Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia

Abstract

Augmented breaths, or "sighs," commonly destabilize respiratory rhythm, precipitating apneas and variability in the depth and rate of breathing, which may then exacerbate sleep-disordered breathing in vulnerable individuals. We previously demonstrated that hypocapnia is a unique condition associated with a high prevalence of augmented breaths during exposure to hypoxia; the prevalence of augmented breaths during hypoxia can be returned to normal simply by the addition of CO(2) to the inspired air. We hypothesized that counteracting the effect of respiratory alkalosis during hypocapnic hypoxia by blocking carbonic anhydrase would yield a similar effect. We, therefore, investigated the effect of acetazolamide on the prevalence of augmented breaths in the resting breathing cycle in five awake, adult male rats. We found a 475% increase in the prevalence of augmented breaths in animals exposed to hypocapnic hypoxia compared with room air. Acetazolamide treatment (100 mg/kg i.p. bid) for 3 days resulted in a rapid and potent suppression of the generation of augmented breaths during hypoxia. Within 90 min of the first dose of acetazolamide, the prevalence of augmented breaths in hypoxia fell to levels that were no greater than those observed in room air. On cessation of treatment, exposure to hypocapnic hypoxia once again caused a large increase in the prevalence of augmented breaths. These results reveal a novel means by which acetazolamide acts to stabilize breathing and may help explain the beneficial effects of the drug on breathing stability at altitude and in patients with central forms of sleep-disordered breathing.

A sigh of relief or a sigh of expected relief: Sigh rate in response to dyspnea relief

“…Third, sighs prevent atelectasis (i.e., the progressive collapse of alveoli) by restoring lung compliance and dysregulated blood gas levels. Although it is unlikely that the mild resistances applied in this study would alter lung compliance or blood gas levels (Bartlett, ; Bell et al, ; Bell & Haouzi, ; Bendixen et al, ; Caro et al, ; Cherniack et al, ; Ferris & Pollard, ; Golder et al, ; McIlroy et al, ; Mead & Collier, ; Reynolds, ), severe dyspnea may evoke reductions in lung compliance and elicit hypoxia and/or hypo‐ or hypercapnia, which sighs during dyspnea relief may help to restore. Future studies could systematically examine the proposed variables mediating sighs during dyspnea relief.…”

“…Physiologically, sighs regulate mechanical and chemical properties of the respiratory system. Sighs prevent atelectasis (i.e., the progressive collapse of alveoli when breathing at constant volumes), restore lung compliance (Bendixen, Smith, & Mead, ; Caro, Butler, & DuBois, ; Ferris & Pollard, ; Golder, Reier, Davenport, & Bolser, ; McIlroy, Butler, & Finley, ; Mead & Collier, ; Reynolds, ), and reduce hypoxia and hypercapnia (Bartlett, ; Bell, Ferguson, Kehoe, & Haouzi, ; Bell & Haouzi, ; Cherniack, Euler, Glogowska, & Homma, ). Moreover, sighs reset healthy breathing variability (Vlemincx, Van Diest, Lehrer, Aubert, & Van den Bergh, ; Wuyts, Vlemincx, Bogaerts, Van Diest, & Van den Bergh, ).…”

Carbon dioxide-dependent signal transduction in mammalian systems

“…AE1 and NBC1 have also been shown to interact with CAIV to increase their HCO À 3 flux [31]. Owing to the mechanism of action of the CAs, CA inhibitors such as acetazolamide have been of great interest for the treatment of conditions which result in alterations in blood pH and/or CO 2 content, such as high altitude sickness, chronic obstructive pulmonary disease (COPD) and sleep apnoea [32][33][34]. CA inhibition is beneficial in the context of hypocapnia.…”

The physiological determinants of Sudden Infant Death Syndrome

“…In this context, the sigh can be considered as a central nervous system adaptation that responds to changes in blood gases and initiates a series of events that lead to arousal. Indeed, the generation of the sigh is very sensitive to hypoxic challenges (Cherniack et al, 1981; Bell and Haouzi, 2009, 2010). Moreover, the very network that is responsible for the generation of the sigh, the preBötC, is intrinsically sensitive to hypoxia and facilitates the generation of sighs (Lieske et al, 2000; Telgkamp et al, 2002; Tryba et al, 2008; Hill et al, 2011).…”