title: Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels.
abstract: 'Compound A' (4(ı)-(N-(4-acetamidobenzyl))-2,2-dimethyl-2,3-dihydro-5(ı)H-spiro[chromene-4,2(ı)-[1,4]oxazinan]-5(ı)-one) is a new spiro-cyclic benzopyran activator of the mitochondrial ATP-dependent potassium channels (mitoKATP). We researched the effect of compound A on ischemia/reperfusion (I/R)-induced ventricular arrhythmias. We also tested the hypothesis that the application of the activation of mitoKATP in combination with the inhibition of sarcolemmal ATP-dependent potassium channels (sarcKATP) may produce a stronger antiarrhythmic effect. In anesthetized rats, myocardial ischemia was performed by ligating the left main coronary artery followed by reperfusion. At a dose of 10 mg/kg, compound A significantly decreased arrhythmia scores and the total length of arrhythmias, whereas this was found to be ineffective at a dose of 3 mg/kg. Pre-treatment with 5-HD, a selective mitoKATP blocker, abolished the antiarrhythmic effect of compound A. Both diazoxide, a selective mitoKATP opener and HMR 1098, a selective sarcKATP blocker, significantly decreased the total length of arrhythmias. However, the combination of neither diazoxide nor compound A with HMR 1098 showed no additional therapeutic benefit. These results reveal that compound A may have a dose-dependent antiarrythmic effect, which is more pronounced than the antiarrhythmic effect of diazoxide. The antiarrhythmic effect of compound A may possibly depend on mitoKATP activation.
authors.affiliation: Department of Biology, Faculty of Art and Sciences, Bülent Ecevit University, Zonguldak, Turkey. ersozgonca67@hotmail.com.
authors.forename: Ersöz
authors.initials: E
authors.lastname: Gonca
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.affiliation: Department of Biology, Faculty of Art and Sciences, Bülent Ecevit University, Zonguldak, Turkey.
authors.forename: Faruk
authors.initials: F
authors.lastname: Darıcı
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Harran University, Şanliurfa, Turkey.
authors.forename: Zehra
authors.initials: Z
authors.lastname: Yılmaz
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000819:agonists* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel
keywords: Diazoxide; HMR 1098; Spiro-cyclic benzopyran; Ventricular arrhythmias