Kinetics of CO₂ excretion and intravascular pH disequilibria during carbonic anhydrase inhibition

Inhibition of carbonic anhydrase (CA) activity (activity in red blood cells and activity available on capillary endothelium) results in decrements in CO₂ excretion (V̇CO₂) and plasma-erythrocyte CO₂-HCO₃/^-H⁺ disequilibrium as blood travels around the circulation. To investigate the kinetics of changes in blood PCO₂ and pH during progressive CA inhibition, we used our previously detailed mathematical model of capillary gas exchange to analyze experimental data of V̇CO₂ and blood-gas/pH parameters obtained from anesthetized, paralyzed, and mechanically ventilated dogs after treatment with acetazolamide (Actz, 0-100 mg/kg iv). Arterial and mixed venous blood samples were collected via indwelling femoral and pulmonary arterial catheters, respectively. Cardiac output was measured by thermodilution. End-tidal PCO₂, as a measure of alveolar PCO₂, was obtained from continuous records of airway PCO₂ above the carina. Experimental results were analyzed with the aid of a mathematical model of lung and tissue-gas exchange. Progressive CA inhibition was associated with stepwise increments in the equilibrated mixed venous-alveolar PCO₂ gradient (9, 19, and 26 Torr at 5, 20, and 100 mg/kg Actz, respectively). The maximum decrements in V̇CO₂ were 10, 24, and 26% with 5, 20, and 100 mg/kg Actz, respectively, without full recovery of V̇CO₂ at 1 h postinfusion. Equilibrated arterial PCO₂ overestimated alveolar PCO₂, and tissue PCO₂ was underestimated by the measured equilibrated mixed venous blood PCO₂. Mathematical model computations predicted hysteresis loops of the instantaneous CO₂-HCO₃/^-H⁺ relationship and in vivo blood PCO₂-pH relationship due to the finite reaction times for CO₂-HCO₃/^-H⁺ reactions. The shape of the hysteresis loops was affected by the extent of Actz inhibition of CA in red blood cells and plasma.