Paroxysmal beta-adrenergic Receptor-mediated Alterations in Ventricular Repolarization at Rapid Heart Rates During Inhibition of Delayed Rectifier Currents

作者：Overholser Brian R^*; Zheng Xiaomei; Tisdale James E

来源：Journal of Cardiovascular Pharmacology, 2009, 54(3): 253-262.

DOI：10.1097/fjc.0b013e3181b2b706

• beta-adrenergic receptor activation
• delayed rectifier currents
• torsades de pointes
• action potential duration
• ventricular repolarization

The contribution of the slow component of the delayed rectifier current (I(Ks)) 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 (I(Kr) inhibitor), or (3) sparfloxacin and HMR 1556 (I(Ks) inhibitor). The mean standard error of the mean epicardial action potential duration at 90% repolarization (APD(90)) increased from baseline with I(Kr) inhibition (12.9% +/- 4.7%) and dual I(Kr)/I(Ks), inhibition (25.1% +/- 5.3). Paroxysmal isoproterenol (0.01 and 1.0 nM) significantly decreased APD(90) in the presence of I(Kr) inhibition but was attenuated with the addition of I(Ks) inhibition. Spontaneous episodes of polymorphic ventricular tachycardia were observed with isoproterenol during dual I(Kr) and I(Ks) inhibition. The endocardial expression of KCNQI increased greater than 2-fold after exposure to I(Kr) and dual I(Kr)/I(Ks) inhibition relative to control but was not altered in epicardial tissue. The beta-adrenergaic receptor-mediated decrease in APD(90) during I(Kr) inhibition is reversed in the presence of I(Ks) inhibition at rapid heart rates. I(Ks) may serve as an important compensatory mechanism to protect against adrenergically induced arrhythmias when the repolarization reserve is depleted.

• 出版日期2009-9