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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