Published online Apr 28, 2015. doi: 10.3748/wjg.v21.i16.4817
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
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.
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.