Search

Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37°C with 1-100 µmol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra- performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance ([V.sub.max] and [K.sub.m]) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased [K.sub.m] and (or) decreased [V.sub.max] values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone. Key words: CYP2D6, variants, propafenone, metabolism, vitro. Le cytochrome P450 2D6 (CYP2D6) est un membre important de la superfamille des cytochromes P450, plus de 100 variants alleliques de CYP2D6 ayant deja ete rapportes. Le but de cette etude etait d'evaluer les caracteristiques catalytiques de 25 alleles (CYP2D6.1 et 24 variants de CYP2D6) et leurs effets sur le metabolisme de la propafenone in vitro. Vingt-cinq alleles CYP2D6 ont ete exprimes dans les cellules d'insecte Spodoptera frugiperda (Sf) 21 et chaque variant a ete evalue a l'aide de la propafenone comme substrat. Les reactions ont ete realisees a 37°C avec 1-100 µmol/L de propafenone pendant 30 min. A la fin, la 5-OH-propafenone a ete extraite et detectee par UPLC. Comparativement au CYP2D6.1, les valeurs de clairance intrinseque ([V.sub.max]/[K.sub.m]) de tous les variants etaient significativement modifiees. Trois variants (CYP2D6.87, CYP2D6.90 CYP2D6.F219S) presentaient des valeurs de clairance intrinseque fortement accrues (129 a 165 %), alors que 21 variants presentaient des valeurs significativement diminuees (16 a 85 %), a cause des valeurs de [K.sub.m] accrues et (ou) de [V.sub.max] diminuees. Ces resultats indiquaient que la majorite des alleles testes possedaient une activite catalytique significativement modifiee quant a l'hydroxylation de la propafenone dans ce systeme d'expression. Les sujets portant ces alleles rares devraient etre attentivement surveilles s'ils sont traites a la propafenone. [Traduit par la Redaction] Mots-cles: CYP2D6, variants, propafenone, metabolisme, vitro., Introduction Propafenone (PPF) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias (Stoschitzky et al. 2015). It undergoes extensive first-pass metabolism by liver to form [...]

Purpose We investigated the effect of low-dose droperidol on heart rate-corrected QT (QTc) interval and interaction with propofol. Methods Seventy-two patients undergoing upper limb surgery were included in this study. Patients were randomly allocated to one of three groups: group S (n = 24), which received 1 ml saline; group D1 (n = 24), which received 1.25 mg droperidol; or group D2 (n = 24), which received 2.5 mg droperidol. One minute later, fentanyl (3 µg/kg) was administered. Two minutes after fentanyl administration, anesthesia was induced using propofol (1.5 mg/kg) and vecronium. Tracheal intubation was performed 3 min after the administration of propofol. Heart rate, mean arterial pressure, bispectral index, and QTc interval were recorded at the following time points: immediately before the droperidol injection (baseline); 3 min after the saline or droperidol injection; 3 min after the propofol injection; and 2 min after tracheal intubation. Results Compared to baseline, the QTc interval in group S and group D1 was significantly shorter after propofol injection, but recovered after tracheal intubation. In group D2, the QTc interval was significantly prolonged after droperidol injection, but recovered after propofol injection, and was significantly prolonged after tracheal intubation. Conclusions We found that saline or 1.25 mg droperidol did not prolong QTc interval, whereas 2.5 mg droperidol prolonged the QTc interval significantly, and that propofol injection counteracted the prolongation of the QTc interval induced by 2.5 mg droperidol. Keywords Droperidol * Propofol * QT interval * QT dispersion * Arrhythmia, Introduction Droperidol, an anesthetic agent, has a low cost and is a very effective antiemetic when administered at a low dose. The maximum recommended initial dose is 2.5 mg by [...]

Summary This article describes the aetiology of Wolff-Parkinson-White syndrome and discusses the benefits and disadvantages of some of the available cardioversion medications with which it can be treated. Keywords Atrial [...]

Electrophysiological alternans is a beat-to-beat alternation of the action potential duration and/or [Ca.sup.2+] transient amplitude and is linked to ventricular arrhythmias. We investigated the significance of various rate parameters under different experimental conditions with respect to alternans incidence and the propensity for spiral wave formation. Voltage and [Ca.sup.2+] were optically mapped in monolayers of neonatal rat ventricular myocytes. Alternans did not occur at physiological temperature, but its incidence increased significantly at lowered temperatures. Pacing cycle length for spatially concordant alternans onset ([PCL.sub.c]), PCL for spatially discordant alternans onset ([PCL.sub.D]), and minimum cycle length for loss of 1:1 or 2:2 capture (MCL) also significantly increased with lower temperature but in a way such that the differences between PCLc and MCL and between [PCL.sub.D] and MCL widened. These results provided the rationale to identify the former difference as the alternans vulnerable window (AVW; in ms) and the latter difference as the discordant alternans vulnerable window (AVWD; in ms). Computational simulations showed that interventions that widen AVW, including altered [Ca.sup.2+] cycling and enhanced [K.sup.+] currents, also promote alternans, regardless of whether PCLc or MCL increased or decreased. The simulation results were confirmed experimentally by addition of the ATP-sensitive [K.sup.+] channel agonist pinacidil. Mathematical analysis provided a theoretical basis linking the size of AVW to the incidence of alternans. Finally, experiments showed that the size of AVWD is related to the incidence of spatially discordant alternans and, additionally, to the incidence of spiral wave formation. In conclusion, vulnerable windows can be defined that are strongly correlated with alternans incidence, spatial discordance, and spiral wave formation. electrophysiology; arrhythmia; optical mapping; computational model doi: 10.1152/ajpheart.01036.2009.

Though many consider the magnitude of respiratory sinus arrhythmia as an index of cardiac vagal control, its physiological origins remain unclear. One influential model postulates that the systolic pressure rise within a given beat stimulates the baroreflex arc to adjust the following heart period such that diastolic pressure is 'stabilized' and hence displays lesser fluctuation. Accordingly, the magnitude of diastolic pressure fluctuations with respiration should change reciprocally after augmentation or inhibition of respiratory sinus arrhythmia. To test this, we augmented and subsequently inhibited respiratory sinus arrhythmia with vagotonic and vagolytic atropine administration in 19 healthy young volunteers to assess the relation between respiratory R-R interval and diastolic pressure fluctuations. Respiratory diastolic pressure fluctuations showed parallel rather than inverse changes in relation to those in respiratory sinus arrhythmia: they increased with augmented respiratory sinus arrhythmia (138 and 190% of baseline in the frequency and time domains, both P < 0.05) and tended to decrease with inhibited respiratory sinus arrhythmia (82 and 93% of baseline in frequency and time domains, P = 0.20 and P = 0.07). Furthermore, >60% of the change in diastolic pressure fluctuations was explained by the change in respiratory sinus arrhythmia (R: = 0.62; P < 0.001), that is, an ~50-ms increase or decrease in respiratory sinus arrhythmia resulted in a parallel ~1-mmHg change in diastolic pressure fluctuations. Thus, in young healthy individuals during supine rest, respiratory fluctuations in R-R interval do not buffer against diastolic pressure fluctuations but actually cause diastolic pressure fluctuations. Therefore, our data provide little evidence for a predominant role of a baroreflex feedback mechanism underlying respiratory sinus arrhythmia during supine rest. R-R interval; baroreflex; diastolic blood pressure; atropine doi: 10.1152/ajpheart.00974.2009.

Previous reports demonstrated that cilostazol, a phosphodiesterase 3 inhibitor, affected cellular electrophysiology and reduced episodes of ventricular fibrillation (VF) in patients with Brugada syndrome. However, its effects on VF induction and defibrillation efficacy have never been investigated. We tested the hypothesis that cilostazol increases the VF threshold (VFT) and decreases the upper limit of vulnerability (ULV) and the defibrillation threshold (DFT). A total of 48 pigs were randomly assigned to defibrillation and VF induction studies. The diastolic pacing threshold (DPT), VFT, ULV, DFT, and effective refractory period were determined before and after the infusion of cilostazol at 6 mg/kg, 3 mg/kg, or vehicle. The DPT was significantly increased after administration of 3 and 6 mg/kg cilostazol. The ULV and DFT were significantly decreased after administration of 6 mg/kg cilostazol only. The ULV in the 6 mg/kg group had 12% lower peak voltage and 25% lower total energy, and the DFT had 13% lower peak voltage and 25% lower total energy. The VFT was not altered in any experimental group. This study shows that cilostazol administration significantly increased the DPT, which was associated with significantly reduced DFT and ULV. Key words: cilostazol, phosphodiesterase 3, ventricular fibrillation threshold, defibrillation threshold, upper limit of vulnerability, arrhythmia inducibility. Des rapports anterieurs ont demontre que le cilostazol, un inhibiteur de la phosphodiesterase III, influe sur l'electrophysiologie cellulaire et reduit les episodes de fibrillation ventriculaire (FV) dans le syndrome de Brugada. Toutefois ses effets sur l'induction de la FV et l'efficacite de la defibrillation n'ont jamais ete examinees. Nous avons veerifie rhypothese que le cilostazol augmente le seuil de FV (SFV), et diminue la limite maximale de vulnerabilite (LMV) et le seuil de defibrillation (SDF). Nous avons reparti 48 porcs au hasard dans des groupes d'induction de fibrillation ventriculaire et de defibrillation. Nous avons determine le seuil de stimulation diastolique (SSD), la peeriode refractaire efficace, le SVF, la LMV et le SDF, avant et apres la perfusion 6 mg/kg de cilostazol, de 3 mg/kg, ou d'un vehicule. L'administration de cilostazol a augmente; le SDF de maniere significative. La perfusion de 6 mg/kg a augmente significativement la LMV et le SDF. La LSV du groupe 6 mg/kg a eu une tension de crete de 12% inferieure et une energie totale de 25% infeerieure. Le SDF de ce groupe a eu une tension de crete de 13% inferieure et une eenergie totale de 25% inferieure. Le SFV est demeure stable chez tous les groupes experimentaux. Ainsi, l'administration de cilostazol a augmente significativement le SSD, ce qui a eetee associee a une reduction significative du SDF et de la LMV. Mots-cles: cilostazol, phosphodiesterase 3, seuil de fibrillation ventriculaire, defibrillation, limite maximale de vulnerabilite, inductibilitee d'arythmies. [Traduit par la Redaction], Introduction Cilostazol is a selective phosphodiesterase 3 (PDE3) inhibitor (Cone et al. 1999). Because of its potent effect on vasodilatation and antiplatelet aggregation, cilostazol was approved by the US Food [...]

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone. narcotics; pain; respiratory depression; arrhythmia; opioids doi: 10.1152/ajpregu.00140.2009.

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding [Na.sup.+] channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding [I.sub.Na] blockers affect AF, we developed realistic mathematical models of state-dependent [Na.sup.+] channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two-and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulatedreceptor theory and maximum affinity for activated [Na.sup.+] channels. Lidocaine produced frequency-dependent [Na.sup.+] channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum ~89% at 60 [micro]M). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source [Na.sup.+] current in the face of large ACh-sensitive [K.sup.+] current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF. state-dependent channel; cardiac action potential; antiarrhythmic drug therapy; computer simulations; heart arrhythmia models

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing [K.sup.+] channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of [I.sub.Ks] and [I.sub.Kr] currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary [I.sub.Kr] and [I.sub.Ks] without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type [alpha] subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death., Introduction The long QT syndrome (LQTS) is a familial, usually autosomal dominant disease, characterized by prolongation of the QT interval in the surface ECG, spontaneous polymorphic ventricular tachycardia (VT, often [...]

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors., Introduction Congenital long QT syndrome (LQTS) is characterized by the prolongation of the QT interval on surface ECGs and an increased risk of potentially fatal ventricular arrhythmias, especially torsade de [...]

The synthetic evidence related to the optimal use of amiodarone for various arrhythmias in the U.S. is presented. The findings recommend judicious use with close follow-up in patients likely to derive the most benefits.

nearly 1 million Americans are hospitalized with heart failure each year, and this cardiac problem is the most frequent cause of hospitalization in patients more than 65 years old. (1) [...]

A study aims to determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Oral aminodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and might be safe overall and in important patient subgroups.