Characterization of cardiac repolarization in the Göttingen minipig.
BACKGROUND
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 I(Kr) blocker dofetilide increased action potential duration (APD). The I(Ks) blocker HMR1556 increased APD and triangulation only when I(Kr) was blocked with dofetilide. In the presence of I(Kr) and I(Ks) blockade a reduction of [K+](e) resulted in a marked increase in APD(90) in isolated hearts. I(K1) 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.


CONCLUSIONS
Our results point toward the minipig being a promising species for cardiac safety research.
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark. morl@lundbeck.com
Morten
M
Laursen
Søren-Peter
SP
Olesen
Morten
M
Grunnet
Tomas
T
Mow
Thomas
T
Jespersen
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D054849:Cardiac Electrophysiology; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004699:Endocardium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature / Q000378:metabolism / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D007473:Ion Channels; D010627:Phenethylamines; D012333:RNA, Messenger; D013449:Sulfonamides; D007545:Isoproterenol; C063533:dofetilide; D011188:Potassium