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Even though rodents are accessible model animals, their electrophysiological properties are deeply different from those of humans, making the translation of rat studies to humans rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of humans by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the [I.sub.K1] current (10 [micro]mol/L barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dogs, and did not affect it in humans. On the contrary, [I.sub.Kr] inhibition (50 nmol/L dofetilide) significantly prolonged repolarization in humans, rabbits, and dogs, but not in rats. Inhibition of the [I.sub.Kur] current (1 [micro]mol/L XEN-D0101) only prolonged rat ventricular repolarization and had no effect in humans or dogs. Inhibition of the [I.sub.Ks] (500 nmol/L HMR-1556) and [I.sub.to] currents (100 [micro]mol/L chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest translational value and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments. Key words: action potential duration, ion currents, human, comparison Les rongeurs constituent des modeles chez les animaux bien accessibles, mais leurs proprietes electrophysiologiques sont bien differentes de celles des humains, ce qui rend l'application des etudes chez le rat a l'humain plutot difficile. Nous avons compare les modes d'action de la repolarisation ventriculaire dans divers modeles chez les animaux a ceux des humains par l'enregistrement de potentiels d'action dans des preparations de muscle papillaire ventriculaire a l'aide de microelectrodes classiques, de meme que de l'application d'inhibiteurs selectifs de divers canaux potassiques transmembranaires. L'inhibition du courant [I.sub.K1] (chlorure de baryum a 10 [micro]M) entrainait une prolongationmarquee de la repolarisation ventriculaire chez le rat, mais seulement une legere prolongation chez le chien, sans effet sur ce parametre chez l'humain. Inversement, l'inhibition du courant [I.sub.Kr] (dofetilide a 50 nM) entrainait une prolongation marquee chez l'humain, le lapin et le chien, mais pas chez le rat. L'inhibition du courant [I.sub.Kur] (XEN-D0101 a 1 [micro]M) prolongeait la repolarisation ventriculaire uniquement chez le rat, sans effet chez l'humain ni chez le chien. L'inhibition des courants [I.sub.Ks] (HMR-1556 a 500 nM) et [I.sub.to] (chromanol-293B a 100 [micro]M) entrainait des effets similaires chez toutes les especes etudiees. Nous en arrivons a la conclusion que les preparations canines de ventricule permettent de realiser les experiences d'electrophysiologie cardiaque les plus robustes quant a leur application chez l'humain, alors que les moins robustes sur ce plan sont celles qui sont realisees a l'aide de preparations de ventricule de rat. [Traduit par la Redaction] Mots-cles : duree du potentiel d'action, courants ioniques, humain, comparaison, Introduction The translational value of electrophysiological experiments can be largely dependent on the animal model used (Varro et al. 1993), and some mammalian hearts are more similar to the human [...]

Aims: Atrial fibrillation (AF) is the most common chronic/recurrent arrhythmia, which significantly impairs quality of life and increases cardiovascular morbidity and mortality. Therefore, the aim of the present study was to investigate the properties of three repolarizing potassium currents which were shown to contribute to AF-induced electrical remodeling, i.e., the transient outward (Ito), inward rectifier (IK1) and acetylcholine-sensitive (IK,ACh) potassium currents in isolated atrial myocytes obtained from dogs either with sinus rhythm (SR) or following chronic atrial tachypacing (400/min)-induced AF. Methods: Atrial remodeling and AF were induced by chronic (4–6 weeks of) right atrial tachypacing (400/min) in dogs. Transmembrane ionic currents were measured by applying the whole-cell patch-clamp technique at 37 °C. Results: The Ito current was slightly downregulated in AF cells when compared with that recorded in SR cells. This downregulation was also associated with slowed inactivation kinetics. The IK1 current was found to be larger in AF cells; however, this upregulation was not statistically significant in the voltage range corresponding with atrial action potential (−80 mV to 0 mV). IK,ACh was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either in inward or outward directions. The selective IK,ACh inhibitor tertiapin (10 nM) blocked the outward CCh-induced current by 61%. In atrial cardiomyocytes isolated from dogs with AF, the presence of a constitutively active IK,ACh was observed, blocked by 59% with 10 nM tertiapin. However, in "AF atrial myocytes", CCh activated an additional, significant ligand-dependent and tertiapin-sensitive IK,ACh current. Conclusions: In our dog AF model, Ito unlike in humans was downregulated only in a slight manner. Due to its slow inactivation kinetics, it seems that Ito may play a more significant role in atrial repolarization than in ventricular working muscle myocytes. The presence of the constitutively active IK,ACh in atrial myocytes from AF dogs shows that electrical remodeling truly developed in this model. The IK,ACh current (both ligand-dependent and constitutively active) seems to play a significant role in canine atrial electrical remodeling and may be a promising atrial selective drug target for suppressing AF. [ABSTRACT FROM AUTHOR]

To understand the large inter-species variations in drug effects on repolarization, the properties of the rapid (IKr) and the slow (IKs) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch clamp and conventional microelectrode techniques at 37 °C. The amplitude of the E-4031-sensitive IKr tail current measured at −40 mV after a 1 s long test pulse of 20 mV, which was very similar in HM and DM but significant larger in RM and GM. The L-735,821-sensitive IKs tail current was considerably larger in GM than in RM. In HM, the IKs tail was even smaller than in DM. At 30 mV, the IKr component was activated extremely rapidly and monoexponentially in each studied species. The deactivation of the IKr component in HM, DM, and RM measured at −40 mV. After a 30 mV pulse, it was slow and biexponential, while in GM, the IKr tail current was best fitted triexponentially. At 30 mV, the IKs component activated slowly and had an apparent monoxponential time course in HM, DM, and RM. In contrast, in GM, the activation was clearly biexponential. In HM, DM, and RM, IKs component deactivation measured at −40 mV was fast and monoexponential, while in GM, in addition to the fast component, another slower component was also revealed. These results suggest that the IK in HM resembles that measured in DM and RM and considerably differs from that observed in GM. These findings suggest that the dog and rabbit are more appropriate species than the guinea pig for preclinical evaluation of new potential drugs expected to affect cardiac repolarization. [ABSTRACT FROM AUTHOR]

The addition of alloying elements is a crucial factor in improving the mechanical properties of pure copper, particularly in terms of enhancing its yield strength and hardness. This study examines the influence of scandium additions (up to 0.27 wt.%) on low-alloyed copper. Following the casting and solution-annealing processes, the alloys were quenched in water to maintain a supersaturated state. The mechanical properties were evaluated by tensile tests to measure the yield strength and the dynamic resonance method to determine the modulus of rigidity. Additionally, X-ray diffraction was utilized to analyze changes in lattice parameters, elucidating the structural modifications induced by scandium. This study dissects the parelastic and dielastic effects underlying the solid solution hardening mechanism, providing insights into how scandium alters copper's mechanical properties. The findings align with the solid solution hardening theories proposed by Fleischer and Labusch, providing a comprehensive understanding of the observed phenomena. [ABSTRACT FROM AUTHOR]

Activation of the parasympathetic nervous system has been reported to have an antiarrhythmic role during ischemiareperfusion injury by decreasing the arrhythmia triggers. Furthermore, it was reported that the parasympathetic neurotransmitter acetylcholine is able to modulate the ATP-dependent potassium current ([I.sub.K-ATP]), a crucial current activated during hypoxia. However, the possible significance of this current modulation in the antiarrhythmic mechanism is not fully clarified. Action potentials were measured using the conventional microelectrode technique from canine left ventricular papillary muscle and free-running Purkinje fibers, under normal and hypoxic conditions. Ionic currents were measured using the whole-cell configuration of the patch-clamp method. Acetylcholine at 5 [micro]mol/L did not influence the action potential duration (APD) either in Purkinje fibers or in papillary muscle preparations. In contrast, it significantly lengthened the APD and suppressed the Purkinje-ventricle APD dispersion when it was administered after 5 [micro]mol/L pinacidil application. Carbachol at 3 [micro]mol/L reduced the pinacidil-activated [I.sub.K-ATP] under voltage-clamp conditions. Acetylcholine lengthened the ventricular action potential under simulated ischemia condition. In this study, we found that acetylcholine inhibits the [I.sub.K-ATP] and thus suppresses the ventricle-Purkinje APD dispersion. We conclude that parasympathetic tone may reduce the arrhythmogenic substrate exerting a complex antiarrhythmic mechanism during hypoxic conditions. Key words: acetylcholine, Purkinje fibers, papillary muscles, hypoxia. On a rapporte que l'activation du systeme nerveux parasympathique joue un role antiarythmique pendant l'ischemie reperfusion par l'inhibition des declencheurs des arythmies. En outre, on a rapporte que l'acetylcholine, neurotransmetteur parasympathique, est en mesure de moduler le courant potassique ATP dependant ([I.sub.K-ATP]), un courant essentiel qui est active pendant l'hypoxie. Cependant, la signification eventuelle de la modulation de ce courant dans le mode d'action antiarythmique n'a pas ete entierement clarifie. Nous avons mesure des potentiels d'action a l'aide de la technique de microelectrode classique dans le muscle papillaire et des fibres de Purkinje libres de ventricule gauche, en situations normale et hypoxique chez le chien. Nous avons mesure les courants ioniques a l'aide de la configuration sur cellules entieres de la methode de << patch clamp >>. L'acetylcholine a 5 [micro]mol/L n'avait pas d'influence sur la duree du potentiel d'action (DPA), tant dans les preparations de fibres de Purkinje que dans le muscle papillaire. Cependant, elle entrainait un allongement de la DPA et une inhibition complete de la dispersion de la DPA entre le Purkinje et le muscle quand elle etait administree apres l'administration de pinacidil a 5 [micro]mol/L. Le carbachol a 3 [micro]mol/L entrainait une diminution du courant [I.sub.K-ATP] active par le pinacidil sous clampage du voltage. L'acetylcholine entrainait un allongement de la DPA ventriculaire en situation d'ischemie reperfusion. Dans cette etude, nous avons observe que l'acetylcholine entraine une inhibition du courant [I.sub.K-ATP] et consequemment une inhibition complete de la dispersion de la DPA entre le muscle et le Purkinje. Nous en arrivons a la conclusion que le tonus parasympathique pourrait permettre d'attenuer le substrat arythmogene exerqant un mode d'action antiarythmique complexe en situation d'hypoxie. [Traduit par la Redaction] Mots-cles: acetylcholine, fibres de Purkinje, muscles papillaires, hypoxie., Introduction The parasympathetic nervous system has a crucial role in controlling the actual heart rate and impulse propagation by influencing the sinoatrial and atrioventricular nodes (Higgins et al. 1973). The [...]

Ibuprofen is a widely used nonsteroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 [micro]M; n = 6) and rabbit (100 [micro]M; n = 7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 [micro]M) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n = 7). In dog myocytes, ibuprofen (250 [micro]M) did not significantly influence [I.sub.K1], but decreased the amplitude of [I.sub.to] and [I.sub.Kr] potassium currents by 28.2% (60 mV) and 15.2% (20 mV), respectively. Ibuprofen also depressed [I.sub.NaL] and [I.sub.Ca] currents by 19.9% and 16.4%, respectively. We conclude that ibuprofen seems to be free from effects on action potential parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients. Key words: ibuprofen, levofloxacin, repolarization reserve. L'ibuprofene est un anti-inflammatoire non steroidien largement utilise, qui a recemment ete associe avec un accroissement du risque cardiovasculaire, mais ses effets electrophysiologiques n'ont pas encore ete etudies adequatement dans des preparations de coeur isole. A l'aide de la technique de microelectrode classique et de la technique de << patch-clamp >> avec configuration sur cellules entieres, nous avons etudie les effets de l'ibuprofene sur les caracteristiques du potentiel d'action ainsi que sur plusieurs courants ioniques transmembranaires dans des preparations de coeur et de myocytes ventriculaires isoles enzymatiquement. Dans le muscle papillaire de chien (200 [micro]M; n = 6) et de lapin (100 [micro]M; n = 7) stimule a une frequence de 1 Hz, l'ibuprofene entrainait une prolongation de la repolarisation notable, bien que moderee. Dans les fibres de Purkinje canines, la duree et la vitesse maximale de la repolarisation diminuaient de maniere frequence-dependante. Chez le lapin (n = 7), la levofloxacine (40 [micro]M) administree seule n'entrainait pas de modification de la repolarisation, mais bien une augmentation du prolongement de la repolarisation obtenu avec l'ibuprofene. Dans les myocytes canins, l'ibuprofene (250 [micro]M) n'avait pas d'influence marquee sur [I.sub.K1], mais entrainait une diminution de l'amplitude des courants potassiques Ito et [I.sub.Kr] de 28,2 (60 mV) et de 15,2 % (20 mV), respectivement. L'ibuprofene entrainait aussi une depression des courants [I.sub.NaL] et [I.sub.Ca] de 19,9 et de 16,4 %, respectivement. Nous en arrivons a la conclusion que l'ibuprofene ne semble pas avoir d'effet sur les parametres du potentiel d'action a de faibles concentrations. Cependant, a des concentrations plus elevees, il pourrait porter atteinte a la reserve de repolarisation, participant ainsi au risque proarythmique observe chez les patients. [Traduit par la Redaction] Mots-cles : ibuprofene, levofloxacine, reserve de repolarisation., Introduction Ibuprofen is one of the most widely used nonsteroidal antiinflammatory drugs (NSAIDs) (Rainsford 2009). However, a recent Danish nationwide case-time-control study (Sondergaard et al. 2017) found that short-term therapy [...]

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion and reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged the frequency-corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations, blocked [I.sub.Kr] in isolated cardiomyocytes (Class III effects), and reduced the maximum rate of depolarization ([V.sub.max]) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent reentry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes. Key words: action potential duration, atrial fibrillation, combined Class I/B and Class III effects, ventricular fibrillation, Torsades de Pointes. Les maladies cardiovasculaires sont les premieres causes de mortalite. La mort subite cardiaque est le plus souvent causee par une fibrillation ventriculaire (FV). La fibrillation auriculaire (FA) est la plus frequente cause d'arythmie cardiaque et une des plus importantes causes d'AVC et d'insuffisance cardiaque. La prise en charge pharmacologique de la FV et de la FA demeure suboptimale en raison de l'efficacite limitee des medicaments antiarythmiques, ainsi que de leurs effets indesirables proarythmiques sur les ventricules. Cette etude portait sur les effets antiarythmiques et sur l'electrophysiologie cardiaque cellulaire du SZV-270, un nouveau compose, dans des modeles chez le lapin et le chien. Le SZV-270 entrainait une diminution marquee de la frequence d'apparition de la FV chez des lapins apres l'occlusion d'une artere coronaire suivie d'une reperfusion, ainsi que de la FA induite par salves de stimulations dans un modele de FA chez le chien conscient avec pacing rapide. Le SZV-270 entrainait un prolongement de l'intervalle QT corrige pour la frequence, de la duree du potentiel d'action et de la periode refractaire effective dans des preparations de ventricule et d'auricule, ainsi qu'une inhibition du courant [I.sub.Kr] dans des cardiomyocytes isoles (effet de classe III). Il entrainait aussi une diminution de la vitesse maximale de la depolarisation ([V.sub.max]) a des durees de cycle inferieures a 1000 ms dans des preparations de ventricule (effet de classe I/B). Il est important de noter que le SZV-270 n'entrainait pas de torsades de pointes dans un modele de proarythmie chez le lapin anesthesie caracterise par une reserve de repolarisation diminuee. En conclusion, avec ses effets de classe I/b et de classe III combines, le SZV-270 peut permettre de prevenir les arythmies par reentree avec une decroissance du risque de provoquer des torsades de pointes induites par les medicaments. [Traduit par la Redaction] Mots-cles : duree du potentiel d'action, fibrillation auriculaire, effets de classe I/B et de classe III combines, fibrillation ventriculaire, torsades de pointes., Introduction Cardiovascular diseases remain the leading causes of mortality in the developed world. Approximately 18 million lives are lost annually due to sudden cardiac death, most commonly caused by severe [...]