Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2016; 22(48): 10545-10556
Published online Dec 28, 2016. doi: 10.3748/wjg.v22.i48.10545
Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis
Gloria Segarra, Belén Cortina, María Dolores Mauricio, Susana Novella, Paloma Lluch, Javier Navarrete-Navarro, Inmaculada Noguera, Pascual Medina
Gloria Segarra, Belén Cortina, María Dolores Mauricio, Susana Novella, Javier Navarrete-Navarro, Inmaculada Noguera, Pascual Medina, Department of Physiology, University of Valencia and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain
Paloma Lluch, Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain
Author contributions: Segarra G, Cortina B and Medina P designed and supervised the study; Segarra G, Cortina B, Mauricio MD, Novella S, Navarrete-Navarro J and Noguera I collected samples and performed the experiments; Segarra G, Cortina B, Mauricio MD, Novella S, Lluch P, Noguera I and Medina P acquired and analyzed the data; all authors drafted the article, made critical revisions related to the intellectual content of the manuscript and approved the final version of the article for publication.
Supported by Consellería de Sanidad of the Generalitat Valenciana, No. AP-052/08.
Institutional review board statement: The study was reviewed and approved by the University of Valencia Institutional Ethics Committee.
Institutional animal care and use committee statement: All protocols were approved by the Institutional Ethics Committee at the University of Valencia (No. UV20121124), and conformed to the Guide for the Care and Use of Laboratory Animals published in Directive 2010/63/EU of the European Parliament.
Conflict-of-interest statement: The authors declare no conflict of interests.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Pascual Medina, PhD, Department of Physiology, University of Valencia and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, Avenida Blasco Ibáñez 15, 46010 Valencia, Spain. pascual.medina@uv.es
Telephone: +34-96-3864983 Fax: +34-96-3864642
Received: July 27, 2016
Peer-review started: July 30, 2016
First decision: August 29, 2016
Revised: September 17, 2016
Accepted: October 10, 2016
Article in press: October 10, 2016
Published online: December 28, 2016
Processing time: 152 Days and 2 Hours
Abstract
AIM

To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats.

METHODS

Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-9-3 × 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA.

RESULTS

In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group.

CONCLUSION

Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.

Keywords: Portal hypertension; Cirrhosis; Nitric oxide; Asymmetric dimethylarginine; Nitric oxide inhibitors; Dimethylarginine dimethylaminohydrolase

Core tip: Cirrhosis is associated with renal dysfunction and renal vasoconstriction. This constriction leads to decreased renal blood flow and glomerular filtration. Decreased nitric oxide (NO) bioavailability is involved in these effects. Although plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, are increased in cirrhosis, the effects of ADMA on renal arteries under this pathological condition are unknown. Therefore, the present work studied the effects of ADMA on basal- and stimulated-NO release in renal arteries from portal hypertensive and cirrhotic rats and the renal expression and activity of dimethylarginine dimethylaminohydrolase, an enzyme that catabolizes ADMA.