Carbonic anhydrase inhibition and chemoreflex control of breathing: A litmus test for methazolamide as a viable alternative to acetazolamide

Carbonic anhydrase inhibitors are used in clinical, experimental and environmental settings to regulate acid–base balance in the blood and tissues. Acetazolamide is a carbonic anhydrase inhibitor routinely prescribed in the treatment of pulmonary disorders, glaucoma and sleep-disordered breathing. It is also commonly used prophylactically and therapeutically in acute mountain sickness. In the context of high altitude, acetazolamide is used to accelerate the acclimatization process by inhibiting renal bicarbonate reabsorption, increasing its secretion, thereby inducing a relative systemic metabolic acidosis. Resting ventilation is increased via chemoreceptor stimulation, and resting oxygenation is improved. However, in both animal and human studies, administration of acetazolamide has been shown to cause respiratory muscle dysfunction (Dominelli et al., 2018; Kiwull-Schöne, Teppema, & Kiwull, 2001), which potentially limits its usage. Methazolamide, a sister carbonic anhydrase inhibitor with much higher membrane permeability than acetazolamide, does not cause respiratory muscle impairment (Dominelli et al., 2018; Kiwull-Schöne, Li, Kiwull, & Teppema, 2009) and, as such, might be an effective and suitable alternative. The benign effect of methazolamide on respiratory muscle function is established, whereas its effects on chemoreflex control of breathing are unknown, but are important to establish if consideration is to be given to the potential use of methazolamide as a viable alternative treatment option in clinical and environmental settings. In this issue of Experimental Physiology, Teppema et al. (2020) compare the effects of acetazolamide and methazolamide on chemoreflex control of breathing in young, healthy, male participants, by way of assessment of ventilatory sensitivity to independent and combined oxygen and carbon dioxide gas challenges. In addition, the study explored the utility of a novel index in the assessment of the acute ventilatory response to hypoxia. Participants were exposed on three separate occasions to normoxic hypercapnia and three progressive steps of eucapnic and hypercapnic hypoxia with precise control of end-tidal gases by a custom end-tidal forcing system. In a randomized, double-blind, crossover study design, participants ingested acetazolamide, methazolamide or placebo for 3 days before each laboratory visit. Arterial blood samples were obtained for the determination of blood gas and acid–base status at baseline. Thereafter, arterialized venous blood samples from the dorsal hand were taken during each gas exposure. Comparisons between arterial and arterialized venous blood values demonstrated that at baseline, the partial pressure of oxygen () was substantially lower in the venous sample. However, during hypoxia, the difference between arterial and arterialized venous was negligible. Therefore, when indexing ventilatory changes during gas challenges, arterial values were used at baseline, with arterialized venous used thereafter. Methazolamide and acetazolamide were shown to have equivalent effects on the ventilatory sensitivity to hypoxia and hypercapnia, demonstrated by equivalent slopes in the relationship between ventilation and during eucapnic and hypercapnic hypoxia, and equivalent parallel leftward shifts in the hypercapnic ventilatory response after drug administration compared with placebo. The authors also demonstrated that the relationship between minute ventilation and log was linear during eucapnic and hypercapnic hypoxia. Of particular interest, the change in slope of the hypoxic ventilatory response was greatly underestimated during eucapnic and hypercapnic hypoxic trials when changes in minute ventilation were plotted as a function of oxygen saturation, probably owing to the rightward shift in the oxyhaemoglobin-dissociation curve in the presence of a drug-induced metabolic acidosis. The authors provide a strong argument for the future use of log instead of oxygen saturation for the determination of respiratory chemoreflex responses to hypoxia in the context of acid–base disturbances. Therefore, it is evident that methazolamide is as effective as acetazolamide in driving alterations in the chemoreflex control of breathing. Given that it is established that methazolamide is equivalent to acetazolamide in attenuating hypoxic pulmonary vasoconstriction (Boulet et al., 2018), and superior in the context of respiratory (and skeletal) muscle performance (Kiwull-Schöne et al., 2001, 2009; Dominelli et al., 2018), the collective findings provide support for methazolamide as a viable and potentially better alternative to acetazolamide. Further comparisons in clinical and field studies are warranted, but this remains an open issue, given that acetazolamide, but not methazolamide, improves plasma non-enzymatic antioxidant capacity (Boulet et al., 2018), which is relevant to conditions of chronic hypoxic stress related to cardiorespiratory disease and exposure to high altitude. The novel use of log of arterialized venous blood in the determination of the magnitude of the ventilatory response during hypoxic exposure, particularly against the backdrop of acid–base disturbances, has potential value to high-altitude settings. Compensatory metabolic acidosis is a hallmark feature of the acclimatization process. Log might be a superior index for tracking changes in hypoxic ventilatory sensitivity during high-altitude exposure compared with oxygen saturation, with and without the use of carbonic anhydrase inhibitors. An obvious limitation to this approach is the invasive nature of blood sampling compared with non-invasive determination of peripheral oxygen saturation levels using pulse oximetry, but repeated arterialized venous sampling for the estimation of arterial in the context of acute or steady-state hypoxia is an attractive proposition. Further validation of the utility of the measurement in laboratory, field and clinical studies is warranted. None declared.

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