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Catecholaminergic Effects on Ventricular Repolarization During Inhibition of the Rapid Component of the Delayed Rectifier Potassium Current in a Perfused Heart Model
Author(s) -
Overholser Brian R.,
Zheng Xiaomei,
Tisdale James E.
Publication year - 2008
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.28.11.1315
Subject(s) - epinephrine , repolarization , catecholamine , medicine , norepinephrine , endocrinology , bolus (digestion) , cardiology , chemistry , anesthesia , electrophysiology , dopamine
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°C. Thirteen hearts were administered sparfloxacin 20 μg/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.