New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic I(NCX)/I(Ca) currents.
BACKGROUND
Computer simulations have predicted that the balance of various electrogenic sarcolemmal ion currents may control the amplitude and phase of beat-to-beat alternans of membrane potential (V(m)). However, experimental evidence for the mechanism by which alternans of calcium transients produces alternation of V(m) (V(m)-ALT) is lacking.


OBJECTIVE
To provide experimental evidence that Ca-to-V(m) coupling during alternans is determined by the balanced influence of 2 Ca-sensitive electrogenic sarcolemmal ionic currents: I(NCX) and I(Ca).


RESULTS
V(m)-ALT and Ca-ALT were measured simultaneously from isolated guinea pig myocytes (n = 41) by using perforated patch and Indo-1(AM) fluorescence, respectively. There were 3 study groups: (1) control, (2) I(NCX) predominance created by adenoviral-induced NCX overexpression, and (3) I(Ca) predominance created by I(NCX) inhibition (SEA-0400) or enhanced I(Ca) (As(2)O(3)). During alternans, 14 of 14 control myocytes demonstrated positive Ca-to-V(m) coupling, consistent with I(NCX), but not I(Ca), as the major electrogenic current in modulating action potential duration. Positive Ca-to-V(m) coupling was maintained during I(NCX) predominance in 8 of 8 experiments with concurrent increase in Ca-to-V(m) gain (P <.05), reaffirming the role of increased forward-mode electrogenic I(NCX). Conversely, I(Ca) predominance produced negative Ca-to-V(m) coupling in 14 of 19 myocytes (P < .05) and decreased Ca-to-V(m) gain compared with control (P <.05). Furthermore, computer simulation demonstrated that Ca-to-V(m) coupling changes from negative to positive because of a shift from I(Ca) to I(NCX) predominance with increasing pacing rate.


CONCLUSIONS
These data provide the first direct experimental evidence that coupling in phase and magnitude of Ca-ALT to V(m)-ALT is strongly determined by the relative balance of the prominence of I(NCX) vs I(Ca) currents.
Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA. xwan@metrohealth.org
Xiaoping
X
Wan
Michael
M
Cutler
Zhen
Z
Song
Alain
A
Karma
Toshio
T
Matsuda
Akemichi
A
Baba
David S
DS
Rosenbaum
D000704:Analysis of Variance; D000814:Aniline Compounds; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010647:Phenyl Ethers; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D002118:Calcium