title: Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts.
abstract: This study compared the effects of ATP-regulated potassium channel (K(ATP)) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the K(ATP) targets K(ir)6.1, K(ir)6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by -21±3% and -27±13%, p<0.01) and ventricles (by -28±7% and -28±4%, p<0.01). Diazoxide did not change APD (0±5%) in NF atria. Pinacidil significantly decreased APDs in both atria (-46 to -80%, p<0.01) and ventricles (-65 to -93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4±6.1 Hz and 17.5±5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K(ATP) targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K(ATP) channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Glukhov
authors.forename: Christina M
authors.initials: CM
authors.lastname: Ambrosi
authors.forename: Geran
authors.initials: G
authors.lastname: Kostecki
authors.forename: Roger
authors.initials: R
authors.lastname: Chang
authors.forename: Deborah
authors.initials: D
authors.lastname: Janks
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schuessler
authors.forename: Nader
authors.initials: N
authors.lastname: Moazami
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000503:physiopathology; D020110:Pinacidil / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D054086:KATP Channels; D012333:RNA, Messenger; D014665:Vasodilator Agents; D020110:Pinacidil; D003981:Diazoxide