Paroxysmal beta-adrenergic receptor-mediated alterations in ventricular repolarization at rapid heart rates during inhibition of delayed rectifier currents.
The contribution of the slow component of the delayed rectifier current (IKs) to ventricular repolarization is increased during rapid heart rates and prolonged repolarization. The objective was to characterize physiologically relevant paroxysmal beta-adrenergic receptor-mediated alterations on ventricular repolarization under these conditions. Paced guinea pig hearts were perfused with (1) control, (2) sparfloxacin (IKr inhibitor), or (3) sparfloxacin and HMR 1556 (IKs inhibitor). The mean +/- standard error of the mean epicardial action potential duration at 90% repolarization (APD90) increased from baseline with IKr inhibition (12.9% +/- 4.7%) and dual IKr/IKs inhibition (25.1% +/- 5.3). Paroxysmal isoproterenol (0.01 and 1.0 nM) significantly decreased APD90 in the presence of IKr inhibition but was attenuated with the addition of IKs inhibition. Spontaneous episodes of polymorphic ventricular tachycardia were observed with isoproterenol during dual IKr and IKs inhibition. The endocardial expression of KCNQ1 increased greater than 2-fold after exposure to IKr and dual IKr/IKs inhibition relative to control but was not altered in epicardial tissue. The beta-adrenergic receptor-mediated decrease in APD90 during IKr inhibition is reversed in the presence of IKs inhibition at rapid heart rates. IKs may serve as an important compensatory mechanism to protect against adrenergically induced arrhythmias when the repolarization reserve is depleted.
Overholser
Brian R
BR
Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 46202, USA. boverhol@purdue.edu
Zheng
Xiaomei
X
Tisdale
James E
JE
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D000072237:ERG1 Potassium Channel; D004699:Endocardium / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D010496:Pericardium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000633:toxicity; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013614:Tachycardia, Paroxysmal / Q000139:chemically induced / Q000503:physiopathology*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000503:physiopathology*; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel; D049990:Membrane Transport Modulators; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta