Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man

Abstract

The carbonic anhydrase inhibitor acetazolamide may have both inhibitory and stimulatory effects on breathing. In this placebo-controlled double-blind study we measured the effect of an intravenous dose (4 mg kg −1 ) of this agent on the acute isocapnic hypoxic ventilatory response in 16 healthy volunteers (haemoglobin oxygen saturation 83-85%) and examined whether its inhibitory effects on this response could be reversed by antioxidants (1 g ascorbic acid I.V. and 200 mg α-tocopherol P.O.). The subjects were randomly divided into an antioxidant (Aox) and placebo group. In the Aox group, acetazolamide reduced the mean normocapnic and hypercapnic hypoxic responses by 37% (P < 0.01) and 55% (P < 0.01), respectively, and abolished the O 2 -CO 2 interaction, i.e. the increase in O 2 sensitivity with rising P CO 2 . Antioxidants completely reversed this inhibiting effect on the normocapnic hypoxic response, while in hypercapnia the reversal was partial. In the placebo group, acetazolamide reduced the normo-and hypercapnic hypoxic responses by 33 and 47%, respectively (P < 0.01 versus control in both cases), and also abolished the O 2 -CO 2 interaction. Placebo failed to reverse these inhibitory effects of acetazolamide in this group. We hypothesize that either an isoform of carbonic anhydrase may be involved in the regulation of the redox state in the carotid bodies or that acetazolamide and antioxidants exert independent effects on oxygen-sensing cells, in which both carbonic anhydrase and potassium channels may be involved. The novel findings of this study may have clinical implications, for example with regard to a combined use of acetazolamide and antioxidants at high altitude.

Arterial [H+] and the ventilatory response to hypoxia in humans: influence of acetazolamide-induced metabolic acidosis

“…An inhibitory effect, however, is not supported by the finding that both in normoxia and hypoxia acetazolamide increases ventilation (36,41). This is clearly different from the effect of intravenous administration in both animals and humans when acetazolamide, in a dose too low to have direct effects on the central nervous system, has inhibitory effects on both the hypoxic response and the O 2 -CO 2 interaction (36,40,42). Why in humans an inhibitory effect seems solely present after acute administration aimed at reaching equal plasma levels of the agent (36) remains unclear.…”

“…Details of measuring ventilation, respiratory gases, and oxygen saturation and the technique of dynamic end-tidal forcing are provided elsewhere (40,41).…”

Methazolamide does not impair respiratory work performance in anesthetized rabbits

“…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).…”

The Antioxidative Effect of a Novel Free Radical Scavenger 4′-Hydroxyl-2-substituted Phenylnitronyl Nitroxide in Acute High-Altitude Hypoxia Mice

“…7,[20][21][22] It is concerned that antioxidants may interfere with the action of ACZ on the normocapnic hypoxic ventilatory response. 23) In our work we chose ACZ as a positive drug to compare the effects of HPN with ACZ. The first step of the present study was to prepare the free radical scavenger by literature reported procedures.…”