Abstract:
:Myocytes overlying a zone of infarction form the primary substrate for serious reentrant ventricular arrhythmias. In vitro and in vivo studies suggest that antiarrhythmic agents affect Na+ channels of cells from the epicardial border zone (EBZ) of the 5-day infarcted heart differently than they affect those of normal muscle. However, the mechanisms responsible for this difference remain unclear. Previous studies have revealed differences in Na+ current (INa) density and inactivation gating kinetics in myocytes dispersed from the EBZ (IZs). Since changes in inactivation gating could influence lidocaine action, we examined the effects of lidocaine on INa of IZs (n=38) and epicardial myocytes from the noninfarcted heart (NZs) (n=50) using the whole-cell variation of the patch-clamp technique. In drug-free conditions, the voltage dependence of steady-state inactivation of IZs was shifted negative to that of NZs, causing greater inactivation of IZ channels at depolarized (> or = -100-mV) holding potentials. Consistent with a high affinity for the inactivated channel conformation, lidocaine produced more tonic block in IZs than NZs at depolarized holding potentials. Additionally, in drug-free conditions, IZ INa exhibited an enhanced rate of inactivation from closed states, a delay in recovery from inactivation, and increased use-dependent reduction in amplitude during rapid (1- to 3-Hz) pulse trains. In both IZs and NZs, lidocaine (20 to 120 micromol/L) accelerated the rate of time-dependent loss of availability and markedly delayed recovery from availability, inducing significant use-dependent reduction of INa. However, at drug concentrations > or =60 micromol/L, the difference in use-dependent current reduction between IZs and NZs was minimized. The action of lidocaine to render Na+ channel inactivation in NZs more similar to that of IZs may be central to its (pro)antiarrhythmic effects.
journal_name
Circ Resjournal_title
Circulation researchauthors
Pu J,Balser JR,Boyden PAdoi
10.1161/01.res.83.4.431subject
Has Abstractpub_date
1998-08-24 00:00:00pages
431-40issue
4eissn
0009-7330issn
1524-4571journal_volume
83pub_type
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