Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium

被引：7

作者：

Hezso, Tamas ^{[1
]}

Naveed, Muhammad ^{[2
]}

Dienes, Csaba ^{[1
]}

Kiss, Denes ^{[1
]}

Prorok, Janos ^{[2
,3
]}

Arpadffy-Lovas, Tamas ^{[2
]}

Varga, Richard ^{[2
]}

Fujii, Erika ^{[1
]}

Mercan, Tanju ^{[4
]}

Topal, Leila ^{[2
]}

Kistamas, Kornel ^{[1
]}

Szentandrassy, Norbert ^{[1
,5
]}

Almassy, Janos ^{[1
]}

Jost, Norbert ^{[2
,3
]}

Magyar, Janos ^{[1
,6
]}

Banyasz, Tamas ^{[1
]}

Baczko, Istvan ^{[2
,7
]}

Varro, Andras ^{[2
,3
,7
]}

Nanasi, Peter P. ^{[1
,8
]}

Virag, Laszlo ^{[2
,7
]}

Horvath, Balazs ^{[1
,9
]}

机构：

[1] Univ Debrecen, Dept Physiol, Fac Med, Nagyerdei Krt 98, H-4012 Debrecen, Hungary

[2] Univ Szeged, Dept Pharmacol & Pharmacotherapy, Fac Med, Dom Ter 12, H-6701 Szeged, Hungary

[3] Hungarian Acad Sci, MTA SZTE Res Grp Cardiovasc Pharmacol, Szeged, Hungary

[4] Akdeniz Univ, Sch Med, Dept Biophys, Antalya, Turkey

[5] Univ Debrecen, Dept Basic Med Sci, Fac Dent, Debrecen, Hungary

[6] Univ Debrecen, Div Sport Physiol, Dept Physiol, Fac Med, Debrecen, Hungary

[7] Univ Szeged, Dept Pharmacol & Pharmacotherapy, Interdisciplinary Excellence Ctr, Szeged, Hungary

[8] Univ Debrecen, Dept Dent Physiol & Pharmacol, Fac Dent, Debrecen, Hungary

[9] Univ Debrecen, Fac Pharm, Debrecen, Hungary

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

关键词：

LATE SODIUM CURRENT; LATE NA+ CURRENT; ACTION-POTENTIAL DURATION; SHORT-TERM VARIABILITY; TO-BEAT VARIABILITY; ANTIARRHYTHMIC-DRUGS; SELECTIVE-INHIBITION; ION CHANNELS; REPOLARIZATION; MYOCYTES;

D O I：

10.1038/s41598-021-88903-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Enhancement of the late Na+ current (I-NaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of I-NaL. In the present study, effects of GS967 on I-NaL 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 mu M) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 mu M). Under conventional voltage clamp conditions, I-NaL was significantly suppressed by GS967 and mexiletine, causing 80.4 +/- 2.2% and 59.1 +/- 1.8% reduction of the densities of I-NaL 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 I-NaL towards negative potentials. GS967 and mexiletine dissected inward I-NaL 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 (I-NaP) 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 I-NaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block I-NaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.

引用

页数：11

共 63 条

[1] Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential [J].