Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis
Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monop...
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| creator | Sandner, Peter Tinel, Hanna Affaitati, Giannapia Costantini, Raffaele Giamberardino, Maria Adele |
| description | Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain. |
| doi_str_mv | 10.1371/journal.pone.0141477 |
| format | Article |
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New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0141477</identifier><identifier>PMID: 26509272</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analgesics ; Animals ; Autopsy ; Behavior, Animal ; Cardiology ; Care and treatment ; Colic ; Cyclic GMP ; Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry ; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism ; Disease Models, Animal ; Drug therapy ; Enzyme Activators - administration & dosage ; Enzyme Activators - pharmacology ; Expulsion ; Female ; Gender differences ; Gene Expression ; Gene Expression Profiling ; Genetic aspects ; Guanosine ; Guanylate Cyclase - genetics ; Guanylate Cyclase - metabolism ; Health aspects ; Hyoscine ; Hyperalgesia ; Inhibitors ; Ketoprofen ; Laboratories ; Lithiasis - drug therapy ; Lithiasis - genetics ; Lithiasis - metabolism ; Lithiasis - pathology ; Lithotripsy ; Localization ; Male ; Muscle contraction ; Muscle Contraction - drug effects ; Muscles ; Nitric oxide ; Pain ; Pain perception ; Pharmacology ; Phosphodiesterase ; Phosphodiesterase 5 Inhibitors - administration & dosage ; Phosphodiesterase 5 Inhibitors - pharmacology ; R&D ; Rats ; Research & development ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Sildenafil ; Smooth muscle ; Stimulators ; Stone ; Ureter ; Ureter - drug effects ; Ureteral Calculi - drug therapy ; Ureteral Calculi - genetics ; Ureteral Calculi - metabolism ; Ureteral Calculi - pathology ; Ureteral diseases ; Urogenital system ; Urology</subject><ispartof>PloS one, 2015-10, Vol.10 (10), p.e0141477-e0141477</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Sandner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Sandner et al 2015 Sandner et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-49621fadc3ae069272a46fa71fff8956fcd5e1f1b3da2869e1a065191c04eb553</citedby><cites>FETCH-LOGICAL-c692t-49621fadc3ae069272a46fa71fff8956fcd5e1f1b3da2869e1a065191c04eb553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624930/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624930/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26509272$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sandner, Peter</creatorcontrib><creatorcontrib>Tinel, Hanna</creatorcontrib><creatorcontrib>Affaitati, Giannapia</creatorcontrib><creatorcontrib>Costantini, Raffaele</creatorcontrib><creatorcontrib>Giamberardino, Maria Adele</creatorcontrib><title>Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.</description><subject>Analgesics</subject><subject>Animals</subject><subject>Autopsy</subject><subject>Behavior, Animal</subject><subject>Cardiology</subject><subject>Care and treatment</subject><subject>Colic</subject><subject>Cyclic GMP</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drug therapy</subject><subject>Enzyme Activators - administration & dosage</subject><subject>Enzyme Activators - pharmacology</subject><subject>Expulsion</subject><subject>Female</subject><subject>Gender differences</subject><subject>Gene Expression</subject><subject>Gene Expression Profiling</subject><subject>Genetic aspects</subject><subject>Guanosine</subject><subject>Guanylate Cyclase - genetics</subject><subject>Guanylate Cyclase - metabolism</subject><subject>Health aspects</subject><subject>Hyoscine</subject><subject>Hyperalgesia</subject><subject>Inhibitors</subject><subject>Ketoprofen</subject><subject>Laboratories</subject><subject>Lithiasis - drug therapy</subject><subject>Lithiasis - genetics</subject><subject>Lithiasis - metabolism</subject><subject>Lithiasis - pathology</subject><subject>Lithotripsy</subject><subject>Localization</subject><subject>Male</subject><subject>Muscle contraction</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscles</subject><subject>Nitric oxide</subject><subject>Pain</subject><subject>Pain perception</subject><subject>Pharmacology</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase 5 Inhibitors - administration & dosage</subject><subject>Phosphodiesterase 5 Inhibitors - pharmacology</subject><subject>R&D</subject><subject>Rats</subject><subject>Research & development</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Sildenafil</subject><subject>Smooth muscle</subject><subject>Stimulators</subject><subject>Stone</subject><subject>Ureter</subject><subject>Ureter - drug effects</subject><subject>Ureteral Calculi - drug therapy</subject><subject>Ureteral Calculi - genetics</subject><subject>Ureteral Calculi - metabolism</subject><subject>Ureteral Calculi - pathology</subject><subject>Ureteral diseases</subject><subject>Urogenital system</subject><subject>Urology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkJw0eKvOPENUlXKqDQ0tDFurRPHbj25cYkdBP8ep-2mBu0C-SLWyfO-x-fYJ8teYjTFtMQfbn3fteCmW9_qKcIMs7J8lJ1iQcmEE0QfH-1Psmch3CJU0Irzp9kJ4QUSpCSnmVwYo1UMuTf5t0-LIl-2a1vb6LuQQ9vk4XyeX0e76R3sYrbNIb-CmH_1jXaDatZFa6yy4PKbTkfdpc0cnOqdDzY8z54YcEG_OHzPspvPi-_zL5OLy_PlfHYxUVyQOGGCE2ygURQ04sPRgHEDJTbGVKLgRjWFxgbXtAFScaExIF5ggRViui4Kepa93vtuU1p56E2QuCSlqFKxNBHLPdF4uJXbzm6g-yM9WLkL-G4lIZWinJZ1XenSVAxEyZgmvDKEc6w4IXVTkGLw-njI1tcb3SjdxlT2yHT8p7VrufK_JOOECYqSwbuDQed_9jpEubFBaeeg1b7fnbviZcFEldA3_6APV3egVpAKsK3xKa8aTOWMUSI4opgnavoAlVajN1alh2Rsio8E70eCxET9O66gD0Eur6_-n738MWbfHrFrDS6ug3d9tL4NY5DtQdX5EDpt7puMkRzm4K4bcpgDeZiDJHt1fEH3oruHT_8Czd4Atg</recordid><startdate>20151028</startdate><enddate>20151028</enddate><creator>Sandner, Peter</creator><creator>Tinel, Hanna</creator><creator>Affaitati, Giannapia</creator><creator>Costantini, Raffaele</creator><creator>Giamberardino, Maria Adele</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20151028</creationdate><title>Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis</title><author>Sandner, Peter ; Tinel, Hanna ; Affaitati, Giannapia ; Costantini, Raffaele ; Giamberardino, Maria Adele</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-49621fadc3ae069272a46fa71fff8956fcd5e1f1b3da2869e1a065191c04eb553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Analgesics</topic><topic>Animals</topic><topic>Autopsy</topic><topic>Behavior, Animal</topic><topic>Cardiology</topic><topic>Care and treatment</topic><topic>Colic</topic><topic>Cyclic GMP</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Drug therapy</topic><topic>Enzyme Activators - administration & dosage</topic><topic>Enzyme Activators - pharmacology</topic><topic>Expulsion</topic><topic>Female</topic><topic>Gender differences</topic><topic>Gene Expression</topic><topic>Gene Expression Profiling</topic><topic>Genetic aspects</topic><topic>Guanosine</topic><topic>Guanylate Cyclase - genetics</topic><topic>Guanylate Cyclase - metabolism</topic><topic>Health aspects</topic><topic>Hyoscine</topic><topic>Hyperalgesia</topic><topic>Inhibitors</topic><topic>Ketoprofen</topic><topic>Laboratories</topic><topic>Lithiasis - drug therapy</topic><topic>Lithiasis - genetics</topic><topic>Lithiasis - metabolism</topic><topic>Lithiasis - pathology</topic><topic>Lithotripsy</topic><topic>Localization</topic><topic>Male</topic><topic>Muscle contraction</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscles</topic><topic>Nitric oxide</topic><topic>Pain</topic><topic>Pain perception</topic><topic>Pharmacology</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase 5 Inhibitors - administration & dosage</topic><topic>Phosphodiesterase 5 Inhibitors - pharmacology</topic><topic>R&D</topic><topic>Rats</topic><topic>Research & development</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Sildenafil</topic><topic>Smooth muscle</topic><topic>Stimulators</topic><topic>Stone</topic><topic>Ureter</topic><topic>Ureter - drug effects</topic><topic>Ureteral Calculi - drug therapy</topic><topic>Ureteral Calculi - genetics</topic><topic>Ureteral Calculi - metabolism</topic><topic>Ureteral Calculi - pathology</topic><topic>Ureteral diseases</topic><topic>Urogenital system</topic><topic>Urology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sandner, Peter</creatorcontrib><creatorcontrib>Tinel, Hanna</creatorcontrib><creatorcontrib>Affaitati, Giannapia</creatorcontrib><creatorcontrib>Costantini, Raffaele</creatorcontrib><creatorcontrib>Giamberardino, Maria Adele</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sandner, Peter</au><au>Tinel, Hanna</au><au>Affaitati, Giannapia</au><au>Costantini, Raffaele</au><au>Giamberardino, Maria Adele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-10-28</date><risdate>2015</risdate><volume>10</volume><issue>10</issue><spage>e0141477</spage><epage>e0141477</epage><pages>e0141477-e0141477</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP)/phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a) the sex-specific PDE5 distribution in the rat ureter; b) the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c) the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26509272</pmid><doi>10.1371/journal.pone.0141477</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-10, Vol.10 (10), p.e0141477-e0141477 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1727985093 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analgesics Animals Autopsy Behavior, Animal Cardiology Care and treatment Colic Cyclic GMP Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism Disease Models, Animal Drug therapy Enzyme Activators - administration & dosage Enzyme Activators - pharmacology Expulsion Female Gender differences Gene Expression Gene Expression Profiling Genetic aspects Guanosine Guanylate Cyclase - genetics Guanylate Cyclase - metabolism Health aspects Hyoscine Hyperalgesia Inhibitors Ketoprofen Laboratories Lithiasis - drug therapy Lithiasis - genetics Lithiasis - metabolism Lithiasis - pathology Lithotripsy Localization Male Muscle contraction Muscle Contraction - drug effects Muscles Nitric oxide Pain Pain perception Pharmacology Phosphodiesterase Phosphodiesterase 5 Inhibitors - administration & dosage Phosphodiesterase 5 Inhibitors - pharmacology R&D Rats Research & development RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Sildenafil Smooth muscle Stimulators Stone Ureter Ureter - drug effects Ureteral Calculi - drug therapy Ureteral Calculi - genetics Ureteral Calculi - metabolism Ureteral Calculi - pathology Ureteral diseases Urogenital system Urology |
| title | Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis |
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