Carbonic anhydrase and control of breathing: different effects of benzolamide and methazolamide in the anaesthetized cat.

Teppema, L.J.; Berkenbosch, A.; DeGoede, J.; Olievier, C.N.

doi:10.1113/jphysiol.1995.sp021008

Cited by 26 publications

(23 citation statements)

References 30 publications

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“…In the intact animals the slope decreased to a mean value of 32 + 7 % of the control value. In all animals a large decrease in B was seen, corresponding to that encountered during complete inhibition of erythrocytic carbonic anhydrase induced by an infusion of 70 mg kg-' benzolamide (Teppema, Berkenbosch DeGoede & Olievier, 1995).…”

Section: Resultsmentioning

confidence: 74%

The effect of low‐dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

Wagenaar

Teppema

Berkenbosch

et al. 1996

The Journal of Physiology

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1. The effect of 4 mg kg-' acetazolamide (i.v.) on the slope (S) and intercept on the Pa,co2 axis (B) of the ventilatory CO2 response curve of anaesthetized cats with intact or denervated carotid bodies was studied using the technique of dynamic end-tidal forcing.2. This dose did not induce an arterial-to-end-tidal PCO2 (P(a-ET),co2) gradient, indicating that erythrocytic carbonic anhydrase was not completely inhibited. Within the first 2 h after administration, this small dose caused only a slight decrease in mean standard bicarbonate of 1P8 and 1P7 mmol F' in intact (n = 7) and denervated animals (n = 7), respectively. Doses of acetazolamide larger than 4 mg kg-1 (up to 32 mg kg-1) caused a significant increase in the P(a-ET),CO2 gradient. from 4'0 + 05 to 3'0 + 0-6 kPa, respectively, not significantly different from the changes encountered in the denervated animals. 5. It is argued that the effect of acetazolamide on the CO2 sensitivity of the peripheral chemoreflex loop in intact cats may be caused by a direct effect on the carotid bodies. Both in intact and in denervated animals the effects of the drug on S, and B may not be due to a direct action on the central nervous system, but rather to an effect on cerebral vessels resulting in an altered relationship between brain blood flow and brain tissue PCo2

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Section: Resultsmentioning

confidence: 74%

The effect of low‐dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

Wagenaar

Teppema

Berkenbosch

et al. 1996

The Journal of Physiology

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“…Therefore, MTZ is distributed rather rapidly and evenly to many tissues, including brain cells, where it accumulates about 4-fold compared with ACTZ (20). Thus, besides the complete inhibition of red blood cell CA, effective blockade of membrane-bound CA at the luminal surface of brain capillary endothelium will impair removal of CO 2 from brain tissue and thus add to the chemical drive from central chemoreceptors (29,33). The latter explanation also applies to low-dose MTZ, as smaller amounts of this highly diffusible inhibitor may effectively block the easily accessible brain endothelial CA as well and cause some degree of tissue acidosis (29).…”

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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“…Although local chemoreceptor CA inhibition may also reduce baseline ventilation [25], this is rarely seen in vivo because any direct depression is overridden by the powerful opposing stimulant action of local retention of CO 2 from red cell and brain tissue CA inhibition [19,20,26] and the metabolic acidosis from renal CA inhibition. With respect to the peripheral chemoreceptors, the findings are somewhat analogous.…”

Section: Ventilatory Effects Of Ca Inhibitorsmentioning

confidence: 99%

“…Over the past decade, TEPPEMA and coworkers [2,26,[29][30][31][32] have provided convincing in vivo evidence for si-milar effects of CA inhibitors on ventilation and ventilatory responses. In the present investigation in hypoxaemic cats [2] and in normoxic cats [29] they chose a low dose of acetazolamide, 4 mg·kg -1 , administered intravenously and studied ventilatory responses to CO 2 within the first hour to avoid the complicating factors of systemic metabolic and respiratory acidosis.…”

Section: Ventilatory Effects Of Ca Inhibitorsmentioning

confidence: 99%

Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression

Swenson¹

1998

Eur Respir J

131

133

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Carbonic anhydrase and control of breathing: different effects of benzolamide and methazolamide in the anaesthetized cat.

Abstract: 1. The effect of inhibition of erythrocyte carbonic anhydrase on the ventilatory response to CO2 was studied by administering benzolamide (70 mg kg- ', i.v.)

Cited by 26 publications

References 30 publications

The effect of low‐dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

The effect of low‐dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat.

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression

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