RESUMEN

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

RESUMEN

AIM: We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex-vivo and in-vivo guinea pig hearts. METHODS: The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin-GLY], docosahexaenoyl glycine [DHA-GLY], N-arachidonoyl taurine [N-AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug-induced long QT2 model of ex-vivo guinea pig hearts. The effect of DHA-GLY on QT interval was also studied in in-vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs on IKs was studied using Xenopus laevis oocytes expressing human KCNQ1 and KCNE1. RESULTS: All tested PUFAs shortened ADP and QT interval in ex-vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin-GLY was not as effective in shortening APD/QT interval as DHA-GLY in ex-vivo hearts. By constructing a guinea pig-like KCNE1, we found Lin-GLY to induce less activating effect compared with DHA-GLY on human KCNQ1 co-expressed with guinea pig-like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in-vivo guinea pig hearts. CONCLUSION: Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronounced IKs channel activating effect to better restore QT interval suggests that modifying PUFAs to target the IKs channel is a means to improve the QT-shortening effect.

Asunto(s)

RESUMEN

BACKGROUND AND AIMS: Although studies on the relation between arrhythmias and the action potential duration (APD) have been carried out, most of them are based only on electrophysiological factors of the heart and lack experiments that consider cardiac mechanical and electromechanical characteristics. Therefore, we conducted this study to clarify the relevance of the shortening of APD of a cell in relation to the mechanical contraction activity of the heart and the associated risk of arrhythmia. METHODS: The human ventricular model used in this study has two dynamic characteristics: electrophysiological conduction and mechanical contraction. The model simulating electrophysiological characteristics was consisted of lumped parameter circuit that can mimic the phenomenon of ion exchange through the cell membrane of myocyte and consisted of 214,319 tetrahedral finite elements. In contrast, the model simulating mechanical contraction characteristics was constructed to mimic cardiac contraction by means of the crossbridge of a myofilament and consisted of 14,720 hermite-based finite elements to represent a natural 3D curve of the cardiac surface. First, we performed a single cell simulation and the electrophysiological simulation according to the change of the APD by changing the electrical conductivity of the I Ks channel. Thus, we confirmed the correlation between APD and intracellular Ca2+ concentration. Then, we compared mechanical response through mechanical simulation using Ca2+ data from electrical simulation. RESULTS: The APD and the sum of the intracellular Ca2+ concentrations showed a positive correlation. The shortened APD reduced the conduction wavelength of ventricular cells by shortening the plateau and early repolarization in myocardial cells. The decrease in APD reduced ventricular pumping efficiency by more than 60% as compared with the normal group (normal conditions). This change is caused by the decline of ventricular output owing to reduced ATP consumption during the crossbridge of myofilaments and decreased tension. CONCLUSION: The shortening of APD owing to increased electrical conductivity of a protein channel on myocardial cells likely decreases the wavelength and the pumping efficiency of the ventricles. Additionally, it may increase tissue sensitivity to ventricular fibrillation, including reentry, and cause symptoms such as dyspnea and dizziness.

Asunto(s)

RESUMEN

Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits [Ca(2+)]i transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier K(+) (I(Ks)) channel is a cardiac K(+) channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating I(Ks) channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human I(Ks) channel activity by expressing human I(Ks) channels in Xenopus oocytes. We found that gintonin enhances IKs channel currents in concentration- and voltage-dependent manners. The EC50 for the I(Ks) channel was 0.05 ± 0.01 µg/ml. Gintonin-mediated activation of the I(Ks) channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an IP3 receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the I(Ks) channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 [Ca(2+)]i/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on I(Ks) channel. However, gintonin had no effect on hERG K(+) channel activity. These results show that gintonin-mediated enhancement of I(Ks) channel currents is achieved through binding of the [Ca(2+)]i/CaM complex to the C terminus of KCNQ1 subunit.

Asunto(s)