Field and action potential recordings in heart slices: correlation with established in vitro and in vivo models

Abstract

BACKGROUND AND PURPOSE Action potential (AP) recordings in ex vivo heart preparations constitute an important component of the preclinical cardiac safety assessment according to the ICH S7B guideline. Most AP measurement models are sensitive, predictive and informative but suffer from a low throughput. Here, effects of selected anti‐arrhythmics (flecainide, quinidine, atenolol, sotalol, dofetilide, nifedipine, verapamil) on field/action potentials (FP/AP) of guinea pig and rabbit ventricular slices are presented and compared with data from established in vitro and in vivo models. EXPERIMENTAL APPROACH Data from measurements of membrane currents (hERG, INa), AP/FP (guinea pig and rabbit ventricular slices), AP (rabbit Purkinje fibre), haemodynamic/ECG parameters (conscious, telemetered dog) were collected, compared and correlated to complementary published data (focused literature search). KEY RESULTS The selected anti‐arrhythmics, flecainide, quinidine, atenolol, sotalol, dofetilide, nifedipine and verapamil, influenced the shape of AP/FP of guinea pig and rabbit ventricular slices in a manner similar to that observed for rabbit PF. The findings obtained from slice preparations are in line with measurements of membrane currents in vitro, papillary muscle AP in vitro and haemodynamic/ECG parameters from conscious dogs in vivo, and were also corroborated by published data. CONCLUSION AND IMPLICATIONS FP and AP recordings from heart slices correlated well with established in vitro and in vivo models in terms of pharmacology and predictability. Heart slice preparations yield similar results as papillary muscle but offer enhanced throughput for mechanistic investigations and may substantially reduce the use of laboratory animals.

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions

“…hERG) (Himmel et al, 2012). These findings are in agreement with other studies in conscious telemetred dogs in which similar doses of atenolol were administered (Himmel et al, 2012;Norton, Iacono, & Vezina, 2009).…”

“…A statistically significant difference in QTcR occurred at the 60 min time point after verapamil at both sites but this was inconsistent and, in both cases, this was an isolated occurrence. Other studies in conscious dogs have shown that similar doses of verapamil, a multi-cardiac ion channel blocker, had no effect on QTc interval (Himmel et al, 2012;Toyoshima et al, 2005).…”

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

“…Flecainide is used widely as a class Ic antiarrhythmic drug that, in addition to inhibiting cardiac sodium channels, displays class III antiarrhythmic activity due to inhibition of Kv4.3 and hERG [31,32]. In an elegant study, Caballero and colleagues reported [33] that clinical doses of flecainide increase ventricular I K1 through potentiation of Kir2.1, but not of Kir2.2, Kir2.3, Kir2.1/2.2 or Kir2.1/2.3 channels.…”

Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and Ca2+ transients in murine heart

“…; Himmel et al . ), thus providing a promising experimental model for electrophysiology, Ca 2+ handling, and drug action investigations.…”