Acetazolamide attenuates transvascular fluid flux in equine lungs during intense exercise

Key points During high intensity exercise approximately 4% of the cardiac output leaves the pulmonary circulation into the interstitium. This fluid flux has been attributed to an increase in pulmonary transmural hydrostatic (Starling) forces. Fluid efflux from erythrocytes may account for a considerable fraction of fluid exiting the pulmonary circulation. Transcapillary erythrocyte volume changes are largely determined by the Jacobs–Stewart cycle, a series of intracellular and extracellular diffusion and chemical reaction events of carbon dioxide, water, bicarbonate, hydrogen ions and chloride that are initiated when blood is exposed to a gradient such as when blood enters and traverses systemic and pulmonary capillaries. We tested the hypothesis that the Jacobs–Stewart cycle contributes to pulmonary transvascular fluid fluxes during exercise by inhibiting red cell carbonic anhydrase, the activity of which is critical to rapid completion of the Jacobs–Stewart cycle during capillary transit. Our results indicate that during exercise in horses, transvascular fluid fluxes in the lung appear to be dependent on the Jacobs–Stewart cycle and much less dependent upon transmural hydrostatic (Starling) forces. It also appears that pulmonary circulation transvascular fluid fluxes are mediated by chloride and water egress from erythrocytes directly into the interstitium without transit through plasma, which is likely the result of functional apposition of the erythrocyte and vascular endothelial membranes occurring during capillary transit. Abstract During intense exercise in horses the transvascular fluid flux in the pulmonary circulation (Jv‐a) represents 4% of cardiac output ( ). This fluid flux has been attributed to an increase in pulmonary transmural hydrostatic forces, increases in perfused microvascular surface area, and reversible alterations in capillary permeability under conditions of high flow and pressure. Erythrocyte fluid efflux, however, accounts for a significant fraction of Jv‐a. In the lung the Jacobs–Stewart cycle occurs with diffusion of CO2 into alveolar space with possible accompanying chloride (Cl−) and water movement from the erythrocyte directly into the pulmonary interstitium. We hypothesised that inhibition of carbonic anhydrase in erythrocytes inhibits the Jacobs–Stewart cycle and attenuates Jv‐a. Five horses were exercised on a treadmill until fatigue without (control) and with acetazolamide treatment (30 mg kg−1 30 min before exercise). Erythrocyte fluid efflux, plasma fluid flux across the lung and Jv‐a were calculated using haemoglobin, haematocrit, plasma protein and Q. Fluid fluxes were used to calculate erythrocyte, plasma and whole blood Cl− fluxes across the lung. Cardiac output was not different between control and acetazolamide treatment. During exercise erythrocyte fluid efflux and Jv‐a increased in control (9.3 ± 3.3 and 11.0 ± 4.4 l min−1, respectively) and was higher than after acetazolamide treatment (3.8 ± 1.6 and 1.2 ± 1.2 l min−1, respectively) (P < 0.05). Plasma fluid flux did not change from rest in control and decreased after acetazolamide treatment (−4.5 ± 1.5 l min−1) (P < 0.05). Erythrocyte Cl− flux increased during exercise in control and after acetazolamide treatment (P < 0.05). During exercise plasma Cl− flux across the lung did not change in control; however, it increased with acetazolamide treatment (P= 0.0001). During exercise whole blood Cl− flux increased across the lung in control (P < 0.05) but not after acetazolamide treatment. The results indicate that Jv‐a in the lung is dependent on the Jacobs–Stewart cycle and mostly independent of transmural hydrostatic forces. It also appears that Jv‐a is mediated by Cl− and water egress from erythrocytes directly into the interstitium without transit through plasma.

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