Erythroid anion exchanger-1 (SLC4A1) modulates carbonic anhydrase inhibitor acetazolamide on respiration

Clinically widely used acetazolamide is a potent carbonic anhydrase (CA) inhibitor. CA accelerates CO_2(g)⇌HCO₃ ^-(aq) bidirectional conversion. CAII, the major functional isoform, primarily resides inside 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 CO_2(g)/HCO_3(aq) conversion facilitated by CAII. This study aimed to use CA-inhibiting acetazolamide to find out whether AE1 could modulate intraerythrocytic CA catalysis.

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.

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.

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 the appropriate dosing of acetazolamide for people with the GP.Mur blood type.