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In Experiment 1, saline or vehicle controls and the mu\u2010specific opioids dermorphin\u2010H (Derm\u2010H) and ([<jats:sc>d<\/jats:sc>\u2010Ala2,<jats:italic>N<\/jats:italic>\u2010Me\u2010Phe4, Gly\u2010ol5] enkephalin (<jats:styled-content style=\"fixed-case\">DAMAGO<\/jats:styled-content>); the delta\u20101\u2013specific opioid<jats:sc>d<\/jats:sc>\u2010Pen2,5enkephalin (<jats:styled-content style=\"fixed-case\">DPDPE<\/jats:styled-content>); nociceptin; and the delta\u20102\u2013specific opioids deltorphin\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>(Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>), Delt\u2010Dvariant (Delt\u2010Dvar), and deltorphin\u2010E (Delt\u2010E) were infused 15\u00a0minutes prior to ischemia. In Experiment 2,<jats:styled-content style=\"fixed-case\">DPDPE<\/jats:styled-content>, Delt\u2010D, Delt\u2010Dvar, and Delt\u2010E were infused at 15\u00a0minutes prior to ischemia. The universal opioid receptor antagonist naltrexone, the peripherally acting antagonist naloxone methiodide, the selective \u03b4<jats:sub>1<\/jats:sub>antagonist 7\u2010benzylidene naltrexone maleate, and the specific \u03b4<jats:sub>2<\/jats:sub>antagonist naltriben mesylate were infused 25\u00a0minutes prior to ischemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In Experiment 1, pretreatment with the \u03bc opioids Derm\u2010H and<jats:styled-content style=\"fixed-case\">DAMGO<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">DPDPE<\/jats:styled-content>, and nociceptin at all doses tested did not reduce the incidence of ischemia\u2010induced arrhythmias compared to controls during 45\u00a0minutes of ischemia. The \u03b4<jats:sub>2<\/jats:sub>opioids Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>(0.12\u00a0mg\/kg), Delt\u2010Dvar (0.3\u00a0mg\/kg), and Delt\u2010E (0.18\u00a0mg\/kg) all demonstrated significant antiarrhythmic effects at the 150\u00a0nmol\/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>were tolerant without ventricular arrhythmias to the arrhythmogenic effect of ischemia during the first 10\u00a0minutes of ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35\u00a0minutes of ischemia (phase 1b). Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>also decreased the incidence of premature ventricular contractions and ventricular tachycardia by almost half during phase 1a. Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>did not affect the incidence of ventricular fibrillation (<jats:styled-content style=\"fixed-case\">VF<\/jats:styled-content>). Pretreatment with Delt\u2010Dvar and Delt\u2010E completely blocked the incidence of<jats:styled-content style=\"fixed-case\">VF<\/jats:styled-content>in phase 1b. Delt\u2010E also decreased premature ventricular contractions by 50%, and the incidence of ventricular tachycardia decreased over twofold in phase 1b of ischemia. There was no enhanced tolerance by any of the delta\u20102 opioids to the arrhythmogenic effect of reperfusion after long\u2010term ischemia. In Experiment 2, after 10\u00a0minutes of ischemia and 10\u00a0minutes of reperfusion, Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>(0.12\u00a0mg\/kg) reduced the incidence of premature ventricular contractions and ventricular tachycardia compared to controls, and completely blocked the incidence of<jats:styled-content style=\"fixed-case\">VF<\/jats:styled-content>following 10\u00a0minutes of reperfusion. Delt\u2010Dvar and Delt\u2010E were without effect, as was<jats:styled-content style=\"fixed-case\">DPDPE<\/jats:styled-content>following 10\u00a0minutes of reperfusion. The antiarrhythmic effect of Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>during 10\u00a0minutes of ischemia and 10\u00a0minutes of reperfusion was completely blocked by the peripherally acting opioid receptor inhibitor naloxone methiodide and the selective delta\u20102 opioid receptor inhibitor naltriben mesylate, but not by the selective delta\u20101 inhibitor 7\u2010benzylidene naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Peripheral delta\u20102 opioid receptor activation by Delt\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>, Delt\u2010Dvar, and Delt\u2010E enhanced cardiac tolerance to the arrhythmogenic effects of ischemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acem.12286","type":"journal-article","created":{"date-parts":[[2014,1,6]],"date-time":"2014-01-06T14:13:38Z","timestamp":1389017618000},"page":"31-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Activation of Peripheral Delta Opioid Receptors Increases Cardiac Tolerance to Arrhythmogenic Effect of Ischemia\/Reperfusion"],"prefix":"10.1111","volume":"21","author":[{"given":"Leonid N.","family":"Maslov","sequence":"first","affiliation":[{"name":"The Laboratory of Experimental Cardiology Research Institute of Cardiology Siberian Branch, Russian Academy of Medical Sciences Tomsk Russia"}]},{"given":"Peter R.","family":"Oeltgen","sequence":"additional","affiliation":[{"name":"The Veterans Administration Medical Center University of Kentucky Lexington KY"},{"name":"The Department of Pathology University of Kentucky Lexington KY"}]},{"given":"Yury B.","family":"Lishmanov","sequence":"additional","affiliation":[{"name":"The Laboratory of Experimental Cardiology Research Institute of Cardiology Siberian Branch, Russian Academy of Medical Sciences Tomsk Russia"}]},{"given":"Stephen A.","family":"Brown","sequence":"additional","affiliation":[{"name":"The Veterans Administration Medical Center University of Kentucky Lexington KY"},{"name":"The Department of Medicine University of Kentucky Lexington KY"}]},{"given":"Eva I.","family":"Barzakh","sequence":"additional","affiliation":[{"name":"The Laboratory of Experimental Medicine and Cancer Research The Hebrew University Jerusalem Israel"}]},{"given":"Andrey V.","family":"Krylatov","sequence":"additional","affiliation":[{"name":"The Laboratory of Experimental Cardiology Research Institute of Cardiology Siberian Branch, Russian Academy of Medical Sciences Tomsk Russia"}]},{"given":"Jian\u2010Ming","family":"Pei","sequence":"additional","affiliation":[{"name":"The Department of Physiology Fourth Military Medical University Xi'an Shaanxi Province China"}]}],"member":"311","published-online":{"date-parts":[[2014,1,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.4103\/0974-2700.62109"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199103213241201"},{"key":"e_1_2_8_4_1","unstructured":"UpToDate.Major Side Effects of Amioderone. 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