Pharmacological characterization of electrocardiogram J-Tpeak interval in conscious Guinea pigs

Risks of torsade de pointes (TdP) and sudden cardiac death are increased by drug-induced hERG channel inhibition and QT interval extension. However, some medications have been found to inhibit hERG channels and lengthen QT intervals with low or intermediate TdP risk. This is most likely because these medications also inhibit late Na⁺ and L-type Ca²⁺ currents and other additional inward currents. The J-T_peak interval is a new biomarker of the net balance between inward and outward currents was recently discovered. Recent clinical trials have demonstrated that measuring the J-T_peak interval can be helpful for determining if a medication has caused a proportionate block from inward currents. In preclinical research, conscious telemetered dogs and monkeys serve as the gold standard for assessing in vivo QT. Given that humans and guinea pigs have similar distributions of cardiac ion channels, telemetered guinea pigs are also a good model for measuring QT interval. Furthermore, because only minimal quantities of test substances are needed, conscious telemetered guinea pigs could be good model for in vivo electrocardiogram (ECG) monitoring in preclinical studies.

In a new study published in European Journal of Pharmacology, Kyorin Pharmaceutical Co. Ltd. scientists, Dr. Hisashi Nogawa, Dr. Yukiko Muraki, Dr. Tomoyuki Kawai and Dr. Yoshiharu Kuninishi examined the possibility of using J-T_peak interval, a novel biomarker of inward current block and TdP risk, in conscious telemetered guinea pigs. The authors tested eight reference compounds with various ion channel-blocking properties to see how they affected the J-T_peak and T_peak-T_end durations in awake telemetered guinea pigs.

The research team demonstrated the value of J-T_peak interval assessment in predicting drug-induced balanced block of inward currents and the risk of TdP in conscious guinea pigs. The findings showed that the optimised correction formula’s acquired slope and R² of linear regression were closer to zero and that the formula was appropriate for identifying drug-induced QT and J-T_peak interval extension under experimental settings. Researchers analysed the J-T_peakc intervals’ comprehensive relationships with the QTc interval as well as the impact of reference substances on these intervals. In conscious guinea pigs, dofetilide and sotalol increased the ΔQTcX and ΔJ-T_peakcX intervals, and the ΔΔQTcX-ΔΔJ-T_peakcX inclination appeared significant. These findings supported a clinical investigation on the impacts of dofetilide on ECG parameters. On the other hand, both quinidine and quinine prolonged the ΔQTcX and ΔJ-T_peakcX intervals, with the former having a higher impact. Similar to other potent hERG channel blockers with Ca²⁺ and peak/late Na⁺ channel-blocking action, flecainide caused a moderate increasing trend in the ΔJ-T_peakcX interval and a considerable ΔQTcX lengthening in guinea pigs. In guinea pigs, ranolazine somewhat increased ΔQTcX and ΔJ-T_peakcX intervals, though less significantly than dofetilide and quinidine.

The J-T_peakc interval can be measured in conscious telemetered guinea pigs to assess drug-induced balanced inward current block. The authors made an excellent effort to classify reference substances in accordance with the guinea pigs’ ΔΔJ-T_peakcX and ΔΔQTcX intervals. The findings categorised dofetilide, sotalol, and quinidine as high risk, flecainide, quinine, and ranolazine as intermediate risk and verapamil, and nifedipine as low risk. According to the authors, the J-T_peak interval in the guinea pig model may be beneficial for forecasting the risk of TdP and drug-induced balanced block of inward currents.

In conclusion, the new study showcased the value of analysing the J-T_peakc interval for assessing the danger of TdP and drug-induced balanced block of inward currents in their conscious telemetered guinea pig model. The findings confirmed the value of examining the J-T_peak interval in conscious guinea pigs for identifying a drug-induced balanced block of inward currents and TdP risk when evaluating in vivo ECG in early preclinical research.