title: SNC-80-induced preconditioning: selective activation of the mitochondrial adenosine triphosphate-gated potassium channel.
abstract: Pharmacologic preconditioning by delta-opioid agonists occurs via activation of an adenosine triphosphate (ATP)-gated potassium channel (I(KATP)). Opening of mitochondrial I(KATP) confers pharmacologic preconditioning whereas opening the sarcolemmal I(KATP) shortens action potential duration and is proarrhythmic. This study investigated whether SNC-80, a selective delta-opioid agonist, is associated with development of ventricular arrhythmia due to activation of I(KATP). Rabbit isolated hearts were subjected to 12 min of hypoxia and 40 min of reoxygenation after pretreatment with SNC-80 (1 microM, n = 6), pinacidil (1.25 microM, n = 12), or BMS-191095 (6.0 microM, n = 4). Nine additional hearts served as controls. The cytoprotective effects of SNC-80 at a concentration of 1 microM were confirmed using 30 min of regional ischemia followed by 120 min of reperfusion. Ventricular fibrillation (VF) developed in 11 of 12 pinacidil-treated hearts whereas none of the SNC-80-treated (zero of six) hearts developed VF (P < 0.001 compared with pinacidil pretreatment) and zero of four BMS-191095-pretreated hearts developed VF. Similarly, zero of nine control hearts developed VF. SNC-80 reduced infarct size expressed as a percentage of the area at risk from 33 +/- 4% to 14 +/- 3% (P = 0.004) compared with control. SNC-80, which selectively activates the delta-opioid receptor, provided cytoprotection but did not induce VF after hypoxia reoxygenation. The results indicate that pinacidil-induced nonselective activation of I(KATP) results in proarrhythmia that is dependent on activation of the sarcolemmal I(KATP). Selectivity for the mitochondrial I(KATP) is necessary to prevent induction of a proarrhythmic state.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Fischbach
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Reed
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications; D015425:Myocardial Reperfusion; D020110:Pinacidil / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D015221:Potassium Channels; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000819:agonists*; D014665:Vasodilator Agents / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control
chemical_list: D001549:Benzamides; D008565:Membrane Proteins; D010879:Piperazines; D015221:Potassium Channels; D017465:Receptors, Opioid, delta; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D020110:Pinacidil; D000255:Adenosine Triphosphate