We previously demonstrated that altering extracellular
sodium (
Nao) and
calcium (Cao) can modulate a form of electrical communication between cardiomyocytes termed "ephaptic coupling" (
EpC), especially during loss of gap junction coupling. We hypothesized that altering
Nao and Cao modulates conduction velocity (CV) and arrhythmic burden during
ischemia. Electrophysiology was quantified by optically mapping Langendorff-perfused guinea pig ventricles with modified
Nao (147 or 155 mM) and Cao (1.25 or 2.0 mM) during 30 min of simulated metabolic
ischemia (pH 6.5,
anoxia, aglycemia). Gap junction-adjacent perinexal width ( WP), a candidate cardiac ephapse, and
connexin (Cx)43
protein expression and
Cx43 phosphorylation at S368 were quantified by transmission electron microscopy and Western immunoblot analysis, respectively. Metabolic
ischemia slowed CV in hearts perfused with 147 mM
Nao and 2.0 mM Cao; however, theoretically increasing
EpC with 155 mM
Nao was arrhythmogenic, and CV could not be measured. Reducing Cao to 1.25 mM expanded WP, as expected during
ischemia, consistent with reduced
EpC, but attenuated CV slowing while delaying
arrhythmia onset. These results were further supported by osmotically reducing WP with
albumin, which exacerbated CV slowing and increased early arrhythmias during
ischemia, whereas
mannitol expanded WP, permitted conduction, and delayed the onset of arrhythmias.
Cx43 expression patterns during the various interventions insufficiently correlated with observed CV changes and arrhythmic burden. In conclusion, decreasing perfusate
calcium during metabolic
ischemia enhances perinexal expansion, attenuates conduction slowing, and delays arrhythmias. Thus, perinexal expansion may be cardioprotective during metabolic
ischemia. NEW & NOTEWORTHY This study demonstrates, for the first time, that modulating perfusate ion composition can alter cardiac electrophysiology during simulated metabolic
ischemia.