AIM:To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.METHODS:Wild type,e NOS-/-and i NOS-/-mice receivedpartial 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-1contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph.RESULTS:In wild type and i NOS-/-mice splenic pulp pressure increased from 7.5±1.1 mm Hg and 7.2±1 mm Hg to 25.4±3.1 mm Hg and 22±4 mm Hg respectively.In e NOS-/-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 mm Hg and 7.3±0.8 mm Hg respectively,P=0.3).Abdominal aortic flow was increased by 80%and 73%in 7 d portal vein ligated wild type and i NOS when compared to shams,whereas there was no significant difference in 7 d portal vein ligated e NOS-/-mice when compared to shams.Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type,e NOS-/-and i NOS-/-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,e NOS-/-and i NOS-/-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. AIM: To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.METHODS: Wild type, e NOS - / - and i NOS - / - mice receivedpartial 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, thoraci cortisol endothelin-1contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph. Results: In wild type and i NOS - / - mice splenic pulp pressure increased from 7.5 ± 1.1 mm Hg and 7.2 ± 1 mm Hg to 25.4 ± 3.1 mm Hg and 22 ± 4 mm Hg respectively. In NOS - / - mice with 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 mm Hg and 7.3 ± 0.8 mm Hg respectively, P = 0.3) .Abdominal aortic flow was increased by 80% and 73% in 7 d portal vein ligated wild type and i NOS when compared to shams, there was no significant difference in 7 d portal vein ligated e NOS - / - mice when compared to shams. Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type, e NOS - / - and i NOS (50% ± 8%, 73% ± 9% and 47% ± 9% respectively) .Following portal vein ligation endothelin-1 reduction in blood flow was significantly diminished in each mo use 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.