Volume 138, Issue 4, Pages 1574-1584 (April 2010) Losartan Prevents Portal Hypertension-Induced, Redox-Mediated Endothelial Dysfunction in the Mesenteric Artery in Rats  Stéphanie Dal–Ros, Monique Oswald–Mammosser, Tatiana Pestrikova, Christa Schott, Nelly Boehm, Christian Bronner, Thierry Chataigneau, Bernard Gény, Valérie B. Schini–Kerth  Gastroenterology  Volume 138, Issue 4, Pages 1574-1584 (April 2010) DOI: 10.1053/j.gastro.2009.10.040 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 CBDL induced blunted EDHF-mediated relaxations in mesenteric artery rings. Concentration-relaxation curves to ACh and RWPs in mesenteric artery rings with endothelium in sham and CDBL rats: panels A and C in the presence of indomethacin and apamin plus charybdotoxin; panels B and D in the presence of indomethacin and Nω-nitro-L-arginine. Results are shown as mean ± SEM of 5–7 different rats; *P = .001 and **P = .003 for sham vs CBDL. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 CBDL induced down-regulation of connexins (panels A–C) and potassium channels (panels D and E) in the mesenteric artery: protective effect of apocynin and losartan. Top: representative immunofluorescent staining; bottom: corresponding cumulative data. Similar results have been observed in 4 other rats in each group. The lumen is on the right side of each image, and scale bar corresponds to 50 μm. *P < .001 for Cx37 and IKCa, P = .04 for Cx40, P = .004 for Cx43, and P < .01 for SKCa when comparing CBDL with sham rats; #P < .01 for Cx47, IKCa and SKCa, P < .03 for Cx40, and P < .001 for Cx43 when comparing CBDL with treated CBDL rats. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions

Figure 3 CBDL induced the formation of reactive oxygen species (ROS, panel A) and peroxynitrites (panel C), an up-regulation of eNOS (panel B) and NADPH oxidase subunits (panel D) in mesenteric artery: protective effect of apocynin and losartan. Top: representative immunofluorescent staining; bottom: corresponding cumulative data. Similar results have been observed in 4 other rats in each group. The lumen is on the right side of each image, and scale bar corresponds to 50 μm. *P < .02 and **P < .001 for CBDL vs sham rats, #P < .04 for ROS and eNOS, P < .01 for nitrotyrosine, and P < .001 for p22phox and nox1 when comparing CBDL with treated CBDL rats. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions

Figure 4 Characterization of the CBDL-induced formation of ROS in mesenteric artery. The effects of MnTMPyP (a SOD analogue), DPI (an inhibitor of flavin-dependent enzymes), apocynin (an inhibitor of NADPH oxidase), and L-NA (an inhibitor of eNOS) are shown. Top: representative immunofluorescent staining; bottom: corresponding cumulative data. Similar results have been observed in 4 other rats in each group. The lumen is on the right side of each image, and scale bar corresponds to 50 μm. *P < .01 for CBDL vs sham rats, #P < .01 for CBDL vs treated CBDL rats. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions

Figure 5 CBDL induced formation of reactive oxygen species (ROS, panel A) and peroxynitrites (nitrotyrosine, panel C) and an up-regulation of eNOS (panel B) in the pulmonary artery: effect of MnTMPyP (a SOD analogue). The protective effect of apocynin and losartan is also shown. Top: representative immunofluorescent staining; bottom: corresponding cumulative data. Similar results have been observed in 3 other rats in each group. The lumen is on the right side of each image, and scale bar corresponds to 50 μm. *P < .001 for CBDL vs sham rats, #P < .001 for CBDL vs treated CBDL rats, **P < .001 for control vs MnTMPyP in CBDL rats. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions

Figure 6 Treatments with either apocynin (panels A and B) or losartan (panels C and D) prevented the blunted EDHF-mediated-relaxation in mesenteric artery rings from CBDL rats. Results are shown as mean ± SEM of 5–7 different rats. *P < .001 for CBDL vs treated CBDL rats; NS, not significant. Gastroenterology 2010 138, 1574-1584DOI: (10.1053/j.gastro.2009.10.040) Copyright © 2010 AGA Institute Terms and Conditions