Attila S. Farkas

Relevance of anaesthesia for dofetilide-induced torsades de pointes in α1-adrenoceptor-stimulated rabbits

No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro‐arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α‐chloralose anaesthesia on the pro‐arrhythmic activity of the class III anti‐arrhythmic dofetilide in α1‐adrenoceptor‐stimulated rabbits.

Na+/Ca2+ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart

Background and purpose: The Na+/Ca2+ exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na+ concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 μM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na+ concentrations in rabbit and rat hearts.

The role of the Na+/Ca2+ exchanger, INa and ICaL in the genesis of dofetilide-induced torsades de pointes in isolated, AV-blocked rabbit hearts

Background and purpose:  The Na+/Ca2+ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide‐induced TdP.

Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α1-adrenoceptor-stimulated, anaesthetized rabbits

Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug‐induced TdP.

Correlation Between Flow-Mediated Dilation and Erectile Dysfunction

We hypothesized that there is a correlation between the magnitude of endothelial-mediated dilation of brachial artery and erectile function in patients. Thus, flow-mediated dilation of the brachial artery (FMD)-used to assess the function of endothelium-was measured in 56 patients (aged ~35 years) having erectile dysfunction for 6-12 months. The patients were grouped based on International Index of Erectile Dysfunction: severe (5-10), moderate (11-16), mild to moderate (17-21), and mild (22-25). As compared to the mild group (8.8 ± 1.7%), FMD was significantly reduced in the mild-to-moderate group (5.7 ± 1.1%), moderate group (5.3 ± 0.8%), and severe group (4.4 ± 0.6%). Also, there was a positive correlation between the magnitude of endothelial and erectile dysfunction. Patients were treated with the 5-phosphodiesterase inhibitor sildenafil, known to elevate vascular cGMP level and thus the vascular efficacy of internal nitric oxide, for 3 to 6 months prior to the study. The mean doses of sildenafil used were as follows: severe group, 100 mg/event; moderate group, 86.1 ± 21.4 mg/event; mild-to-moderate group, 71.8 ± 23.2 mg/event; mild group, 25 mg/event. We found a positive correlation between the sildenafil dose requirement and the severity of erectile dysfunction. On the bases on these findings, together with the known mechanism of action of sildenafil, we propose that vascular endothelial dysfunction could contribute to erectile dysfunction and that erectile dysfunction may be an early marker of peripheral vascular disease.

Absolute beat-to-beat variability and instability parameters of ECG intervals: biomarkers for predicting ischaemia-induced ventricular fibrillation

Predicting lethal arrhythmia liability from beat‐to‐beat variability and instability (BVI) of the ECG intervals is a useful technique in drug assessment. Most investigators use only arrhythmia‐free ECGs for this. Recently, it was shown that drug‐induced torsades de pointes (TdP) liability can be predicted more accurately from BVI measured irrespective of rhythm, even during arrhythmias (absolute BVI). The present study tested the broader applicability of this assessment by examining whether absolute BVI parameters predict another potential lethal arrhythmia, ischaemia‐induced ventricular fibrillation (VF).

Assessment of efficacy of proarrhythmia biomarkers in isolated rabbit hearts with attenuated repolarization reserve.

Abstract: Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve. Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested. QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during coperfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. Absolute QT variability parameters seem to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for torsades de pointes in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve.

New in vitro model for proarrhythmia safety screening: IKs inhibition potentiates the QTc prolonging effect of IKr inhibitors in isolated guinea pig hearts

INTRODUCTION Preclinical in vivo QT measurement as a proarrhythmia essay is expensive and not reliable enough. The aim of the present study was to develop a sensitive, cost-effective, Langendorff perfused guinea pig heart model for proarrhythmia safety screening. METHODS Low concentrations of dofetilide and cisapride (inhibitors of the rapid delayed rectifier potassium current, IKr) were tested alone and co-perfused with HMR-1556 (inhibitor of the slow delayed rectifier potassium current, IKs) in Langendorff perfused guinea pig hearts. The electrocardiographic rate corrected QT (QTc) interval, the Tpeak-Tend interval and the beat-to-beat variability and instability (BVI) of the QT interval were determined in sinus rhythm. RESULTS Dofetilide and HMR-1556 alone or co-perfused, prolonged the QTc interval by 20±2%, 10±1% and 55±10%, respectively. Similarly, cisapride and HMR-1556 alone or co-perfused, prolonged the QTc interval by 11±3%, 11±4% and 38±6%, respectively. Catecholamine-induced fast heart rate abolished the QTc prolonging effects of the IKr inhibitors, but augmented the QTc prolongation during IKs inhibition. None of the drug perfusions increased significantly the Tpeak-Tend interval and the sinus BVI of the QT interval. DISCUSSION IKs inhibition increased the QTc prolonging effect of IKr inhibitors in a super-additive (synergistic) manner, and the QTc interval was superior to other proarrhythmia biomarkers measured in sinus rhythm in isolated guinea pig hearts. The effect of catecholamines on the QTc facilitated differentiation between IKr and IKs inhibitors. Thus, QTc measurement in Langendorff perfused guinea pig hearts with pharmacologically attenuated repolarization reserve and periodic catecholamine perfusion seems to be suitable for preclinical proarrhythmia screening.

Na +/Ca 2+ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart (British Journal of Pharmacology (2008) 154, (93-104) DOI: 10.1038/bjp.2008.83)

Diastolic P (mm Hg) Control 0.1±0.6 8.3±0.9 2.4±0.7 0.8±0.6 0.4±0.6 1.3±0.6 2.1±0.6 3.4±0.6 4.8±0.5 6.7±0.5 0.5±0.6 0.1 (mm) 0.1±0.6 10.9±1.2 2.2±0.7 0.6±0.6 0.8±0.7 1.4±0.7 2.5±0.8 4.1±0.9 3.9±0.7 6.0±1.1 0.3±0.6 0.3 (mm) 0.1±0.3 8.7±0.6 2.3±0.2 0.5±0.2 0.8±0.3 1.8±0.3 2.4±0.4 3.0±0.3 4.0±0.3 5.4±0.4 0.1±0.3 1.0 (mm) 0.6±0.3 11.2±0.6 2.3±0.3 0.0±0.4 1.2±0.4 2.4±0.5 3.2±0.6 4.3±0.9 6.0±1.0 5.8±0.7 0.6±0.4

Absolute beat-to-beat variability and instability parameters of ECG intervals: biomarkers for predicting ischaemia-induced ventricular fibrillation: Absolute BVI parameters predict ischaemic VF

Predicting lethal arrhythmia liability from beat‐to‐beat variability and instability (BVI) of the ECG intervals is a useful technique in drug assessment. Most investigators use only arrhythmia‐free ECGs for this. Recently, it was shown that drug‐induced torsades de pointes (TdP) liability can be predicted more accurately from BVI measured irrespective of rhythm, even during arrhythmias (absolute BVI). The present study tested the broader applicability of this assessment by examining whether absolute BVI parameters predict another potential lethal arrhythmia, ischaemia‐induced ventricular fibrillation (VF).