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Regional and frequency-dependent changes in action potentials and transient outward K+ currents in ventricular
Ivan Kocic1, Yuji Hirano, Seiko Kawano
1Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical & Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510 Tokyo, Japan.
Insights
In cardiomyopathic hamsters, epicardial cells show reduced transient outward potassium currents (I(to)), altering action potential duration (APD) differences between epicardial and endocardial myocytes. This clarifies the role of I(to) in cardiac dysfunction.
Area of Science:
- Cardiology
- Electrophysiology
- Molecular Cardiology
Background:
- Ventricular myocytes in cardiomyopathic hamsters exhibit prolonged action potential duration (APD) and reduced transient outward potassium currents (I(to)).
- Previous studies have not fully elucidated the regional differences in I(to) between epicardial and endocardial myocytes and their impact on frequency-dependent APD changes in cardiomyopathy.
Purpose of the Study:
- To investigate the electrophysiological differences in epicardial and endocardial myocytes from J-2 hamsters with and without cardiomyopathy (CM).
- To clarify the role of transient outward potassium currents (I(to)) in the observed frequency-dependent changes in action potential duration (APD).
Main Methods:
- Whole-cell patch-clamp technique was employed to record membrane potentials and ionic currents.
- Experiments were conducted on epicardial and endocardial myocytes isolated from control and cardiomyopathic (CM) J-2 hamsters.
Main Results:
- In control hamsters, endocardial myocytes had longer APDs than epicardial myocytes, with APDs lengthening at higher stimulation frequencies.
- In CM hamsters, epicardial APDs lengthened beyond endocardial APDs without frequency dependence; I(to) density significantly decreased in epicardial myocytes with altered recovery from inactivation.
- Inward rectifier K+ current and L-type Ca2+ current were also reduced in CM hamsters.
Conclusions:
- Decreased current density and altered recovery from inactivation of transient outward potassium currents (I(to)) in epicardial myocytes are the primary drivers of APD differences between epicardial and endocardial myocytes in cardiomyopathic hamsters.
- These findings highlight the regional electrophysiological remodeling in heart failure and its underlying ionic mechanisms.
Objectives:
Although lengthening of action potential duration (APD) and decreased transient outward K+ currents (I(to)) have been observed in ventricular myocytes from cardiomyopathic hamsters, epi- and endo-cardial differences in I(to) and their roles in frequency-dependent changes in APD have not been clarified.
Methods:
The patch-clamp technique of whole-cell configuration was used to record membrane potentials and currents in epicardial and endocardial myocytes of the J-2 hamster germline without (control) and with cardiomyopathy (CM).
Results:
In control, APD in endocardial myocytes was longer than that in epicardial myocytes at 0.1 Hz. APD significantly lengthened with increased frequencies of stimulation from 0.1 to 6.0 Hz in both groups with the longer APD in endocardial myocytes. In CM, APD lengthened in epicardial myocytes exceeding the endocardial APD without a frequency-dependent prolongation. Pretreatment with 4 mM 4-aminopyridine completely abolished the frequency-dependent changes and abolished APD differences between epicardial and endocardial myocytes, and between control and CM hamsters. The transient outward K+ current (I(to)) significantly decreased in epicardial myocytes from CM hamsters compared with that of control (17.5 +/- 1.5 pA/pF in control vs. 9.5 +/- 2.5 pA/pF in CM at +60 mV) with altered recovery from inactivation, without changes in the endocardial I(to). Moreover, the inward rectifier K+ current decreased in epicardial myocytes from CM hamsters and the L-type Ca2+ current reduced in both regions from CM compared to control.
Conclusion:
Results indicate that differences in APD between epi- and endocardial myocytes in CM hamsters are mainly caused by a decreased current density and altered recovery from inactivation of I(to) in epicardial myocytes.
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