Erythroid Anion Exchanger-1 (SLC4A1) Modulates Carbonic Anhydrase Inhibitor Acetazolamide on Respiration

Abstract

Introduction: Clinically widely-used acetazolamide is a potent carbonic anhydrase (CA) inhibitor. CA accelerates CO2(g)⇌HCO3-(aq) bidirectional conversion. CAII, the major functional isoform, primarily resides inside the red blood cells (RBCs). Erythrocyte-specific anion transporter or anion exchanger-1 (AE1) determines HCO3-permeability across the cell membrane, and is considered the rate-limiting factor for intraerythrocytic CO2(g)/HCO3(aq) conversion facilitated by CAII. This study aimed to use CA-inhibiting acetazolamide to find out whether AE1 could modulate intraerythrocytic CA catalysis. Methods: To explore whether erythroid AE1 could modulate the respiratory effects of acetazolamide, we utilized the GPMur mouse model characteristic of higher erythroid AE1 expression for respiratory measurements using whole-body plethysmography (WBP). The effects of acetazolamide and hypercapnia on murine respiration were compared. Results: We found that acetazolamide influenced respiration in the same direction as hypercapnia. Increased erythroid AE1 expression (GPMur) counteracted the impacts of hypercapnia/acetazolamide. Importantly, GPMur/higher AE1 increased respiratory sensitivity and limited responses to acetazolamide. Conclusion: Both acetazolamide and hypercapnia drove acidosis. GPMur/increased AE1 reduced the impacts of acidosis with faster respiratory responses. This supports that AE1 and CAII function in concert to facilitate intraerythrocytic CO2/HCO3-conversion for CO2 expiration. Since murine RBC-AE1 could help sensitize respiratory responses to acetazolamide-induced systemic CA inhibition, it warrants future clinical investigation to identify appropriate dosing of acetazolamide for people with the GP.Mur blood type.