Dipyridamole inhibition of HCO₃^--Cl^- exchange in human erythrocytes

Effects of dipyridamole (DP) on Band 3-mediated HCO₃^--Cl^- exchange were investigated in human red cells at 37°C. The kinetics of net HCO₃^--Cl^- exchange were monitored using a stopped-flow rapid reaction apparatus, under conditions in which HCO₃^--Cl^- exchange was rate-limiting for pH equilibration across the red cell membrane. DP was found to be a rapidly acting, potent inhibitor of HCO₃^--Cl^- exchange, with an apparent I₅₀ of 4 μM. DP produced a mixed competitive-noncompetitive inhibition of HCO₃-Cl^- exchange. Greater than 50% of the inhibitory effect occurred within 20 msec of DP-red cell interaction, consistent with DP binding to an outward-facing site on the cell membrane. Interaction of red cells with DP was associated with a pH-dependent decrement in the equilibrium Donnan H⁺ ratio. Because HCO₃^--Cl^- exchange is crucial in vivo for ensuing rapid pH equilibration across the red cell membrane, these effects of DP may have important implications, particularly in the development of high-dose DP regimes for use as an adjunctive agent in cancer chemotherapy.