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Enhanced functional expression of transient outward current in hypertrophied feline myocytes
R E Ten Eick1, K Zhang, R D Harvey
1Department of Pharmacology, Northwestern University Chicago, IL.
Insights
Cardiac hypertrophy alters heart electrical activity. Increased transient outward current (I(to)) density in hypertrophied cells explains these changes, potentially offering new therapeutic targets for sudden cardiac death.
Area of Science:
- Cardiology
- Electrophysiology
- Molecular Biology
Background:
- Cardiac hypertrophy impairs myocardial contractility and alters heart electrophysiology.
- Hypertrophied ventricular cells show depressed action potential plateau voltages and prolonged durations.
- Previous studies noted changes in feline right ventricular (RV) myocytes' transient outward current (I(to)).
Purpose of the Study:
- To determine if altered I(to) explains electrophysiological changes in hypertrophied cardiocytes.
- To investigate if hypertrophy affects the kinetic properties of I(to) channels.
- To assess the role of I(to) density in hypertrophy-induced action potential alterations.
Main Methods:
- Whole-cell patch voltage-clamp studies on feline RV myocytes.
- Kinetic comparison of I(to) in hypertrophied versus normal RV myocytes.
- Investigating the impact of I(to) enhancement on action potential characteristics.
Main Results:
- The primary difference in hypertrophied RV myocytes was an increased density of the 4-amino-pyridine-sensitive I(to).
- No kinetic differences were found in I(to) channels between hypertrophied and normal myocytes.
- Increased I(to) density fully accounted for hypertrophy-induced changes in RV action potential plateau voltage and duration.
Conclusions:
- Hypertrophy increases I(to) by expressing additional normal channels, not a new subtype.
- Altered I(to) density is the key electrophysiological change in cardiac hypertrophy.
- Selective I(to) blockers may reduce sudden death risk in patients with myocardial hypertrophy.
Abstract:
Cardiac hypertrophy can decrease myocardial contractility and alter the electrophysiological activity of the heart. It is well documented that action potentials recorded from hypertrophied feline ventricular cells can exhibit depressed plateau voltages and prolonged durations. Similar findings have been made by others in rabbit, rat, guinea pig, and human heart. Whole-cell patch voltage-clamp studies designed to explain these changes in the action potential suggest that the only component of the membrane current recorded from feline right ventricular (RV) myocytes found to be substantially different from normal is the 4-amino-pyridine-sensitive transient outward current (I(to)). However, it was not clear if the change in I(to) could explain the changes in the action potential of hypertrophied cardiocytes, nor was it clear if these changes reflect an alteration in the electrophysiological character of the channels underlying I(to). A kinetic comparison of I(to) elicited by hypertrophied RV myocytes with that elicited by comparable normal RV myocytes previously revealed no differences, suggesting that the increased magnitude of the peak I(to) recorded from hypertrophied myocytes arises because the current density increases and not because of any alteration in the kinetic parameters governing the current. This finding suggests that in hypertrophy additional normal channels are expressed rather than a kinetically different channel subtype emerging. Investigations designed to determine if enhancement of I(to) could explain the hypertrophy-induced changes in plateau voltage and action potential duration suggest that a change in I(to) density can indeed explain the entire effect of hypertrophy on RV action potentials. If this notion is correct, the likelihood of "sudden death" in patients with myocardial hypertrophy might be decreased by a blocker selective for cardiac I(to).