Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

摘要

Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization. AmJPhysiol Heart Circ Physiol 295: H2264-H2272, 2008. First published October 3, 2008; doi:10.1152/ajpheart.00680.2008.?Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents (/ks) or rapidly activating K+ currents (/kt) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks 7Ks, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current (7Ki), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both 7Ks and 7Ki, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block 7kt, 7Ks, or 7Ki, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pYT under isoflurane and propofol, underlining the proarrhythmic risk of 7Ks blockers in subjects with reduced 7kt 1 Dollars 1001N200306467Dollars 1200