Canine Action Potential Research Articles

HERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment

Since the discovery of the link that exists between drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new drugs inhibiting this channel. hERG inhibition is routinely screened for in new drugs and, typically, IC50 values are compared to projected plasma concentrations to define a safety margin. We aimed to show that drugs with similar hERG potency are not uniformly pro-arrhythmic-this depends on the drug binding kinetics and mode of action (trapped or not) rather than the IC50 value only. We used a mathematical model of hERG and its related encoded current IKr to simulate drug binding in different configurations. Expression systems mimicking the screening process were first investigated. hERG model was then incorporated into a canine action potential (AP) and tissue model to study the impact of drug binding configurations on AP and pseudo-ECG (QT interval prolongation). Our data show that: (1) trapped and not trapped configurations and different binding kinetics could be identified during hERG screening; (2) slow binding, not trapped drugs, induced less AP prolongation and minimal QT interval prolongation (4.7%) at a concentration equal to the IC50 whereas maximal pro-arrhythmic risk was observed for trapped drugs at the same concentration (QT interval prolongation, 23.1%). Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, drug mode of action and TdP, and the need to question the current regulatory guidance.

Modeling the Effect of Kv1.5 Block on the Canine Action Potential

A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the I Kur current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a downscaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD 90 was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD 90. This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.

Evidence for gender differences in electrophysiological properties of canine Purkinje fibres

Women are more prone to develop torsades de pointes, a rare life-threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block I(Kr) (rapid delayed rectifier cardiac K(+) current) and to prolong the QT interval. Blockade of I(Kr), hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K(+) conditions exhibited significantly longer AP durations at 50% (APD(50)) and 90% (APD(90)) of repolarisation as compared with APDs of fibres from male animals. Gender-related difference to rate adaptation was also present in APD(90) of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD(90), incidence of early afterdepolarisations, triggered and sustained-triggered activities (TAs) in fibres from female animals compared to males in either normal or low K(+) conditions. The sustained TAs were reversed by raising the concentration of [K(+)](0) in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product.