Role of the transient outward current in regulating mechanical properties of canine ventricular myocytes.
BACKGROUND
The transient outward current (I(to)) is a major repolarizing current in the heart. Reduction of I(to) density is consistently observed in human heart failure (HF) and animal HF models. It has been proposed that I(to), via its influence on phase-1 repolarization of the action potential, facilitates L-type Ca(2+) current (I(Ca-L)) activation and sarcoplasmic reticulum Ca(2+) release, and that its down-regulation may contribute to the impaired contractility in failing heart.


RESULTS
We used the dynamic clamp to quantitatively examine the influence of I(to) on the mechanical properties of canine left ventricular myocytes at 34 degrees C. In endocardial myocytes, where the native I(to) is small, simulation of an epicardial-level artificial I(to) accentuated the phase-1 repolarization and significantly suppressed cell shortening. The peak amplitude of Ca(2+) transient was also reduced in the presence of simulated I(to), although the rate of rise of the Ca(2+) transient was increased. Conversely, subtraction, or "blockade" of the native I(to) enhanced contractility in epicardial cells. These results agree with the inverse correlation between I(to) levels and myocyte contractility and Ca(2+) transient amplitude in epicardial and endocardial myocytes. Action potential clamp studies showed that the phase-1 repolarization/I(to) versus I(Ca-L) relationship had an inverted-J shape; small I(to) enhanced peak I(Ca-L) while moderate-to-large I(to) decreased peak I(Ca-L) and markedly reduced early Ca(2+) influx.


CONCLUSIONS
Our results show that epicardial-level of I(to) acts as a negative, rather than positive regulator of myocyte mechanical properties in canine ventricular myocytes.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575, USA.
Min
M
Dong
Sujuan
S
Yan
Yamei
Y
Chen
Paul J
PJ
Niklewski
Xiaoyin
X
Sun
Kathryn
K
Chenault
Hong-Sheng
HS
Wang
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D002469:Cell Separation; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D006352:Heart Ventricles; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000502:physiology*
D015220:Calcium Channels; D050051:Transient Receptor Potential Channels; D002118:Calcium