Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress.
Mechanical stretch and oxidative stress have been shown to prolong action potential duration (APD) and produce early afterdepolarizations (EADs). Here, we developed a simulation model to study the role of stretch-activated channel (SAC) currents in triggering EADs in ventricular myocytes under oxidative stress. We adapted our coupling clamp circuit so that a model ionic current representing the actual SAC current was injected into ventricular myocytes and added as a real-time current. This current was calculated as I(SAC) = G(SAC) * (V(m) - E(SAC)), where G(SAC) is the stretch-activated conductance, V(m) is the membrane potential, and E(SAC) is the reversal potential. In rat ventricular myocytes, application of G(SAC) did not produce sustained automaticity or EADs, although turn-on of G(SAC) did produce some transient automaticity at high levels of G(SAC). Exposure of myocytes to 100 microM H(2)O(2) induced significant APD prolongation and increase in intracellular Ca(2+) load and transient, but no EAD or sustained automaticity was generated in the absence of G(SAC). However, the combination of G(SAC) and H(2)O(2) consistently produced EADs at lower levels of G(SAC) (2.6 +/- 0.4 nS, n = 14, P < 0.05). Pacing myocytes at a faster rate further prolonged APD and promoted the development of EADs. SAC activation plays an important role in facilitating the development of EADs in ventricular myocytes under acute oxidative stress. This mechanism may contribute to the increased propensity to lethal ventricular arrhythmias seen in cardiomyopathies, where the myocardium stretch and oxidative stress generally coexist.
Wang
Yanggan
Y
Dept. of Pediatrics, Emory Univ., 2015 Uppergate Dr., Rm. 364, Atlanta, GA 30322, USA. yanggan.wang@emory.edu
Joyner
Ronald W
RW
Wagner
Mary B
MB
Cheng
Jun
J
Lai
Dongwu
D
Crawford
Brian H
BH
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D002412:Cations; D048430:Cell Shape / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013997:Time Factors
D002412:Cations; D007473:Ion Channels; D016877:Oxidants; D006861:Hydrogen Peroxide