Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium
Abstract Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL and action potential (AP) morphology were...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/73d50e33846d4bc7818bb17c0e8b0687 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:73d50e33846d4bc7818bb17c0e8b0687 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:73d50e33846d4bc7818bb17c0e8b06872021-12-02T14:49:26ZMexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium10.1038/s41598-021-88903-32045-2322https://doaj.org/article/73d50e33846d4bc7818bb17c0e8b06872021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88903-3https://doaj.org/toc/2045-2322Abstract Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, INaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of INaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of INaL towards negative potentials. GS967 and mexiletine dissected inward INaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of −0.37 ± 0.07 and −0.28 ± 0.03 A/F, and current integrals of −56.7 ± 9.1 and −46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na+ current (INaP) were assessed by recording the maximum velocity of AP upstroke (V+ max) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V+ max block. However, since GS967 depressed V+ max and INaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block INaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.Tamás HézsőMuhammad NaveedCsaba DienesDénes KissJános ProrokTamás Árpádffy-LovasRichárd VargaErika FujiiTanju MercanLeila TopalKornél KistamásNorbert SzentandrássyJános AlmássyNorbert JostJános MagyarTamás BányászIstván BaczkóAndrás VarróPéter P. NánásiLászló VirágBalázs HorváthNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Tamás Hézső Muhammad Naveed Csaba Dienes Dénes Kiss János Prorok Tamás Árpádffy-Lovas Richárd Varga Erika Fujii Tanju Mercan Leila Topal Kornél Kistamás Norbert Szentandrássy János Almássy Norbert Jost János Magyar Tamás Bányász István Baczkó András Varró Péter P. Nánási László Virág Balázs Horváth Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| description |
Abstract Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, INaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of INaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of INaL towards negative potentials. GS967 and mexiletine dissected inward INaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of −0.37 ± 0.07 and −0.28 ± 0.03 A/F, and current integrals of −56.7 ± 9.1 and −46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na+ current (INaP) were assessed by recording the maximum velocity of AP upstroke (V+ max) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V+ max block. However, since GS967 depressed V+ max and INaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block INaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent. |
| format |
article |
| author |
Tamás Hézső Muhammad Naveed Csaba Dienes Dénes Kiss János Prorok Tamás Árpádffy-Lovas Richárd Varga Erika Fujii Tanju Mercan Leila Topal Kornél Kistamás Norbert Szentandrássy János Almássy Norbert Jost János Magyar Tamás Bányász István Baczkó András Varró Péter P. Nánási László Virág Balázs Horváth |
| author_facet |
Tamás Hézső Muhammad Naveed Csaba Dienes Dénes Kiss János Prorok Tamás Árpádffy-Lovas Richárd Varga Erika Fujii Tanju Mercan Leila Topal Kornél Kistamás Norbert Szentandrássy János Almássy Norbert Jost János Magyar Tamás Bányász István Baczkó András Varró Péter P. Nánási László Virág Balázs Horváth |
| author_sort |
Tamás Hézső |
| title |
Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| title_short |
Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| title_full |
Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| title_fullStr |
Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| title_full_unstemmed |
Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium |
| title_sort |
mexiletine-like cellular electrophysiological effects of gs967 in canine ventricular myocardium |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/73d50e33846d4bc7818bb17c0e8b0687 |
| work_keys_str_mv |
AT tamashezso mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT muhammadnaveed mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT csabadienes mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT deneskiss mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT janosprorok mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT tamasarpadffylovas mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT richardvarga mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT erikafujii mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT tanjumercan mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT leilatopal mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT kornelkistamas mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT norbertszentandrassy mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT janosalmassy mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT norbertjost mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT janosmagyar mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT tamasbanyasz mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT istvanbaczko mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT andrasvarro mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT peterpnanasi mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT laszlovirag mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium AT balazshorvath mexiletinelikecellularelectrophysiologicaleffectsofgs967incanineventricularmyocardium |
| _version_ |
1718389452274925568 |