Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts
ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphoryla...
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| Published in: | Circulation research 2004-04, Vol.94 (7), p.960-966 |
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Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts |
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Gross, Eric R Hsu, Anna K Gross, Garrett J |
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Aminophenols - pharmacology Androstadienes - pharmacology Animals Benzamides - pharmacology Biological and medical sciences Cardiotonic Agents - pharmacology Cardiotonic Agents - therapeutic use Chromones - pharmacology Fundamental and applied biological sciences. Psychology Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - physiology Glycogen Synthase Kinase 3 beta Indoles - pharmacology Male Maleimides - pharmacology Morphine - pharmacology Morpholines - pharmacology Myocardial Infarction - metabolism Myocardial Infarction - pathology Narcotic Antagonists - pharmacology Nuclear Receptor Subfamily 1, Group F, Member 3 Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - physiology Piperazines - pharmacology Premedication Rats Rats, Sprague-Dawley Receptors, Opioid, delta - drug effects Receptors, Retinoic Acid - antagonists & inhibitors Receptors, Retinoic Acid - physiology Receptors, Thyroid Hormone - antagonists & inhibitors Receptors, Thyroid Hormone - physiology Signal Transduction - drug effects Sirolimus - pharmacology Vertebrates: cardiovascular system |
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Circulation research, 2004-04, Vol.94 (7), p.960-966 |
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ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the δ-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 μg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 μg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P |
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Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the δ-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 μg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 μg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P <0.001) and showed similar protection when administered 5 minutes before reperfusion (43.6±2.3, 40.2±2.6, 44.8±2.8, 39.4±0.8%, respectively; P <0.001). Wortmannin, LY294002, and rapamycin were found to inhibit OIC; however, they did not abrogate SB21-induced infarct size reduction. At 5 minutes of reperfusion, both MOR and BW increased P-GSKβ at Ser in the ischemic zone compared with vehicle (181±20, 178±15 versus 75±17 DU, respectively; P <0.05), and this effect was abrogated by prior administration of wortmannin or rapamycin in MOR-treated rats. Furthermore, no differences were seen in phosphorylation of GSKα (Ser or Tyr) or phosphorylation of GSKβ (Tyr). These data indicate that OIC occurs via the phosphorylation of GSKβ at Ser during reperfusion.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.RES.0000122392.33172.09</identifier><identifier>PMID: 14976126</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Aminophenols - pharmacology ; Androstadienes - pharmacology ; Animals ; Benzamides - pharmacology ; Biological and medical sciences ; Cardiotonic Agents - pharmacology ; Cardiotonic Agents - therapeutic use ; Chromones - pharmacology ; Fundamental and applied biological sciences. Psychology ; Glycogen Synthase Kinase 3 - antagonists & inhibitors ; Glycogen Synthase Kinase 3 - physiology ; Glycogen Synthase Kinase 3 beta ; Indoles - pharmacology ; Male ; Maleimides - pharmacology ; Morphine - pharmacology ; Morpholines - pharmacology ; Myocardial Infarction - metabolism ; Myocardial Infarction - pathology ; Narcotic Antagonists - pharmacology ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - physiology ; Piperazines - pharmacology ; Premedication ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, delta - drug effects ; Receptors, Retinoic Acid - antagonists & inhibitors ; Receptors, Retinoic Acid - physiology ; Receptors, Thyroid Hormone - antagonists & inhibitors ; Receptors, Thyroid Hormone - physiology ; Signal Transduction - drug effects ; Sirolimus - pharmacology ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 2004-04, Vol.94 (7), p.960-966</ispartof><rights>2004 American Heart Association, Inc.</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4426-d67f0cf4ce1547d334f8ba963b8976e079e3d54049b97226e770d22e01c7d87b3</citedby><cites>FETCH-LOGICAL-c4426-d67f0cf4ce1547d334f8ba963b8976e079e3d54049b97226e770d22e01c7d87b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,787,791,27985,27986</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15643783$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14976126$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gross, Eric R</creatorcontrib><creatorcontrib>Hsu, Anna K</creatorcontrib><creatorcontrib>Gross, Garrett J</creatorcontrib><title>Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the δ-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 μg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 μg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P <0.001) and showed similar protection when administered 5 minutes before reperfusion (43.6±2.3, 40.2±2.6, 44.8±2.8, 39.4±0.8%, respectively; P <0.001). Wortmannin, LY294002, and rapamycin were found to inhibit OIC; however, they did not abrogate SB21-induced infarct size reduction. At 5 minutes of reperfusion, both MOR and BW increased P-GSKβ at Ser in the ischemic zone compared with vehicle (181±20, 178±15 versus 75±17 DU, respectively; P <0.05), and this effect was abrogated by prior administration of wortmannin or rapamycin in MOR-treated rats. Furthermore, no differences were seen in phosphorylation of GSKα (Ser or Tyr) or phosphorylation of GSKβ (Tyr). These data indicate that OIC occurs via the phosphorylation of GSKβ at Ser during reperfusion.</description><subject>Aminophenols - pharmacology</subject><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Cardiotonic Agents - therapeutic use</subject><subject>Chromones - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycogen Synthase Kinase 3 - antagonists & inhibitors</subject><subject>Glycogen Synthase Kinase 3 - physiology</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Indoles - pharmacology</subject><subject>Male</subject><subject>Maleimides - pharmacology</subject><subject>Morphine - pharmacology</subject><subject>Morpholines - pharmacology</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Infarction - pathology</subject><subject>Narcotic Antagonists - pharmacology</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 3</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - physiology</subject><subject>Piperazines - pharmacology</subject><subject>Premedication</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid, delta - drug effects</subject><subject>Receptors, Retinoic Acid - antagonists & inhibitors</subject><subject>Receptors, Retinoic Acid - physiology</subject><subject>Receptors, Thyroid Hormone - antagonists & inhibitors</subject><subject>Receptors, Thyroid Hormone - physiology</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - pharmacology</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNpFkN2O0zAQhSMEYsvCK6AICe4S_Bc75g6VZbdipUpduLYce7I1pE6xHVZ9LR6EZ8JpK9U3I1nfmTPnFMU7jGqMOf6IcL25eahRfpgQKklNKRakRvJZscANYRVrBH5eLDIgK0Epuipexfgz44wS-bK4wkwKjglfFIf13o3OVitvJwO2XOpg3bgPYwKT3OjLtTFTiOUfp8vb4WDGR_Dlw8GnrY5QfnN-Hv_-liu_dZ07Kr5MwfnHcgN7CP0U5y_nM5C0SeVGp_IOdEjxdfGi10OEN-d5Xfz4evN9eVfdr29Xy8_3lWGM8Mpy0SPTMwO4YcJSyvq205LTrs0ZAAkJ1DYMMdlJQQgHIZAlBBA2wraio9fFh9PeHOr3BDGpnYsGhkF7GKeoBG4pR5xm8NMJNGGMMUCv9sHtdDgojNRcvEJY5eLVpXh1LF4hmcVvzy5TtwN7kZ6bzsD7M6Cj0UMftDcuXriGMyra-Qp24p7GIUGIv4bpCYLagh7S9mhNs3lFEMqZMUfVfAyn_wFHyZzQ</recordid><startdate>20040416</startdate><enddate>20040416</enddate><creator>Gross, Eric R</creator><creator>Hsu, Anna K</creator><creator>Gross, Garrett J</creator><general>American Heart Association, Inc</general><general>Lippincott</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20040416</creationdate><title>Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts</title><author>Gross, Eric R ; Hsu, Anna K ; Gross, Garrett J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4426-d67f0cf4ce1547d334f8ba963b8976e079e3d54049b97226e770d22e01c7d87b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Aminophenols - pharmacology</topic><topic>Androstadienes - pharmacology</topic><topic>Animals</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Cardiotonic Agents - therapeutic use</topic><topic>Chromones - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glycogen Synthase Kinase 3 - antagonists & inhibitors</topic><topic>Glycogen Synthase Kinase 3 - physiology</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Indoles - pharmacology</topic><topic>Male</topic><topic>Maleimides - pharmacology</topic><topic>Morphine - pharmacology</topic><topic>Morpholines - pharmacology</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Infarction - pathology</topic><topic>Narcotic Antagonists - pharmacology</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 3</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - physiology</topic><topic>Piperazines - pharmacology</topic><topic>Premedication</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Opioid, delta - drug effects</topic><topic>Receptors, Retinoic Acid - antagonists & inhibitors</topic><topic>Receptors, Retinoic Acid - physiology</topic><topic>Receptors, Thyroid Hormone - antagonists & inhibitors</topic><topic>Receptors, Thyroid Hormone - physiology</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - pharmacology</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gross, Eric R</creatorcontrib><creatorcontrib>Hsu, Anna K</creatorcontrib><creatorcontrib>Gross, Garrett J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gross, Eric R</au><au>Hsu, Anna K</au><au>Gross, Garrett J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2004-04-16</date><risdate>2004</risdate><volume>94</volume><issue>7</issue><spage>960</spage><epage>966</epage><pages>960-966</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the δ-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 μg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 μg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P <0.001) and showed similar protection when administered 5 minutes before reperfusion (43.6±2.3, 40.2±2.6, 44.8±2.8, 39.4±0.8%, respectively; P <0.001). Wortmannin, LY294002, and rapamycin were found to inhibit OIC; however, they did not abrogate SB21-induced infarct size reduction. At 5 minutes of reperfusion, both MOR and BW increased P-GSKβ at Ser in the ischemic zone compared with vehicle (181±20, 178±15 versus 75±17 DU, respectively; P <0.05), and this effect was abrogated by prior administration of wortmannin or rapamycin in MOR-treated rats. Furthermore, no differences were seen in phosphorylation of GSKα (Ser or Tyr) or phosphorylation of GSKβ (Tyr). These data indicate that OIC occurs via the phosphorylation of GSKβ at Ser during reperfusion.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>14976126</pmid><doi>10.1161/01.RES.0000122392.33172.09</doi><oa>free_for_read</oa></addata></record> |