and perfused rat livers by dose-response curves to acetylcholine. In addition, in 6 control and 6 cirrhotic human livers NADPH-oxidase activity and expression were evaluated.

RESULTS:

Rat cirrhotic livers had no increased NADPH-oxidase protein expression or activity in relation to control livers. NADPH-oxidase inhibition did not modify splanchnic or systemic hemodynamics in control or cirrhotic rats and did not improve the impaired endothelial-dependent vasodilatory response to acetylcholine of cirrhotic livers. Human cirrhotic livers also did not exhibit increased NADPH-oxidase expression or activity.

CONCLUSIONS:

Our study shows that NADPH-oxidase activity is decreased in the cirrhotic livers and therefore cannot explain increased hepatic O(2)(-), endothelial dysfunction, and increased vascular tone in cirrhotic livers.

• Authors: Jorge Gracia-Sancho, Bàrbara Laviña, Aina Rodríguez-Vilarrupla, Ralf P Brandes, Mercedes Fernández, Jaume Bosch, Joan-Carles García-Pagán
• Journal: Gastroenterology (Gastroenterology) Vol. 133 Issue 3 Pg. 959-66 (Sep 2007) ISSN: 0016-5085 [Print] United States
• PMID: 17854599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Antioxidants
• RNA, Messenger
• Superoxides
• acetovanillone
• Carbon Tetrachloride
• Nitric Oxide Synthase Type III
• NADPH Oxidases

Topics

• Acetophenones (pharmacology)
• Adult
• Aged
• Animals
• Antioxidants (pharmacology)
• Blood Pressure (drug effects, physiology)
• Carbon Tetrachloride
• Dose-Response Relationship, Drug
• Endothelium, Vascular (metabolism, physiopathology)
• Female
• Hepatic Artery (metabolism, physiopathology)
• Humans
• Liver Cirrhosis (chemically induced, metabolism, physiopathology)
• Male
• Middle Aged
• NADPH Oxidases (genetics, metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Regional Blood Flow (drug effects, physiology)
• Superoxides (metabolism)