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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 | Preliminary characterisation of new reference materials for microanalysis: Chinese geological standard glasses CGSG-1, CGSG-2, CGSG4 and CGSG-5 显示文摘 | Hu M Y Fan X T Stoll B Kuzmin D Liu Y Liu Y S Sun W D Wang G Zhan X C Jochum K P | 2011 | Geostandards and Geoanalytical Research2011，35，： | 1 |
| 3 | Vascular risk factors in sudden hearing loss显示文摘 | Rudaek C Langer C Stoll W | 2006 | Thromb Haemost2006，95，3： | 1 |
| 4 | Listening to tailor?made notched music reduces tinnitus loudness and tinnitus-related auditory cortex activity显示文摘 | Okamoto H Stracke H Stoll W | 2010 | Proc Natl Acad Sci USA2010，107，3： | 1 |
| 5 | Molecular mechanisms of cellular interactions in peripheral nerve regeneration显示文摘 | Kury P Stoll G Muller H W | 2001 | Curr Opin Neurol2001，14，5： | 1 |
| 6 | Port placement planning in robot-assisted coronary artery bypass显示文摘 | Cannon J W Stoll J A Selha S D | 2003 | IEEE Transactions on Robotics and Automation2003，19，5： | 1 |
| 7 | Necrotising enterocolitis显示文摘 | Lin P W Stoll B J | 2006 | The Lancet2006，368，9543： | 1 |
| 8 | Optic never decompression in the comatose and conscious patients after trauma显示文摘 | Stoll W Crenzebach U | 2001 | Laryngoscope2001，111，2： | 1 |
| 9 | Rotatory stability of the knee after arthroscopie meniscus suture repair:a 5-to-17-year follow-up study of isolated medial and lateral meniscus tears 显示文摘 | Majewski M Stoll R Mttller W | 2009 | Acta Orthop Belg2009，75，3： | 1 |
| 10 | Use of the 'double barrel' free vascularized fibula in mandibular reconsruction显示文摘 | Bahr W Stoll P Wachler R | 1998 | Oral Manxillofacial Surgery1998，56，1： | 1 |
| 11 | Energy shocks and financial markets显示文摘 | Huang R D Masulis R W Stoll H R | 1996 | Journal of Futures Markets1996，16，： | 1 |
| 12 | Toward field-scale wettabilitymodificafion the limitation of diffusive transport显示文摘 | Stoll W M Hofman J P Ligtheim | 2008 | SPE Reser-voir Evaluation & Engineering2008，11，3： | 1 |
| 13 | Direct observa- tion of the vortex core magnetization and its dynam- ics显示文摘 | Chou K W Puzic A Stoll H | 2007 | Applied Physics Letters2007，90，20： | 1 |
| 14 | A genomic-systems biology map for cardiovascular function显示文摘 | Stoll M Cowley A W Tonellato P J et a1 | 2001 | Science2001，98，294： | 1 |
| 15 | Use of the 'double barrel' free vascularized fibula in mandibular reconstruction 显示文摘 | Bahr W Stoll P Wachtet R | 1998 | J Oral Maxillofac Surg1998，56，1： | 1 |
| 16 | Evaluation of treament results with ragard to initial anterior commissure involvement in early glottic carcinoma treated by external partial surgery or transoral laser microresection显示文摘 | SACHSE F STOLL W RUDACK C | 2009 | Head Neck2009，31，： | 1 |
| 17 | Dynamic behavior of fluorescent whitening agents in Greifensee: Field measurements combined with mathematical modeling of sedimentation and photoiysis显示文摘 | Stoll Jean-Marc A Ulrich M M Giger W | 1998 | Environmental Science & Technology1998，32，13： | 1 |
| 18 | Nasal surgery in patients with systemic disorders显示文摘 | Sachse F Stoll W | 2010 | Laryngorhinootologie2010，89，1： | 1 |
| 19 | Olfactory function after functional endoscopic sinus surgery for chronic sinusitis 显示文摘 | Delank KW Stoll W | 1998 | Rhinology1998，36，1： | 1 |
| 20 | Effect of prednislone on cytokine synthesis in nasal polyps显示文摘 | Bachert C Stoll W | 1999 | J Interferon Cytokine Kes1999，19，9： | 1 |
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