TY - JOUR
T1 - Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts
AU - Fedorov, Vadim V.
AU - Glukhov, Alexey V.
AU - Ambrosi, Christina M.
AU - Kostecki, Geran
AU - Chang, Roger
AU - Janks, Deborah
AU - Schuessler, Richard B.
AU - Moazami, Nader
AU - Nichols, Colin G.
AU - Efimov, Igor R.
N1 - Funding Information:
The project was supported by NIH R01 HL085369 (IRE), AHA Beginning Grant In Aid 0860047Z (VVF), and NIH grant R01 Hl95010 (CGN).
PY - 2011/8
Y1 - 2011/8
N2 - This study compared the effects of ATP-regulated potassium channel (KATP) 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 KATP targets Kir6.1, Kir6.2, 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±6.1Hz and 17.5±5.1Hz, respectively. Glibenclamide (10μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP 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 KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.
AB - This study compared the effects of ATP-regulated potassium channel (KATP) 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 KATP targets Kir6.1, Kir6.2, 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±6.1Hz and 17.5±5.1Hz, respectively. Glibenclamide (10μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP 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 KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.
KW - Arrhythmias
KW - Heart failure
KW - Human heart IKATP
KW - Ischemic heart disease
KW - Optical mapping
UR - http://www.scopus.com/inward/record.url?scp=79959499965&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2011.04.016
DO - 10.1016/j.yjmcc.2011.04.016
M3 - Article
C2 - 21586291
AN - SCOPUS:79959499965
SN - 0022-2828
VL - 51
SP - 215
EP - 225
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -