Brian R Overholser1, Xiaomei Zheng, James E Tisdale. 1. Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 46202, USA. boverhol@purdue.edu
Abstract
STUDY OBJECTIVE: To determine the catecholaminergic effects on the duration of ventricular repolarization during inhibition of the rapid component of the delayed rectifier potassium current (I(Kr)). DESIGN: Isolated perfused heart model. SETTING: University research center. ANIMALS: Eighteen male Dunkin-Hartley guinea pigs. INTERVENTION: Hearts were excised and perfused in a retrograde manner at a constant aortic pressure of 60 mm Hg and temperature of 37 degrees C. Thirteen hearts were administered sparfloxacin 20 microg/ml (an I(Kr) inhibitor) in a buffered solution; the remaining five hearts were perfused with only the buffered solution to act as controls for potential time-dependent changes in action potential duration (APD). Immediately after the sparfloxacin infusion, six of the 13 hearts were administered a bolus catecholamine infusion of an epinephrine 10 nM-norepinephrine 6 nM admixture; 10 minutes after the start of the first catecholamine infusion, these hearts received another bolus infusion of an epinephrine 5 nM-norepinephrine 3 nM admixture. The other seven hearts were administered only a buffered solution. MEASUREMENTS AND MAIN RESULTS: Hearts were paced (240 beats/min), and left ventricular monophasic action potentials were recorded for determination of APD at 90% and 30% repolarization (APD(90) and APD(30), respectively). The APD(90) and APD(30) increased in all 13 hearts exposed to sparfloxacin. The mean +/- SD APD(90) increase from baseline at 15 minutes was 4.2 +/- 2.5% relative to the five control hearts. In the presence of I(Kr) inhibition, the epinephrine 5 nM-norepinephrine 3 nM and epinephrine 10 nM-norepinephrine 6 nM admixtures altered APD(90), with a mean +/- SD maximum increase in APD(90) of 3.1 +/- 1.2% and 4.5 +/- 3.6%, respectively. This corresponded to a statistically significant increase in APD(90) and APD(30) 2 minutes after the catecholamine infusion in the presence of I(Kr) inhibition. CONCLUSION: A net prolongation of ventricular repolarization was observed after a catecholamine surge in the presence of mild I(Kr) inhibition. This suggests that counteracting mechanisms may contribute to the apparent arrhythmogenic substrate during nonspecific adrenergic receptor activation in the presence of I(Kr) inhibition.
STUDY OBJECTIVE: To determine the catecholaminergic effects on the duration of ventricular repolarization during inhibition of the rapid component of the delayed rectifier potassium current (I(Kr)). DESIGN: Isolated perfused heart model. SETTING: University research center. ANIMALS: Eighteen male Dunkin-Hartley guinea pigs. INTERVENTION: Hearts were excised and perfused in a retrograde manner at a constant aortic pressure of 60 mm Hg and temperature of 37 degrees C. Thirteen hearts were administered sparfloxacin 20 microg/ml (an I(Kr) inhibitor) in a buffered solution; the remaining five hearts were perfused with only the buffered solution to act as controls for potential time-dependent changes in action potential duration (APD). Immediately after the sparfloxacin infusion, six of the 13 hearts were administered a bolus catecholamine infusion of an epinephrine 10 nM-norepinephrine 6 nM admixture; 10 minutes after the start of the first catecholamine infusion, these hearts received another bolus infusion of an epinephrine 5 nM-norepinephrine 3 nM admixture. The other seven hearts were administered only a buffered solution. MEASUREMENTS AND MAIN RESULTS: Hearts were paced (240 beats/min), and left ventricular monophasic action potentials were recorded for determination of APD at 90% and 30% repolarization (APD(90) and APD(30), respectively). The APD(90) and APD(30) increased in all 13 hearts exposed to sparfloxacin. The mean +/- SD APD(90) increase from baseline at 15 minutes was 4.2 +/- 2.5% relative to the five control hearts. In the presence of I(Kr) inhibition, the epinephrine 5 nM-norepinephrine 3 nM and epinephrine 10 nM-norepinephrine 6 nM admixtures altered APD(90), with a mean +/- SD maximum increase in APD(90) of 3.1 +/- 1.2% and 4.5 +/- 3.6%, respectively. This corresponded to a statistically significant increase in APD(90) and APD(30) 2 minutes after the catecholamine infusion in the presence of I(Kr) inhibition. CONCLUSION: A net prolongation of ventricular repolarization was observed after a catecholamine surge in the presence of mild I(Kr) inhibition. This suggests that counteracting mechanisms may contribute to the apparent arrhythmogenic substrate during nonspecific adrenergic receptor activation in the presence of I(Kr) inhibition.
Authors: John Schmittner; Jennifer R Schroeder; David H Epstein; Mori J Krantz; Nicole C Eid; Kenzie L Preston Journal: Pharmacotherapy Date: 2009-05 Impact factor: 4.705