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| 1 | Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension显示文摘AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension. | Denise Schaffner Adhara Lazaro Peter Deibert Peter Hasselblatt Patrick Stoll Lisa Fauth Manfred W Baumstark Irmgard Merfort Annette Schmitt-Graeff Wolfgang Kreisel | 2018 | World Journal of Gastroenterology2018，24，38： | 2 |
| 2 | A triterpene from the bark of Tamarix aphylla 显示文摘 | Merfort I Buddrus J Nawwar M A M | 1992 | Phytochemistry1992，31，： | 1 |
| 3 | Radical scavenger activity of three flavonoid metabolites studied by inhibition of in human PMNs显示文摘 | Merfort I Heilmann J Weiss M | 1996 | Planta Med1996，4，62： | 1 |
| 4 | Tannins from the leaves of Punica granatum显示文摘 | Hussein S A M Barakat H H Merfort I | 1997 | Phyto- chemistry1997，45，4： | 1 |
| 5 | Radical scavenger activity of different 3, 42dihydroxyflavonols and 1, 52dicaffeoylquinic acid studied by inhibit-tion of chemiluminescence显示文摘 | Heilmann J Merfort I Weiss M | 1995 | Planta Med1995，61，5： | 1 |
| 6 | Cytotoxicity of flavonoids and sesquiterpene lactones from Arnica species against the GLC4 and the COLO 320 cell lines 显示文摘 | Woerdenbag H J Merfort I Paβreiter C M | 1994 | Planta Medica1994，60，5： | 1 |
| 7 | Radicalscavenger activity of three flavonoid metabolites stud-ied by inhibition of chemiluminescence in humanPMNs显示文摘 | MERFORT I HEILMANN J WEISS M | 1996 | Planta Medica1996，62，4： | 1 |
| 8 | Tannins from the leaf of Punica granatum显示文摘 | Hussein S A M Barakt H H Merfort I | 1997 | Phytochemistry1997，45，4： | 1 |
| 9 | Inhibition of NF-KB and AP-1 by dimethylfumarate correlates with down-regulated IL-6 secretion and proliferation in human lung fibroblasts 显示文摘 | Seidel P Merfort I Tamm M | 2010 | Swiss medical wkly2010，140，13： | 1 |
| 10 | Modification of the membrane-bound glucose oxidation system in Gluconobacter oxydans significantly increases gluconate and 5-keto-D-gluconic acid accumulation显示文摘 | Merfort M Herrmann U Ha SW | | 0，，5： | 1 |
| 11 | Anti-Oxidant, Anti-Inflammatory and Anti-Allergic Activities of Luteolin显示文摘 | Günter Seelinger Irmgard Merfort Christoph Schempp | 2008 | Planta Med2008，，： | 1 |
| 12 | Acetylated and other flavonoid glycosides from Arnica chamisssonis显示文摘 | MERFORT I | 1988 | Phytochemistry1988，27，10： | 1 |
| 13 | Tumor necrosis factor α sensitizes primary murine hepatocytes to Fas/CD95‐induced apoptosis in a Bim‐ and Bid‐dependent manner显示文摘 | Kathrin Schmich Rebekka Schlatter Nadia Corazza Karine Sá Ferreira Michael Ederer Thomas Brunner Christoph Borner Irmgard Merfort | 2011 | Hepatology2011，，： | 1 |
| 14 | Efficacy and safety of vardenafil for the treatment of erectile dysfunction in men with met- abolic syndrome:results of a randomized, placebo-controlled trial 显示文摘 | Schneider T Gleissner J Merfort F | 2011 | J Sex Med2011，8，10： | 1 |
| 15 | Polyphenolic metabolites of Rhamnus disperma显示文摘 | Marzouk Mohamed S El-Toumy Sayed A A Merfort Irmgard Nawwar Mahmoud A M | 1999 | Phytochemistry1999，52，5： | 1 |
| 16 | A Triterpene from the bark of Tamarix aphylla 显示文摘 | Merfort I Buddrus J Nawwer M A M | 1992 | Phytochemistry1992，31，11： | 1 |
| 17 | High-yield 5-keto-D-gluconic acid formation is mediated by soluble and membrane-bound gluconate-5-dehydrogenases of Gluconobacter oxydans显示文摘 | Marcel Merfort Herrmann U Stephanie BM | | 0，，2： | 1 |
| 18 | Biotransformation of glucose to 5-keto-D-gluconic acid by recombinant Gluconobacter oxydans DSM 2343显示文摘 | Herrmann U Merfort M Jeude M | | 0，，： | 1 |
| 19 | Tannins from the Leaves of Punica Granatum显示文摘 | Barakat HH Irmgard Merfort | 1997 | Phytochemistry1997，45，4： | 1 |
| 20 | Flavonol triglycosides from seeds of Nigella sative 显示文摘 | MERFORT I WRAY V BARAKAT H H | 1997 | Phytochemistry1997，46，2： | 1 |
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