The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat

Teppema, Luc J.; Bijl, Hans; Gourabi, Babak Mousavi; Dahan, Albert

doi:10.1113/jphysiol.2006.110528

Cited by 17 publications

(17 citation statements)

References 47 publications

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“…In humans, metabolic acidosis normally leads to an increase in ventilation, for which the peripheral chemoreceptors may be responsible (26,27,30,36). Already at low doses, ACTZ largely reduced the ventilatory response to hypoxia in humans and cats (35,37), but even a high dose of the much more effective CA inhibitor MTZ entirely failed on that score at least in cats (34). In the same species, only ACTZ, but not MTZ, diminished also the CO 2 sensitivity of the peripheral chemoreflex loop (3).…”

Section: Discussionmentioning

confidence: 99%

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Kiwull-Schöne¹,

Li²,

Kiwull³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Kiwull-Schöne HF, Li Y, Kiwull PJ, Teppema LJ. Methazolamide does not impair respiratory work performance in anesthetized rabbits. Am J Physiol Regul Integr Comp Physiol 297: R648-R654, 2009. First published June 24, 2009 doi:10.1152/ajpregu.00134.2009.-In human medicine, the carbonic anhydrase (CA) inhibitor acetazolamide is used to treat irregular breathing disorders. Previously, we demonstrated in the rabbit that this substance stabilized closed-loop gain properties of the respiratory control system, but concomitantly weakened respiratory muscles. Among others, the highly diffusible CA-inhibitor methazolamide differs from acetazolamide in that it fails to activate Ca 2ϩ -dependent potassium channels in skeletal muscles. Therefore, we aimed to find out, whether or not methazolamide may exert attenuating adverse effects on respiratory muscle performance as acetazolamide. In anesthetized spontaneously breathing rabbits (n ϭ 7), we measured simultaneously the CO 2 responses of tidal phrenic nerve activity, tidal transpulmonary pressure changes, and tidal volume before and after intravenous application of methazolamide at two mean (Ϯ SE) cumulative doses of 3.5 Ϯ 0.1 and 20.8 Ϯ 0.4 mg/kg. Similar to acetazolamide, low-and high-dose methazolamide enhanced baseline ventilation by 52 Ϯ 10% and 166 Ϯ 30%, respectively (P Ͻ 0.01) and lowered the base excess in a dose-dependent manner by up to 8.3 Ϯ 0.9 mmol/l (P Ͻ 0.001). The transmission of a CO2-induced rise in phrenic nerve activity into volume and/or pressure and, hence, respiratory work performance was 0.27 Ϯ 0.05 ml ⅐ kg Ϫ1 ⅐ kPa ⅐ unit Ϫ1 under control conditions, but remained unchanged upon low-or high-dose methazolamide, at 0.30 Ϯ 0.06 and 0.28 Ϯ 0.07 ml ⅐ kg Ϫ1 ⅐ kPa ⅐ unit Ϫ1 , respectively. We conclude that methazolamide does not cause respiratory muscle weakening at elevated levels of ventilatory drive. This substance (so far not used for medication of respiratory diseases) may thus exert stabilizing influences on breathing control without adverse effects on respiratory muscle function. control of breathing; metabolic acidosis; acetazolamide; neuromuscular coupling IN CARDIO-RESPIRATORY MEDICINE, the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is known for beneficial effects in patients with central sleep apnea (12,41). Furthermore, it is used to improve blood gases in obstructive lung disease and to restore acid-base values in metabolic alkalosis, reviewed by (30). ACTZ is also widely used against acute mountain sickness (1, 18, 29), most likely because it is able to reduce hypoxic pulmonary vasoconstriction and to prevent high-altitude pulmonary edema (2, 32). However, there is growing evidence from recent studies in different species that ACTZ may prevent hypoxic pulmonary vasoconstriction entirely independent of carbonic anhydrase inhibition (11) and rather may diminish the hypoxia-induced rise in intracellular Ca 2ϩ in pulmonary arterial smooth muscle cells (25).Among possible side effects of ACTZ, skeletal muscle weakness and fatigue are...

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Section: Discussionmentioning

confidence: 99%

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Kiwull-Schöne¹,

Li²,

Kiwull³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Acetazolamide is known to depress the responsiveness of the carotid body chemoreceptors. Acetazolamide stimulates breathing; however, a paradoxical inhibition of carotid bodies has been described in response to physiological stimuli in the form of hypoxia and CO 2 (51)(52)(53). Although the inhibition of carbonic anhydrase in peripheral chemosensory cells is likely involved in the reduced CO 2 sensitivity (26,55), the mechanism that leads to a decreased hypoxic sensitivity is not known.…”

Section: Mechanism Of Actionmentioning

confidence: 98%

Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia

Bell¹,

Haouzi²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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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.

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“…1997; Teppema et al. 2006a). In this way, a new steady-state level of ventilation is established after about 6 min (Berkenbosch et al.…”

Section: Methodsmentioning

confidence: 99%

“…Methazolamide (MZ), a more lipophilic inhibitor with equal affinity for the various CA isoforms (Maren 1956), surprisingly does not share the same effects of AZ on respiratory muscles and the hypoxic response, suggesting alternative mechanisms other than CA inhibition by which AZ exerts these inhibitory actions on ventilatory control (Teppema et al. 2006a; Kiwull-Schone et al. 2009).…”

Section: Introductionmentioning

confidence: 99%

The noncarbonic anhydrase inhibiting acetazolamide analog N -methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response

Teppema

Swenson

2015

Physiol Rep

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Previous studies have shown that the carbonic anhydrase (CA) inhibitors acetazolamide (AZ) and methazolamide (MZ) have inhibiting actions on breathing. Classically these have been attributed to CA inhibition, but other effects unrelated to CA inhibition have been identified in other tissues. To explore this possibility in the control of ventilation by the central nervous system, we investigated whether an AZ-analog without CA inhibiting properties, by virtue of a single methylation on the sulfonamide moiety, N-methylacetazolamide (NMA), would still display similar actions to acetazolamide and methazolamide. NMA (20 mg kg−1) was given intravenously to anesthetized cats and we measured the responses to steady-state isocapnic hypoxia and stepwise changes in end-tidal pco2 before and after infusion of this AZ analog using the technique of end-tidal forcing. NMA caused a large decrease in the apneic threshold and CO2 sensitivity very similar to those previously observed with AZ and MZ, suggesting that these effects are mediated independently of CA inhibition. In contrast to acetazolamide, but similar to methazolamide, NMA did not affect the steady-state isocapnic hypoxic response. In conclusion, our data reveal complex effects of sulfonamides with very similar structure to AZ that reveal both CA-dependent and CA-independent effects, which need to be considered when using AZ as a probe for the role of CA in the control of ventilation.

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The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat

Cited by 17 publications

References 47 publications

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia

The noncarbonic anhydrase inhibiting acetazolamide analog N -methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response

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