title: Anti-arrhythmic effects of levcromakalim in the ischaemic rat heart: a dual mechanism of action?
abstract: The action of pharmacological openers of K(ATP) channels depends on the availability and levels of various intracellular nucleotides. Since these are subject to change during myocardial ischaemia, K(ATP) channel openers may affect ischaemic and non-ischaemic tissue differentially. Using a recently developed dual coronary perfusion method, we investigated the effects on arrhythmias of the prototypical K(ATP) channel opener levcromakalim when applied selectively to ischaemic and/or non-ischaemic tissue. A novel perfusion cannula was used to independently perfuse the left and right coronary beds of hearts isolated from rats. Selective infusion of levcromakalim (3, 10 or 30 microM) into the left coronary bed in the absence of ischaemia did not induce ventricular arrhythmias. Regional zero-flow ischaemia was induced by cessation of flow to the left coronary bed and hearts received levcromakalim selectively into either the left, right, or both coronary beds. When applied selectively to the ischaemic left coronary bed, levcromakalim (3, 10 or 30 microM; n=10/group) delayed the onset of ventricular tachycardia in a dose-dependent manner (by 21*, 43* and 112%* at 3, 10 and 30 microM; *P<0.05 vs. control). When applied only to the non-ischaemic right coronary bed, levcromakalim reduced the incidence of ventricular tachycardia during later phases of ischaemia (from 100% in controls to 30%*). When present in both coronary beds, levcromakalim had a striking anti-arrhythmic effect--the overall incidence of ventricular tachycardia being reduced from 100% in controls to 20%*. We conclude that levcromakalim may have an anti-arrhythmic effect when applied either to ischaemic or non-ischaemic tissue but that the mechanisms may differ depending on the metabolic state of the heart.
authors.affiliation: Department of Pediatric Cardiology and Physiology and Neurosciences (TH517), New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA. william.coetzee@med.nyu.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: T
authors.initials: T
authors.lastname: Wells
authors.forename: M
authors.initials: M
authors.lastname: Avkiran
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D054086:KATP Channels; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D009249:NADP / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D010725:Phosphocreatine; D019806:Cromakalim; D009249:NADP; D000255:Adenosine Triphosphate