Kinetics of CO₂excretion and intravascular pH disequilibria during carbonic anhydrase inhibition

Abstract

Inhibition of carbonic anhydrase (CA) activity (activity in red blood cells and activity available on capillary endothelium) results in decrements in CO2 excretion (VCO2) and plasma-erythrocyte CO2-HCO(-3)-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 VCO2 and blood-gas/pH parameters obtained from anesthetized, paralyzed, and mechanically ventilated dogs after treatment with acetazolamide (Actz, 0-100 mg/kg i.v.). 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 VCO2 were 10, 24, and 26% with 5, 20, and 100 mg/kg Actz, respectively, without full recovery of VCO2 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-HCO(-3)-H+ relationship and in vivo blood PCO2-pH relationship due to the finite reaction times for CO2-HCO(-3)-H+ reactions. The shape of the hysteresis loops was affected by the extent of Actz inhibition of CA in red blood cells and plasma.

A unique mode of tissue oxygenation and the adaptive radiation of teleost fishes

“…The absence of CA activity in the plasma will slow the Jacobs-Stewart cycle, because plasma bicarbonate dehydration will occur at an uncatalyzed slow rate (t 1/2~2 5-90 s) (Cardenas et al, 1998;Geers and Gros, 2000;Henry and Swenson, 2000). Without plasma-accessible CA, the rate at which protons move from the plasma back into the RBC via the Jacobs-Stewart cycle will be reduced and the volume-regulating RBC NHE and AE systems will, therefore, be both pH-and volume-regulating systems (Fig.…”

“…Once formed, the CO 2 freely enters the RBCs, where it is rapidly hydrated via CA to form bicarbonate and protons; bicarbonate then leaves the cell in exchange for chloride (via Band III). CA is one of the fastest enzymes known, with an average half time (t 1/2 ) of 5×10 −3 to 1×10 −3 s, approximately 6000 times faster than the uncatalyzed reaction (Cardenas et al, 1998;Geers and Gros, 2000;Henry and Swenson, 2000) and is in high concentration inside the RBCs and in many other tissues (Decker et al, 1996;Effros and Weissman, 1979;Geers and Gros, 2000;Gervais and Tufts, 1998;Gilmour et al, 1997;Henry et al, 1997;Henry and Swenson, 2000;Sender et al, 1994;Siffert and Gros, 1982;Yamamoto et al, 1985). Teleost fish possess an assortment of CA isoforms, including both soluble and membrane-bound, and for many of these isoforms, tissue distribution and molecular structure are known (see reviews by Esbaugh and Tufts, 2006;Gilmour and Perry, 2009).…”

“…Upon activation, the βNHE rapidly excretes protons from the RBC (Heming et al, 1987;Berenbrink and Bridges, 1994). CA activity is not available to plasma flowing through the gills and venous system of some, perhaps all, teleost fishes (Rahim et al, 1988;Gilmour et al, 1994;Perry et al, 1997).The absence of CA activity in the plasma will slow the Jacobs-Stewart cycle, because plasma bicarbonate dehydration will occur at an uncatalyzed slow rate (t 1/2~2 5-90 s) (Cardenas et al, 1998;Geers and Gros, 2000;Henry and Swenson, 2000). Without plasma-accessible CA, the rate at which protons move from the plasma back into the RBC via the Jacobs-Stewart cycle will be reduced and the volume-regulating RBC NHE and AE systems will, therefore, be both pH-and volume-regulating systems (Fig.…”

“…Therefore, the rate-limiting step for CO 2 excretion across the gills is bicarbonate entry into the RBCs (Gilmour, 1998;Perry and Gilmour, 1993). Transit time for blood flowing through the gills is of the order of 1 s, which is insufficient for bicarbonate dehydration in the plasma at an uncatalyzed rate (t 1/2~2 5-90 s) (Cardenas et al, 1998;Geers and Gros, 2000;Henry and Swenson, 2000). Excess bicarbonate, therefore, will be left behind in the plasma leaving the gills.…”

Changes in Chemoreflex Characteristics Following Acute Carbonic Anhydrase Inhibition in Humans a Rest

“…However, Hauge et al (1983) and Laux & Raichle (1978) demonstrated that the internal carotid artery retained COµ reactivity, suggesting that the blood vessels had not maximally dilated with ACZ. In addition to blood flow reports, basal ventilation peaked to its new resting level by 15 min in cats (Teppema et al 1990), and COµ excretion at the lungs stabilized by 30 min in dogs (Cardenas et al 1998), providing further evidence that CA was fully inhibited by 30 min and a new steady state established. By 95 min, blood flow begins to decrease (Hauge et al 1983).…”