Pathways of Rb + Influx and Their Relation to Intracellular [Na + ] in the Perfused Rat Heart

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Abstract
The aims of this study were to characterize the routes of influx of the K+ congener, Rb+, into cardiac cells in the perfused rat heart and to evaluate their links to the intracellular Na+ concentration ([Na+]i) using 87Rb and 23Na nuclear magnetic resonance (NMR) spectroscopy. The rate constant for Rb+ equilibration in the extracellular space was 8.5 times higher than that for the intracellular space. The sensitivity of the rate of Rb+ accumulation in the intracellular space of the perfused rat heart to the inhibitors of the K+ and Na+ transport systems has been analyzed. The Rb+ influx rates were measured in both beating and arrested hearts: both procaine (5 mmol/L) and lidocaine (1 mmol/L) halved the Rb+ influx rate. In procaine-arrested hearts, the Na+,K+-ATPase inhibitor ouabain (0.6 mmol/L) decreased Rb+ influx by 76±24% relative to that observed in untreated but arrested hearts. Rb+ uptake was insensitive to the K+ channel blocker 4-aminopyridine (1 mmol/L). The inhibitor of Na+/K+/2 Cl− cotransport bumetanide (30 μmol/L) decreased Rb+ uptake only slightly (by 9±8%). Rb+ uptake was dependent on [Na+]i: it increased by 58±34% when [Na+]i was increased with the Na+ ionophore monensin (1 μmol/L) and decreased by 48±9% when [Na+]i was decreased by the Na+ channel blockers procaine and lidocaine. Dimethylamiloride (15 to 20 μmol/L), an inhibitor of the Na+/H+ exchanger, slightly reduced [Na+]i and Rb+ entry into the cardiomyocytes (by 15±5%). 31P NMR spectroscopy was used to monitor the energetic state and intracellular pH (pHi) in a parallel series of hearts. Treatment of the hearts with lidocaine, 4-aminopyridine, dimethylamiloride, or bumetanide for 15 to 20 minutes at the same concentrations as used for the Rb+ and Na+ experiments did not markedly affect the levels of the phosphate metabolites or pHi. These data show that under normal physiological conditions, Rb+ influx occurs mainly through Na+,K+-ATPase; the contribution of the Na+/K+/2 Cl− cotransporter and K+ channels to Rb+ influx is small. The correlation between Rb+ influx and [Na+]i during infusion of drugs that affect [Na+]i indicates that, in rat hearts at 37°C, Rb+ influx can serve as a measure of Na+ influx. We estimate that, at normothermia, at least 50% of the Na+ entry into beating cardiac cells is provided by the Na+ channels, with only minor contributions (+/K+/2 Cl− cotransporter and the Na+/H+ exchanger.

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