Characterization of cardiac repolarization in the Göttingen minipig

TY - JOUR

T1 - Characterization of cardiac repolarization in the Göttingen minipig

AU - Laursen, Morten

AU - Olesen, Søren-Peter

AU - Grunnet, Morten

AU - Mow, Tomas

AU - Jespersen, Thomas

AU - Jespersen, Thomas

N1 - Copyright © 2010 Elsevier Inc. All rights reserved.

PY - 2011/3

Y1 - 2011/3

N2 - Introduction: The minipig represents an attractive experimental animal within cardiovascular research due to its extensive similarities to the human heart in terms of anatomy and physiology. Although minipigs have been used for cardiovascular research for decades no thorough characterization of the minipig cardiac electrophysiology has been performed. Therefore, we have for the first time characterized the minipig cardiac repolarization in a series of experiments ranging from mRNA quantification to in vivo studies. Methods: Göttingen minipigs were used throughout the study. Cardiac mRNA quantification was performed using quantitative PCR methods. For ex vivo experiments, hearts were excised using cardioplegic procedures and Langendorff and microelectrode action potential recordings were performed. Effects of temperature in vivo were recorded in anesthetized animals. Results: On the mRNA level the expression profile of major cardiac ion channel proteins in both atria and ventricle was very similar to what has been reported for humans. In both intact isolated heart and isolated endocardial strips the IKr blocker dofetilide increased action potential duration (APD). The IKs blocker HMR1556 increased APD and triangulation only when IKr was blocked with dofetilide. In the presence of IKr and IKs blockade a reduction of [K+]e resulted in a marked increase in APD90 in isolated hearts. IK1 blockade with Ba2+ increased APD in whole heart and isolated endocardium. In isolated endocardium, β-adrenergic stimulation with isoprenaline resulted in an increase in APD and potential amplitude but a decrease in triangulation. There was a rate-dependent decrease in APD in both whole heart and isolated endocardium. In vivo and ex vivo investigations revealed a negative correlation between temperature and duration of cardiac repolarization. Discussion: Our results point toward the minipig being a promising species for cardiac safety research.

AB - Introduction: The minipig represents an attractive experimental animal within cardiovascular research due to its extensive similarities to the human heart in terms of anatomy and physiology. Although minipigs have been used for cardiovascular research for decades no thorough characterization of the minipig cardiac electrophysiology has been performed. Therefore, we have for the first time characterized the minipig cardiac repolarization in a series of experiments ranging from mRNA quantification to in vivo studies. Methods: Göttingen minipigs were used throughout the study. Cardiac mRNA quantification was performed using quantitative PCR methods. For ex vivo experiments, hearts were excised using cardioplegic procedures and Langendorff and microelectrode action potential recordings were performed. Effects of temperature in vivo were recorded in anesthetized animals. Results: On the mRNA level the expression profile of major cardiac ion channel proteins in both atria and ventricle was very similar to what has been reported for humans. In both intact isolated heart and isolated endocardial strips the IKr blocker dofetilide increased action potential duration (APD). The IKs blocker HMR1556 increased APD and triangulation only when IKr was blocked with dofetilide. In the presence of IKr and IKs blockade a reduction of [K+]e resulted in a marked increase in APD90 in isolated hearts. IK1 blockade with Ba2+ increased APD in whole heart and isolated endocardium. In isolated endocardium, β-adrenergic stimulation with isoprenaline resulted in an increase in APD and potential amplitude but a decrease in triangulation. There was a rate-dependent decrease in APD in both whole heart and isolated endocardium. In vivo and ex vivo investigations revealed a negative correlation between temperature and duration of cardiac repolarization. Discussion: Our results point toward the minipig being a promising species for cardiac safety research.

U2 - 10.1016/j.vascn.2010.10.001

DO - 10.1016/j.vascn.2010.10.001

M3 - Journal article

C2 - 20951813

SN - 1056-8719

VL - 63

SP - 186

EP - 195

JO - Journal of Pharmacological and Toxicological Methods

JF - Journal of Pharmacological and Toxicological Methods

IS - 2

ER -