Original ArticleParoxysmal β-adrenergic Receptor-mediated Alterations in Ventricular Repolarization at Rapid Heart Rates During Inhibition of Delayed Rectifier CurrentsOverholser, Brian R PharmD*†; Zheng, Xiaomei MS*; Tisdale, James E PharmD*†Author Information From the *Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN; and †Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN. Received for publication February 19, 2009; accepted May 28, 2009. Supported by the American College of Clinical Pharmacy Research Institute-AstraZeneca Cardiovascular Research Award. The authors report on conflicts of interest. Reprints: Brian R. Overholser, PharmD, Purdue University School of Pharmacy and Pharmaceutical Sciences, W7555 Myers Building, WHS, 1001 West 10th St, Indianapolis, IN 46202 (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: September 2009 - Volume 54 - Issue 3 - p 253-262 doi: 10.1097/FJC.0b013e3181b2b706 Buy Metrics Abstract 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 β-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 β-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. © 2009 Lippincott Williams & Wilkins, Inc.