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). METHODS AND 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.
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). METHODS AND 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.