Effect of low-dose acetazolamide on the ventilatory CO2 response during hypoxia in the anaesthetized cat

Abstract

The carbonic anhydrase inhibitor acetazolamide stimulates ventilation, resulting in an improvement in arterial oxygen tension (Pa,O 2 ) in patients with chronic obstructive pulmonary disease (COPD) or central sleep apnoea syndrome and in those suffering from acute mountain sickness [1][2][3][4][5][6][7][8][9][10]. The ventilatory effect with the drug is believed to be mediated by a metabolic acidosis, induced by inhibition of renal carbonic anhydrase [11][12][13][14]. However, other local effects of acetazolamide could also contribute to the observed ventilatory effects, since carbonic anhydrase is present in several tissues of the pathways involved in the control of breathing. For example, the enzyme is present in the peripheral and possibly also the central chemoreceptors [15][16][17][18], erythrocytes [16] and muscles [19] and in lung as well as brain capillary endothelium [20][21][22]. Usually, acetazolamide is administered in doses which do not completely inhibit red cell carbonic anhydrase. Complete inhibition of erythrocytic carbonic anhydrase occurs at a fractional inhibition >99.8%, for which doses >10 mg·kg -1 acetazolamide are required [16,23]. In COPD patients, this situation would result in impeded washout of CO 2 from the lungs, leading to CO 2 accumulation in the tissues. Such an undesired complication can be avoided by administering small doses, preventing an increase in the arterial to endtidal carbon dioxide tension (Pa-ET,CO 2 ) gradient.In a previous study in anaesthetized cats, it was found that doses of up to 4 mg·kg -1 acetazolamide (i.v.) did not cause a Pa-ET,CO 2 gradient [24]. In the same study the effect of 4 mg·kg -1 acetazolamide on the ventilatory response to CO 2 during normoxaemia was also investigated: utilizing the technique of dynamic end-tidal forcing (DEF) [25], decreases in the CO 2 sensitivities of the peripheral (Sp) and central (Sc) chemoreflex loops and in the apnoeic threshold (extrapolated carbon dioxide tension (PCO 2 ) at zero ventilation) were found. These effects were attributed to a possible direct action of acetazolamide on the peripheral chemoreceptors and to a change in the relation between brain tissue PCO 2 (Pbt,CO 2 ) and arterial PCO 2 (Pa,CO 2 ), due to a possible effect of the drug on cerebral blood flow regulation.Since this previous study was performed during normoxia, its results may not be directly relevant to a situation of hypoxaemia, such as frequently occurs in patients with COPD.During hypoxaemia, both cerebral blood flow and the relative contribution of the peripheral chemoreceptors to total ventilation are different from that in normoxaemia. Therefore, the aim of this study, in anaesthetized cats, was Effect of low-dose acetazolamide on the ventilatory CO 2 response during hypoxia in the anaesthetized cat. M. Wagenaar, L. Teppema, A. Berkenbosch, C. Olievier, H. Folgering. ©ERS Journals Ltd 1998. ABSTRACT: Acetazolamide, a carbonic anhydrase inhibitor, is used in patients with chronic obstructive pulmonary diseases and central sleep apnoea sy...

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

“…Our findings are in agreement with previous rebreathing experiments performed on rats (Adams & Johnson, 1990), but not with steady-state experiments performed on humans (Swenson & Hughes, 1993) or cats (Wagenaar et al 1998). They are also in agreement with findings reported from chronic ACZ studies using the rebreathing method (Tojima et al 1986;Bashir et al 1990).…”

“…Other studies have also shown that inhibition of CA blunts or inhibits the peripheral chemoreflex drive to ventilation. This was demonstrated in cats (Wagenaar et al 1998) and humans (Swenson & Hughes, 1993) whereby the ventilatory response to hypoxia was suppressed following ACZ. However, the influence of CA inhibition on the central chemoreflex is less conclusive.…”

“…For instance, using the measurements of pH and PCOµ in the extracellular fluid of the medulla in cats from Teppema et al (1990), we calculated a greater decrease in pH per unit increase in PCOµ, suggesting an enhancement of the medullary response to PCOµ. Furthermore, the decrease in arterial bicarbonate observed in cats following acute CA inhibition may be indicative of bicarbonate diuresis in the kidney (Wagenaar et al 1998). Contrary to Wagenaar et al (1998), Swenson & Hughes (1993) did not report a significant decrease in arterial bicarbonate in humans with acute CA inhibition, nor did they find a decrease in pH suggesting that metabolic acidosis had not developed.…”

“…Furthermore, the decrease in arterial bicarbonate observed in cats following acute CA inhibition may be indicative of bicarbonate diuresis in the kidney (Wagenaar et al 1998). Contrary to Wagenaar et al (1998), Swenson & Hughes (1993) did not report a significant decrease in arterial bicarbonate in humans with acute CA inhibition, nor did they find a decrease in pH suggesting that metabolic acidosis had not developed. This may be a result of using a lower dosage of ACZ (•7 mg kg¢) which would not cause full inhibition of CA (Maren, 1967).…”

“…Although chronic studies have generally agreed, there have been conflicting reports from acute studies. Using steady-state hypercapnia, Wagenaar et al (1998) reported a decrease in both peripheral and central chemoreflexes in cats following ACZ, while Swenson & Hughes (1993) found a decrease in only the peripheral component with no alterations in the central component in humans. Conversely, using the Read rebreathing technique (Read, 1967) on anaesthetized rats, Adams & Johnson (1990) found an increase in central chemosensitivity to COµ.…”