This study investigates the effects of intracellular (pH_i) and extracellular pH (pH_e) on the efflux of Rb⁺ and Li⁺ in isolated rat hearts. ⁸⁷Rb and ⁷Li NMR were used to measure Rb⁺ and Li⁺ content, respectively, of hearts, and ³¹P NMR was used to monitor pH_i, pH_e, and phosphate levels. After 30-min equilibration with Rb⁺ or Li⁺, effluxes were initiated by switching perfusion to a Rb⁺- or Li⁺-free, high-K⁺ (20.7 mM) Krebs-Henseleit buffer with 15 µM bumetanide. Monensin (2 µM) increased pH_i from 7.10 ± 0.05 to 7.32 ± 0.07 and resulted in activation of Rb⁺ efflux; the first-order rate constant (k × 10³, in min¹) increased from 42 ± 2 to 116 ± 16. Glibenclamide (4 µM) did not inhibit monensin-activated Rb⁺ efflux (k = 110 ± 17), whereas quinine (0.2 mM) slightly inhibited it by 19 ± 9%. Infusion of 15 mM NH₄Cl during Rb⁺ washout increased k for Rb⁺ efflux by 93% (81 ± 8), which was glibenclamide and quinine insensitive, and caused a transient increase in pH_i to 7.25 ± 0.08. Intracellular Li⁺ inhibited NH₄Cl-stimulated Rb⁺ efflux by 55%. Monensin and NH₄Cl stimulated Li⁺ efflux by 40%, increasing k from 29 ± 3 to 43 ± 7 and 41 ± 3, respectively. The stimulation was not sensitive to 10 µM dimethylamiloride. Intracellular acidosis that resulted from the washout of NH₄Cl (pH 6.86 ± 0.2) slightly inhibited Rb⁺ efflux (k = 36 ± 5), whereas NH₄Cl itself in the absence of pH_i changes did not markedly affect Rb⁺ efflux. A moderate increase in pH_i (7.17 ± 0.06) produced by washout of 15 mM 2,2-dimethylpropionate (DMP)-Tris from hearts preequilibrated with DMP did not markedly affect Rb⁺ efflux. Neither global alkalosis (pH_i 7.4, pH_e 7.55) nor acidosis (pH_i  pH_e 6.8) produced by 3 mM Tris base or 5 mM MES, respectively, affected Rb⁺ efflux. We suggest that intracellular alkalosis stimulates Rb⁺ (K⁺) and Li⁺ effluxes by activating a nonselective sarcolemmal K⁺ (Li⁺)/cation exchanger or a K⁺ (Li⁺)-anion symporter.