The hypoxia-induced facilitation of augmented breaths is suppressed by the common effect of carbonic anhydrase inhibition

Abstract

The typical respiratory response to hypoxia includes a dramatic facilitation of augmented breaths (ABs) or 'sighs' in the breathing rhythm. We recently found that when acetazolamide treatment is used to promote CO(2) retention and counteract alkalosis during exposure to hypoxia, then the hypoxia-induced facilitation of ABs is effectively prevented. These results indicate that hyperventilation-induced hypocapnia/alkalosis is an essential factor involved in the hypoxia-induced facilitation of augmented breaths. However, acetazolamide is also known to decrease the sensitivity of the arterial chemoreceptors. Therefore, the question remains as to whether acetazolamide prevents the facilitation of ABs during hypoxia by offsetting the effects of respiratory alkalosis, or alternatively by suppressing carotid body afferent activity. In the present study, we addressed this question by studying the effects of treatment with an alternative carbonic anhydrase inhibitor, methazolamide, which has been reported to leave carotid body responsiveness to hypoxia intact. Respiratory variables were monitored before, during and after 2 days of methazolamide treatment (10 mg kg(-1) IP, bid) in unsedated and unrestrained adult male rats. Pre-treatment, the number of ABs observed in a 5 min observation window was 1.2 + or - 0.8 and 17.4 + or - 3.8 in room air and hypoxia, respectively. During methazolamide treatment, the facilitation of ABs in hypoxia was rapidly and reversibly suppressed such that ABs we no longer significantly more frequent than they were in room air. The present results demonstrate that the hypoxia-induced facilitation of ABs can be suppressed via the general effects of carbonic anhydrase inhibition, which are common to both acetazolamide and methazolamide. We discuss these results as they pertain to the mechanisms regulating augmented breath production, and the possible association between hypocapnia/alkalosis and sleep disordered breathing.