Drugs acting at the GABAA receptor attenuate ethanol-induced gastric mucosal damage in vitro
Summary 1. Benzodiazepines (BZ) have been reported to protect against ethanol‐induced gastric damage in rats in both in vivo and in vitro models. However, the effects of some drugs in the new in vitro model do not agree with results reported previously in in vivo studies. 2. Therefore, the aim of th...
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| Veröffentlicht in: | Clinical and experimental pharmacology & physiology 2003-07, Vol.30 (7), p.495-500 |
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| creator | Najim, Rafid A Saaed, Hiwa K |
| description | Summary
1. Benzodiazepines (BZ) have been reported to protect against ethanol‐induced gastric damage in rats in both in vivo and in vitro models. However, the effects of some drugs in the new in vitro model do not agree with results reported previously in in vivo studies.
2. Therefore, the aim of the present study was to modify the new in vitro model to a model that more closely resembles the in vivo model and, using the new in vitro model, to reassess the gastroprotective effects of some BZ and to assess the effects of some new compounds.
3. The rat stomach was isolated from the whole animal and kept in aerated Krebs' solution at 37°C in an organ bath. Gastric mucosal damage was induced by instillation of 1 mL of 100% ethanol into the stomach. Drugs or their vehicle were administered inside the bath 15 min before ethanol instillation into the stomach. One hour after the instillation of ethanol, the stomach was removed from the organ bath, opened along the greater curvature and then examined for gastric mucosal damage.
4. The results indicate that, compared with vehicle pretreatment, ethanol‐induced gastric mucosal damage was significantly reduced in a dose‐dependent manner by pretreatment with clonazepam, a drug that acts as an agonist at central BZ sites of the GABAA receptor, and Ro 15‐4513, a partial inverse agonist at BZ sites of the GABAA receptor. Flumazenil (an antagonist of central BZ sites of the GABAA receptor) did not affect gastric mucosal lesions provoked by ethanol. However, flumazenil significantly reversed the mucosal protective effects of clonazepam and Ro 15‐4513.
5. CGS 9896 (a partial agonist at BZ sites of the GABAA receptor, with anxiolytic and anticonvulsant but no sedative effects) did not offer any protection against ethanol‐induced gastric mucosal damage. Ro 5‐3663, an atypical BZ that binds to the picrotoxin site of the GABAA receptor and reported to be a potent convulsant and only a weak antagonist of GABA, did not show any protection against the development of lesions.
6. The results suggest local gastric mediation of the effects of ethanol, as well as the gastric protective effects of BZ, through an action at local central‐type BZ sites of the GABAA receptor located in the rat stomach. |
| doi_str_mv | 10.1046/j.1440-1681.2003.03866.x |
| format | Article |
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1. Benzodiazepines (BZ) have been reported to protect against ethanol‐induced gastric damage in rats in both in vivo and in vitro models. However, the effects of some drugs in the new in vitro model do not agree with results reported previously in in vivo studies.
2. Therefore, the aim of the present study was to modify the new in vitro model to a model that more closely resembles the in vivo model and, using the new in vitro model, to reassess the gastroprotective effects of some BZ and to assess the effects of some new compounds.
3. The rat stomach was isolated from the whole animal and kept in aerated Krebs' solution at 37°C in an organ bath. Gastric mucosal damage was induced by instillation of 1 mL of 100% ethanol into the stomach. Drugs or their vehicle were administered inside the bath 15 min before ethanol instillation into the stomach. One hour after the instillation of ethanol, the stomach was removed from the organ bath, opened along the greater curvature and then examined for gastric mucosal damage.
4. The results indicate that, compared with vehicle pretreatment, ethanol‐induced gastric mucosal damage was significantly reduced in a dose‐dependent manner by pretreatment with clonazepam, a drug that acts as an agonist at central BZ sites of the GABAA receptor, and Ro 15‐4513, a partial inverse agonist at BZ sites of the GABAA receptor. Flumazenil (an antagonist of central BZ sites of the GABAA receptor) did not affect gastric mucosal lesions provoked by ethanol. However, flumazenil significantly reversed the mucosal protective effects of clonazepam and Ro 15‐4513.
5. CGS 9896 (a partial agonist at BZ sites of the GABAA receptor, with anxiolytic and anticonvulsant but no sedative effects) did not offer any protection against ethanol‐induced gastric mucosal damage. Ro 5‐3663, an atypical BZ that binds to the picrotoxin site of the GABAA receptor and reported to be a potent convulsant and only a weak antagonist of GABA, did not show any protection against the development of lesions.
6. The results suggest local gastric mediation of the effects of ethanol, as well as the gastric protective effects of BZ, through an action at local central‐type BZ sites of the GABAA receptor located in the rat stomach.</description><identifier>ISSN: 0305-1870</identifier><identifier>EISSN: 1440-1681</identifier><identifier>DOI: 10.1046/j.1440-1681.2003.03866.x</identifier><identifier>PMID: 12823265</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Pty</publisher><subject>Animals ; Benzodiazepines - pharmacology ; Benzodiazepines - therapeutic use ; CGS 9896 ; clonazepam ; Clonazepam - pharmacology ; Clonazepam - therapeutic use ; Dose-Response Relationship, Drug ; ethanol ; Ethanol - toxicity ; flumazenil ; GABA Modulators - pharmacology ; GABA Modulators - therapeutic use ; GABA-A Receptor Agonists ; gastric damage ; Gastric Mucosa - drug effects ; Gastric Mucosa - pathology ; in vitro ; In Vitro Techniques ; Male ; rat ; Rats ; Rats, Wistar ; Receptors, GABA-A - physiology ; Ro 15-4513 ; Ro 5-3663</subject><ispartof>Clinical and experimental pharmacology & physiology, 2003-07, Vol.30 (7), p.495-500</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1440-1681.2003.03866.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1440-1681.2003.03866.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12823265$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Najim, Rafid A</creatorcontrib><creatorcontrib>Saaed, Hiwa K</creatorcontrib><title>Drugs acting at the GABAA receptor attenuate ethanol-induced gastric mucosal damage in vitro</title><title>Clinical and experimental pharmacology & physiology</title><addtitle>Clin Exp Pharmacol Physiol</addtitle><description>Summary
1. Benzodiazepines (BZ) have been reported to protect against ethanol‐induced gastric damage in rats in both in vivo and in vitro models. However, the effects of some drugs in the new in vitro model do not agree with results reported previously in in vivo studies.
2. Therefore, the aim of the present study was to modify the new in vitro model to a model that more closely resembles the in vivo model and, using the new in vitro model, to reassess the gastroprotective effects of some BZ and to assess the effects of some new compounds.
3. The rat stomach was isolated from the whole animal and kept in aerated Krebs' solution at 37°C in an organ bath. Gastric mucosal damage was induced by instillation of 1 mL of 100% ethanol into the stomach. Drugs or their vehicle were administered inside the bath 15 min before ethanol instillation into the stomach. One hour after the instillation of ethanol, the stomach was removed from the organ bath, opened along the greater curvature and then examined for gastric mucosal damage.
4. The results indicate that, compared with vehicle pretreatment, ethanol‐induced gastric mucosal damage was significantly reduced in a dose‐dependent manner by pretreatment with clonazepam, a drug that acts as an agonist at central BZ sites of the GABAA receptor, and Ro 15‐4513, a partial inverse agonist at BZ sites of the GABAA receptor. Flumazenil (an antagonist of central BZ sites of the GABAA receptor) did not affect gastric mucosal lesions provoked by ethanol. However, flumazenil significantly reversed the mucosal protective effects of clonazepam and Ro 15‐4513.
5. CGS 9896 (a partial agonist at BZ sites of the GABAA receptor, with anxiolytic and anticonvulsant but no sedative effects) did not offer any protection against ethanol‐induced gastric mucosal damage. Ro 5‐3663, an atypical BZ that binds to the picrotoxin site of the GABAA receptor and reported to be a potent convulsant and only a weak antagonist of GABA, did not show any protection against the development of lesions.
6. The results suggest local gastric mediation of the effects of ethanol, as well as the gastric protective effects of BZ, through an action at local central‐type BZ sites of the GABAA receptor located in the rat stomach.</description><subject>Animals</subject><subject>Benzodiazepines - pharmacology</subject><subject>Benzodiazepines - therapeutic use</subject><subject>CGS 9896</subject><subject>clonazepam</subject><subject>Clonazepam - pharmacology</subject><subject>Clonazepam - therapeutic use</subject><subject>Dose-Response Relationship, Drug</subject><subject>ethanol</subject><subject>Ethanol - toxicity</subject><subject>flumazenil</subject><subject>GABA Modulators - pharmacology</subject><subject>GABA Modulators - therapeutic use</subject><subject>GABA-A Receptor Agonists</subject><subject>gastric damage</subject><subject>Gastric Mucosa - drug effects</subject><subject>Gastric Mucosa - pathology</subject><subject>in vitro</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>rat</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, GABA-A - physiology</subject><subject>Ro 15-4513</subject><subject>Ro 5-3663</subject><issn>0305-1870</issn><issn>1440-1681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkNtOg0AQhjdGY2v1Fcy-ALgHWODCC3oQTRr1osYbk80AC90KtFkWbd9esB6uZvIfJpkPIUyJS4knbjYu9TziUBFSlxHCXcJDIdz9CRr_GadoTDjxHRoGZIQu2nZDCPGJ4OdoRFnIOBP-GL3NTVe2GDKrmxKDxXatcBJP4xgblamd3ZpetarpwCqs7BqabeXoJu8yleMSWmt0husu27ZQ4RxqKBXWDf7Q1mwv0VkBVauufuYEvdwtVrN7Z_mUPMzipaMZ9YQTBpALj4UpzfI0YlEYcM4yKBiJVEEUU73CRBBwBiqNCuYXoUchgsKH_g8v4xN0fby769Ja5XJndA3mIH_f7AO3x8CnrtTh3ydywCk3cqAmB2pywCm_ccq9nC2eh63vO8e-bq3a__XBvEsR8MCXr4-JXNF5IpJgKqf8CwoRdz4</recordid><startdate>200307</startdate><enddate>200307</enddate><creator>Najim, Rafid A</creator><creator>Saaed, Hiwa K</creator><general>Blackwell Science Pty</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>200307</creationdate><title>Drugs acting at the GABAA receptor attenuate ethanol-induced gastric mucosal damage in vitro</title><author>Najim, Rafid A ; Saaed, Hiwa K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i2146-87ad6428b1cdb92987332caf209ef0e2e987267732aeb9f25f841a9af5a2824c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Benzodiazepines - pharmacology</topic><topic>Benzodiazepines - therapeutic use</topic><topic>CGS 9896</topic><topic>clonazepam</topic><topic>Clonazepam - pharmacology</topic><topic>Clonazepam - therapeutic use</topic><topic>Dose-Response Relationship, Drug</topic><topic>ethanol</topic><topic>Ethanol - toxicity</topic><topic>flumazenil</topic><topic>GABA Modulators - pharmacology</topic><topic>GABA Modulators - therapeutic use</topic><topic>GABA-A Receptor Agonists</topic><topic>gastric damage</topic><topic>Gastric Mucosa - drug effects</topic><topic>Gastric Mucosa - pathology</topic><topic>in vitro</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>rat</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, GABA-A - physiology</topic><topic>Ro 15-4513</topic><topic>Ro 5-3663</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Najim, Rafid A</creatorcontrib><creatorcontrib>Saaed, Hiwa K</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical and experimental pharmacology & physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Najim, Rafid A</au><au>Saaed, Hiwa K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drugs acting at the GABAA receptor attenuate ethanol-induced gastric mucosal damage in vitro</atitle><jtitle>Clinical and experimental pharmacology & physiology</jtitle><addtitle>Clin Exp Pharmacol Physiol</addtitle><date>2003-07</date><risdate>2003</risdate><volume>30</volume><issue>7</issue><spage>495</spage><epage>500</epage><pages>495-500</pages><issn>0305-1870</issn><eissn>1440-1681</eissn><abstract>Summary
1. Benzodiazepines (BZ) have been reported to protect against ethanol‐induced gastric damage in rats in both in vivo and in vitro models. However, the effects of some drugs in the new in vitro model do not agree with results reported previously in in vivo studies.
2. Therefore, the aim of the present study was to modify the new in vitro model to a model that more closely resembles the in vivo model and, using the new in vitro model, to reassess the gastroprotective effects of some BZ and to assess the effects of some new compounds.
3. The rat stomach was isolated from the whole animal and kept in aerated Krebs' solution at 37°C in an organ bath. Gastric mucosal damage was induced by instillation of 1 mL of 100% ethanol into the stomach. Drugs or their vehicle were administered inside the bath 15 min before ethanol instillation into the stomach. One hour after the instillation of ethanol, the stomach was removed from the organ bath, opened along the greater curvature and then examined for gastric mucosal damage.
4. The results indicate that, compared with vehicle pretreatment, ethanol‐induced gastric mucosal damage was significantly reduced in a dose‐dependent manner by pretreatment with clonazepam, a drug that acts as an agonist at central BZ sites of the GABAA receptor, and Ro 15‐4513, a partial inverse agonist at BZ sites of the GABAA receptor. Flumazenil (an antagonist of central BZ sites of the GABAA receptor) did not affect gastric mucosal lesions provoked by ethanol. However, flumazenil significantly reversed the mucosal protective effects of clonazepam and Ro 15‐4513.
5. CGS 9896 (a partial agonist at BZ sites of the GABAA receptor, with anxiolytic and anticonvulsant but no sedative effects) did not offer any protection against ethanol‐induced gastric mucosal damage. Ro 5‐3663, an atypical BZ that binds to the picrotoxin site of the GABAA receptor and reported to be a potent convulsant and only a weak antagonist of GABA, did not show any protection against the development of lesions.
6. The results suggest local gastric mediation of the effects of ethanol, as well as the gastric protective effects of BZ, through an action at local central‐type BZ sites of the GABAA receptor located in the rat stomach.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Pty</pub><pmid>12823265</pmid><doi>10.1046/j.1440-1681.2003.03866.x</doi><tpages>6</tpages></addata></record> |
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| ispartof | Clinical and experimental pharmacology & physiology, 2003-07, Vol.30 (7), p.495-500 |
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| subjects | Animals Benzodiazepines - pharmacology Benzodiazepines - therapeutic use CGS 9896 clonazepam Clonazepam - pharmacology Clonazepam - therapeutic use Dose-Response Relationship, Drug ethanol Ethanol - toxicity flumazenil GABA Modulators - pharmacology GABA Modulators - therapeutic use GABA-A Receptor Agonists gastric damage Gastric Mucosa - drug effects Gastric Mucosa - pathology in vitro In Vitro Techniques Male rat Rats Rats, Wistar Receptors, GABA-A - physiology Ro 15-4513 Ro 5-3663 |
| title | Drugs acting at the GABAA receptor attenuate ethanol-induced gastric mucosal damage in vitro |
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