Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2015; 21(16): 4817-4828
Published online Apr 28, 2015. doi: 10.3748/wjg.v21.i16.4817
Murine study of portal hypertension associated endothelin-1 hypo-response
Nicholas Theodorakis, Mary Maluccio, Nicholas Skill
Nicholas Theodorakis, Mary Maluccio, Nicholas Skill, Department of Surgery, Division of Transplant Surgery, Indiana School of Medicine, Indiana University, Indianapolis, IN 46202, United States
Author contributions: Theodorakis N and Skill N performed the research; Skill N and Maluccio M designed the research; Skill N and Maluccio M wrote the paper.
Supported by Indiana University department of surgery and Lilly INGEN research fund provided support for the Research performed in this manuscript.
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: Nicholas Skill, PhD, Assistant Research Professor, Department of Surgery, Division of Transplant Surgery, Indiana School of Medicine, Indiana University, Walthur Cancer Research Building, Rm C519. 980 W. Walnut Street, Indianapolis, IN 46202, United States. nskill@iupui.edu
Telephone: +1-317-2744532 Fax: +1-317-2748046
Received: September 3, 2014
Peer-review started: September 4, 2014
First decision: October 14, 2014
Revised: November 3, 2014
Accepted: December 5, 2014
Article in press: December 8, 2014
Published online: April 28, 2015
Abstract

AIM: To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.

METHODS: Wild type, eNOS-/- and iNOS-/- mice received partial portal vein ligation surgery to induce portal hypertension or sham surgery. Development of portal hypertension was determined by measuring the splenic pulp pressure, abdominal aortic flow and portal systemic shunting. To measure splenic pulp pressure, a microtip pressure transducer was inserted into the spleen pulp. Abdominal aortic flow was measured by placing an ultrasonic Doppler flow probe around the abdominal aorta between the diaphragm and celiac artery. Portal systemic shunting was calculated by injection of fluorescent microspheres in to the splenic vein and determining the percentage accumulation of spheres in liver and pulmonary beds. Endothelin-1 hypo-response was evaluated by measuring the change in abdominal aortic flow in response to endothelin-1 intravenous administration. In addition, thoracic aorta endothelin-1 contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph.

RESULTS: In wild type and iNOS-/- mice splenic pulp pressure increased from 7.5 ± 1.1 mmHg and 7.2 ± 1 mmHg to 25.4 ± 3.1 mmHg and 22 ± 4 mmHg respectively. In eNOS-/- mice splenic pulp pressure was increased after 1 d (P = NS), after which it decreased and by 7 d was not significantly elevated when compared to 7 d sham operated controls (6.9 ± 0.6 mmHg and 7.3 ± 0.8 mmHg respectively, P = 0.3). Abdominal aortic flow was increased by 80% and 73% in 7 d portal vein ligated wild type and iNOS when compared to shams, whereas there was no significant difference in 7 d portal vein ligated eNOS-/- mice when compared to shams. Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type, eNOS-/- and iNOS-/- sham mice (50% ± 8%, 73% ± 9% and 47% ± 9% respectively). Following portal vein ligation endothelin-1 reduction in blood flow was significantly diminished in each mouse group. Abdominal aortic flow was reduced by 19% ± 9%, 32% ± 10% and 9% ± 9% in wild type, eNOS-/- and iNOS-/- mice respectively.

CONCLUSION: Aberrant endothelin-1 response in murine portal hypertension is NOS isoform independent. Moreover, portal hypertension in the portal vein ligation model is independent of ET-1 function.

Keywords: Liver disease, Portal hypertension, Hyper-dynamic circulation, Endothelin-1, Nitric oxide synthase isoforms

Core tip: Portal hypertension (PHT) is a complication associated with vascular derangements in response to liver disease and fibrosis. Perturbations of nitric oxide (NO) and endothelin-1 are believed to be interrelated and play a key role in PHT vasculopathy. This study investigates the importance of NO biosynthesis in endothelin-1 vasoconstriction hypo-response seen in patients with PHT. PHT was induced in wild type, eNOS-/- and iNOS-/- mice by partial portal vein ligation (PVL) and endothelin-1 contractile response was determined. Endothelin-1 (ET-1) induced contraction was significantly reduced following PVL in all mouse groups. Aberrant ET-1 function associated with PHT is NO independent.