The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle
Background Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of...
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| Veröffentlicht in: | Neurogastroenterology and motility 2018-10, Vol.30 (10), p.e13372-n/a |
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| creator | Kraft, M. Zettl, U. K. Noack, T. Patejdl, R. |
| description | Background
Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high‐K+ solution.
Methods
Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L‐NAME, HA‐1100, nifedipine, JTE‐013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high‐K+ contraction obtained under control conditions.
Key Results
From a concentration of 10 μmol L−1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L−1 (P |
| doi_str_mv | 10.1111/nmo.13372 |
| format | Article |
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Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high‐K+ solution.
Methods
Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L‐NAME, HA‐1100, nifedipine, JTE‐013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high‐K+ contraction obtained under control conditions.
Key Results
From a concentration of 10 μmol L−1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L−1 (P < .05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1% ± 7.7%; P < .001). The FTY720‐induced increase in tone was abolished in the absence of extracellular Ca2+ and reduced by nifedipine, HA‐1100, JTE‐013, and suramin. Furthermore, FTY720 increased high‐K+ contractions in the presence of indomethacin.
Conclusions & Inferences
FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor‐dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.
It is not known how FTY720, a drug approved for multiple sclerosis, modulates gastric smooth muscle function. FTY720 increases tone and contractions of fundus smooth muscle by evoking Ca2+ entry and Ca2+ sensitization in a S1P receptor‐dependent manner. The results of this study raise the possibility that gastrointestinal complications in multiple sclerosis patients treated with FTY720 may be due to direct drug effects on gastrointestinal muscle.</description><identifier>ISSN: 1350-1925</identifier><identifier>EISSN: 1365-2982</identifier><identifier>DOI: 10.1111/nmo.13372</identifier><identifier>PMID: 29740911</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Calcium (extracellular) ; Contraction ; Depolarization ; FTY720 ; gastric fundus ; Indomethacin ; Multiple sclerosis ; Muscle contraction ; Nifedipine ; Patients ; Potassium ; Smooth muscle ; sphingosine ; sphingosine receptors ; Stomach ; Suramin</subject><ispartof>Neurogastroenterology and motility, 2018-10, Vol.30 (10), p.e13372-n/a</ispartof><rights>2018 John Wiley & Sons Ltd</rights><rights>2018 John Wiley & Sons Ltd.</rights><rights>Copyright © 2018 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3532-77b725c2ee0f39dd9ef831a243c92b5234800cabc1874bacf7301eedbd39f43d3</citedby><cites>FETCH-LOGICAL-c3532-77b725c2ee0f39dd9ef831a243c92b5234800cabc1874bacf7301eedbd39f43d3</cites><orcidid>0000-0003-4587-4054</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fnmo.13372$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fnmo.13372$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,1432,27922,27923,45572,45573,46407,46831</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29740911$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kraft, M.</creatorcontrib><creatorcontrib>Zettl, U. K.</creatorcontrib><creatorcontrib>Noack, T.</creatorcontrib><creatorcontrib>Patejdl, R.</creatorcontrib><title>The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle</title><title>Neurogastroenterology and motility</title><addtitle>Neurogastroenterol Motil</addtitle><description>Background
Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high‐K+ solution.
Methods
Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L‐NAME, HA‐1100, nifedipine, JTE‐013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high‐K+ contraction obtained under control conditions.
Key Results
From a concentration of 10 μmol L−1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L−1 (P < .05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1% ± 7.7%; P < .001). The FTY720‐induced increase in tone was abolished in the absence of extracellular Ca2+ and reduced by nifedipine, HA‐1100, JTE‐013, and suramin. Furthermore, FTY720 increased high‐K+ contractions in the presence of indomethacin.
Conclusions & Inferences
FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor‐dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.
It is not known how FTY720, a drug approved for multiple sclerosis, modulates gastric smooth muscle function. FTY720 increases tone and contractions of fundus smooth muscle by evoking Ca2+ entry and Ca2+ sensitization in a S1P receptor‐dependent manner. The results of this study raise the possibility that gastrointestinal complications in multiple sclerosis patients treated with FTY720 may be due to direct drug effects on gastrointestinal muscle.</description><subject>Calcium (extracellular)</subject><subject>Contraction</subject><subject>Depolarization</subject><subject>FTY720</subject><subject>gastric fundus</subject><subject>Indomethacin</subject><subject>Multiple sclerosis</subject><subject>Muscle contraction</subject><subject>Nifedipine</subject><subject>Patients</subject><subject>Potassium</subject><subject>Smooth muscle</subject><subject>sphingosine</subject><subject>sphingosine receptors</subject><subject>Stomach</subject><subject>Suramin</subject><issn>1350-1925</issn><issn>1365-2982</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kbtOwzAUhi0E4lIYeAFkiQWGtL4kdTyiipvEZSkDU-TYx61RYhc7Eerbk1JgQOIs5-jo0zf8P0KnlIzpMBPfhjHlXLAddEj5tMiYLNnu5i5IRiUrDtBRSm-EkCnLp_vogEmRE0npIfLzJeC0Wjq_CMl5wMqrJiyw3Twa1waDL27mr4KRSwx-qbyGhLvwBRqsg--i0p1rXLfGweKoOrxQqYtOY9t70yec2hC6JW77pBs4RntWNQlOvvcIvdxcz2d32cPz7f3s6iHTvOAsE6IWrNAMgFgujZFgS04Vy7mWrC4Yz0tCtKo1LUVeK20FJxTA1IZLm3PDR-hi613F8N5D6qrWJQ1NozyEPlWM8KkoJRmMI3T-B30LfRxSGCgqOSuFlBvqckvpGFKKYKtVdK2K64qSalNCNZRQfZUwsGffxr5uwfySP6kPwGQLfLgG1v-bqqfH563yE11EkNU</recordid><startdate>201810</startdate><enddate>201810</enddate><creator>Kraft, M.</creator><creator>Zettl, U. K.</creator><creator>Noack, T.</creator><creator>Patejdl, R.</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4587-4054</orcidid></search><sort><creationdate>201810</creationdate><title>The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle</title><author>Kraft, M. ; Zettl, U. K. ; Noack, T. ; Patejdl, R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3532-77b725c2ee0f39dd9ef831a243c92b5234800cabc1874bacf7301eedbd39f43d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Calcium (extracellular)</topic><topic>Contraction</topic><topic>Depolarization</topic><topic>FTY720</topic><topic>gastric fundus</topic><topic>Indomethacin</topic><topic>Multiple sclerosis</topic><topic>Muscle contraction</topic><topic>Nifedipine</topic><topic>Patients</topic><topic>Potassium</topic><topic>Smooth muscle</topic><topic>sphingosine</topic><topic>sphingosine receptors</topic><topic>Stomach</topic><topic>Suramin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kraft, M.</creatorcontrib><creatorcontrib>Zettl, U. K.</creatorcontrib><creatorcontrib>Noack, T.</creatorcontrib><creatorcontrib>Patejdl, R.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Neurogastroenterology and motility</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kraft, M.</au><au>Zettl, U. K.</au><au>Noack, T.</au><au>Patejdl, R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle</atitle><jtitle>Neurogastroenterology and motility</jtitle><addtitle>Neurogastroenterol Motil</addtitle><date>2018-10</date><risdate>2018</risdate><volume>30</volume><issue>10</issue><spage>e13372</spage><epage>n/a</epage><pages>e13372-n/a</pages><issn>1350-1925</issn><eissn>1365-2982</eissn><abstract>Background
Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high‐K+ solution.
Methods
Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L‐NAME, HA‐1100, nifedipine, JTE‐013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high‐K+ contraction obtained under control conditions.
Key Results
From a concentration of 10 μmol L−1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L−1 (P < .05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1% ± 7.7%; P < .001). The FTY720‐induced increase in tone was abolished in the absence of extracellular Ca2+ and reduced by nifedipine, HA‐1100, JTE‐013, and suramin. Furthermore, FTY720 increased high‐K+ contractions in the presence of indomethacin.
Conclusions & Inferences
FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor‐dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.
It is not known how FTY720, a drug approved for multiple sclerosis, modulates gastric smooth muscle function. FTY720 increases tone and contractions of fundus smooth muscle by evoking Ca2+ entry and Ca2+ sensitization in a S1P receptor‐dependent manner. The results of this study raise the possibility that gastrointestinal complications in multiple sclerosis patients treated with FTY720 may be due to direct drug effects on gastrointestinal muscle.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29740911</pmid><doi>10.1111/nmo.13372</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-4587-4054</orcidid></addata></record> |
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| subjects | Calcium (extracellular) Contraction Depolarization FTY720 gastric fundus Indomethacin Multiple sclerosis Muscle contraction Nifedipine Patients Potassium Smooth muscle sphingosine sphingosine receptors Stomach Suramin |
| title | The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle |
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