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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 | Performance of immobilized tertiary amine solid sorbents for the capture of carbon dioxide显示文摘 | M.L. Gray K.J. Champagne D. Fauth J.P. Baltrus Henry Pennline | 2007 | International Journal of Greenhouse Gas Control2007，，1： | 2 |
| 3 | Electron field emitters based on carbon nanotube films显示文摘 | De Heer W A Bonard J M Fauth K | 1997 | Adv Mater1997，9，： | 1 |
| 4 | Acrylamide and glycidamide: genotoxic effects in V79-cells and human blood 显示文摘 | Baum M Fauth E Fritzen S | 2005 | Mutat Res-Genet Toxicol Environ Mutag2005，580，： | 1 |
| 5 | Electron field emitters based on carbon nanotube films显示文摘 | De Heer W A Bonard J M Fauth K | 1997 | Advance Materials1997，9，： | 1 |
| 6 | Lipoic acid synthetase defi- ciency causes Neonatal-Onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation 显示文摘 | Mayr JA Zimmermann FA Fauth CA | 2011 | Am J Hum Genet2011，89，6： | 1 |
| 7 | Activation of magnesium rich minerals as carbonation feedstock materials for CO2 sequestration显示文摘 | MAROTO-VALER M M FAUTH D J KUCHTA M E | 2005 | Fuel Processing Technology2005，86，： | 1 |
| 8 | 显示文摘 | Daniel J Fauth Elizabeth A Frommell James S Hoffman | 2005 | Fuel Processing Technology2005，86，： | 1 |
| 9 | Multiplex-FISH for pre- and postnatal diagnostic applications显示文摘 | Uhrig S Schuffenhauer S Fauth C | 1999 | Am J Hum Genet1999，65，： | 1 |
| 10 | Dynamic loading of the plantar aponeurosis in walking显示文摘 | ERDEMIR A HAMEL A J FAUTH A R etal | 2004 | J Bone Joint Surg Am2004，86，3： | 1 |
| 11 | Performance of immobilized tertiary amine solid adsorbents for the capture of carbon dioxide显示文摘 | Gray M L Champagne K J Fauth D | 2008 | International Journal of Greenhouse Gas Control2008，2，1： | 1 |
| 12 | An optimized probe set for the detection of small interchromosomal aberrations by 24-color FISH显示文摘 | AZOFEIFA J FAUTH C KRAUS J | 2000 | Am J Hum Genet2000，66，5： | 1 |
| 13 | Galbonolides A and B---two new non-glycosidic antifungal macrolides from Streptomyces galbus 显示文摘 | Achenbach H Muhlenfeld A Fauth U | 1985 | Tetrahedron Lett1985，26，50： | 1 |
| 14 | Designing adsorbents for CO2capture from flue gas-hyperbranched aminosilicas capable of capturing CO2reversibly显示文摘 | HICKS J C DRESE J H FAUTH D J | 2008 | Journal of the American Chemical Society2008，130，10： | 1 |
| 15 | Antiferromagnetic ordering in the cubic superconductor YbPd2Sn显示文摘 | DONNI A FISCHER P FAUTH F CONVERT P AOKI Y SUGAWARA H SATO H | 1999 | Physica B1999，，： | 1 |
| 16 | Activa- tion of magnesium rich minerals as carbonation feedstock materials for CO 2 sequestration显示文摘 | Maroto-Valer M M Fauth D J Kuchta M E | 2005 | Fuel Processing Tech- nology2005，86，14： | 1 |
| 17 | Characterisitics of hexahydro-1,3,5-trinitro-s-triazine and octahydra1,3,5,7-tetranitro-s-tetrazinein nonaqueous 显示文摘 | Fauth M I Frandsen M Havlik B R | 1964 | Anal Chem1964，36，： | 1 |
| 18 | 'Toward more and (better) countertransference research'显示文摘 | Fauth J | | 0，，： | 1 |
| 19 | Order of genetic events is critical determinant of aberrations in chromosome count and structure显示文摘 | Fauth C O'Hare MJ Lederer G | 2004 | Genes Chromosomes Cancer2004，40，4： | 1 |
| 20 | Multiplex-FISH for pre- and postnatal diagnostic applications显示文摘 | Uhrig S Schuffenhauer S Fauth C | 1999 | Am J Hum Genet1999，65，2： | 1 |
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