Effects of carbonic anhydrase inhibition on ventilation-perfusion matching in the dog lung.

Abstract

Lung carbonic anhydrase (CA) permits rapid pH responses when changes in regional ventilation or perfusion alter airway and alveolar Pco2. These pH changes affect airway and vascular resistances and lung compliance to optimize the balance of regional ventilation (VA) and perfusion (Q) in the lung. To test the hypothesis that these or other CA-dependent mechanisms contribute to VA/Q matching, we administered acetazolamide (25 mg/kg intravenously) to six anesthetized and paralyzed dogs and measured VA/Q relationships before and after CA inhibition by the multiple inert gas elimination technique. Four other groups of dogs were studied to control for possible confounding effects of time under anesthesia and nonselective CA inhibition by acetazolamide: (a) saline placebo as a control for duration of anesthesia, (b) 4% CO2 inhalation to mimic systemic CO2 retention, (c) 1 mg/kg benzolamide (a selective renal CA inhibitor) or 0.5 meq /kg HCO to mimic systemic metabolic acidosis, and (d) 500 mg/kg 4,4'-dinitrostilbene-2,2'-disulfonate (an inhibitor of red cell band 3 protein) to mimic the respiratory acidosis arising from an intracapillary block to rapid mobilization ofplasma HCO3 in CO2 exchange. Acetazolamide increased VA/Q mismatch and reduced arterial Po2 measured at equilibrium but these did not occur in the control group. There was no deterioration in VA/Q matching when systemic respiratory acidosis produced either by CO2 inhalation or 4,4'-dinitrostilbene-2,2'-disulfonate or metabolic acidosis (benzolamide or HCl) were imposed to mimic the effects of acetazolamide apart from its inhibition of lung CA. These results support the concept that lung CA subserves VA /Q matching in the normal lung. (J. Clin. Invest. 1993.92:702-709.)

Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition

“…This rich diversity of expression has led some to search for nonclassical (i.e., non-acid-base) functions of the enzyme. Swenson et al (45) showed that CA inhibition impairs ventilation-perfusion matching in the lung, a process that is thought to result from both O 2 -and CO 2 -dependent changes in bronchial and vascular smooth muscle tone. To directly test whether CA inhibition alters HPV, a major mechanism that maintains ventillation perfusion (V A /Q) matching, Deem et al (7) found that AZ blunts and slows HPV in the isolated perfused rabbit lung.…”

Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression

“…red cell and tissue CA inhibition) is <5 mg·kg -1 (250-350 mg) given every 8-12 h. This dose also inhibits vascular endothelial cell membrane CA IV and peripheral chemoreceptor CA. Although higher doses may increase ventilation further as respiratory acidosis develops, this comes at the expense of impairing CO 2 transport [4] and even ventilation-perfusion (V 'A/Q ') matching in the lung [41]. In healthy individuals this can be readily tolerated and even maximal exercise is possible with partial red cell CA inhibition [1,4], since the necessary compensatory hyperventilation does not exceed maximal voluntary ventilation (MVV) capacity.…”

“…The benefits of CA inhibitors stem from the renal effect of mild metabolic acidosis which, at a dose of acetazolamide of 4-5 mg·kg -1 , is virtually maximal. The ventilatory stimulation that this affords is accompanied by insignificant effect on red cell CO 2 transport and efficiency of CO 2 elimination by the lungs [7,41]. Above this dose and the concentrations it achieves, CO 2 retention can be anticipated and the extra ventilation necessary to limit or prevent it may cause respiratory muscle fatigue.…”

The effect of low‐dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

“…In most studies in wNhich a conventional steady-state technique was used, end-tidal PCo2 was taken as an independent variable. However, in patients suffering from lung disease a relatively large P(a-ET),co2 gradient may be present wrhich, in addition, may be altered if lung carbonic anhydrase is inhibited (Swenson, Robertson & Hlastala, 1993 Swenson & Hughes (1993) show-ed that chronic and acute treatments with the drug led to different effects on the CO2 response curve. Although baseline ventilation w\as increased, they concluded that acute (intravenous) treatment has an inhibitory effect on the control of breathing.…”