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Recent studies of cardiac and skeletal muscle suggest that the sites at which Mn2+ uncouples excitation and contraction are restricted to a space functionally equivalent to the interstitium. We sought to corroborate this hypothesis by using the ferrocyanide anion, Fe(CN)6−4. This anion is relatively innocuous to myocardial tissue, is compatible with solutions containing alkaline and alkaline earth cations, but immediately precipitates when combined with cations of the transitionelement series, particularly Mn2+. The finding of interest is that heart tissue pretreated with 20 nut Na4Fe(CN)6 is “protected” from the normal action of Mn2+, the uncoupling of excitation and contraction. This finding would be expected if Fe(CN)64∼ could precipitate Mn2+ influx in one or several compartments. Protection was not a function of the duration of the pretreatment as long as an interval of several minutes was allowed. However, protection markedly declined as a function of the interval following the cessation of Fe(CN)64∼ treatment and preceding the addition of Mn2+. Quantified in this way using thin-diameter papillary and trabecular muscles from rabbits, protection was found to be approximately monoexponential and most likely confined to a single, rapidly effluxing compartment, the interstitium. Studies were conducted using the perfused rabbit septum to divulge the washout kinetics of 54Mn2+ and [14C]Na4Fe(CN)6. Analyses of these washouts suggest that Mn2Fe(CN)6 precipitated in the interstitium not because this was the only compartment reached by both agents but because this was the space in which Mn2+ exerted its uncoupling action.

Ferrocyanide protection against uncoupling of excitation and contraction by manganese in rabbit ventricular myocardium.