Central European Journal of Medicine

, Volume 1, Issue 4, pp 356–369 | Cite as

Factors of lowered respiratory CO2 sensitivity by acetazolamide in anaesthetized rabbits

  • Heidrun F. Kiwull-Schöne
  • Luc J. Teppema
  • Peter J. Kiwull
Research Article


The carbonic anhydrase (CA) inhibitor acetazolamide is a classic drug to treat patients with breathing disorders. Recent studies in rabbits showed that low-dose acetazolamide (not causing appreciable inhibition of red cell CA) significantly weakened respiratory muscle performance, accompanied by diminished ventilatory CO2-sensitivity, which implies stabilizing loop-gain properties. Now is aimed to explore the interaction of these factors under conditions of complete CA-inhibition by acetazolamide in a higher dose-range.

In anesthetized rabbits (N=7), acetazolamide (up to 75 mg·kg−1) distinctly lowered the base excess (to-7.6 ± 0.9mM, mean ± SEM) without respiratory compensation of arterial pH. Ventilatory CO2-sensitivity was nearly abolished to 15.1 ± 5.2% of control, but the transmission of a CO2-mediated rise in tidal phrenic activity into respiratory work was only reduced by 51.6 ± 6.4%, P < 0.001, not very much more than (~38%) already observed at low-doses.

Thus, the large reduction of ventilatory CO2-sensitivity in the high-dose range cannot be ascribed to respiratory muscle weakening, but rather may relate to complete inhibition of red cell CA. Conversely, CA-inhibition may not be the only cause for the weakening effect of acetazolamide on (respiratory) muscles. Adverse effects on respiratory muscles, impaired CO2-transport and acid-base imbalance may limit to make use of stabilizing effects on breathing control functions by high-dose acetazolamide.


Acetazolamide CO2 sensitivity metabolic acidosis respiratory muscle fatigue rabbits 


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  1. [1]
    E.R. Swenson: “Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression”, Eur. Respir. J., Vol. 12, (1998), pp. 1242–1247.PubMedCrossRefGoogle Scholar
  2. [2]
    H. Tojima, F. Kunitomo, H. Kimura, K. Tatsumi, T. Kuriyama and Y. Honda: “Effects of acetazolamide in patients with the sleep apnoea syndrome”, Thorax, Vol. 43, (1988), pp. 113–119.PubMedCrossRefGoogle Scholar
  3. [3]
    E.R. Swenson and J.M.B. Hughes: “Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in man”, J. Appl. Physiol., Vol. 73, (1993), pp. 230–237.Google Scholar
  4. [4]
    L.J. Teppema and A. Dahan: “Acetazolamide and breathing. Does a clinical dose alter peripheral and central CO2 sensitivity?”, Am. J. Respir. Crit. Care Med., Vol. 160, (1999), pp. 1592–1597.PubMedGoogle Scholar
  5. [5]
    L. Teppema, A. Berkenbosch, J. DeGoede and C. Olievier: “Carbonic anhydrase and the control of breathing: different effects of benzolamide and methazolamide in the anaesthetized cat”, J. Physiol. (Lond), Vol. 488, (1995), pp. 767–777.Google Scholar
  6. [6]
    M. Wagenaar, L. Teppema, A. Berkenbosch, C. Olievier and H. Folgering: “The effect of low-dose acetazolamide on the ventilatory CO2 response curve in the anaesthetized cat”, J. Physiol. (Lond), Vol. 495, (1996), pp. 227–237.Google Scholar
  7. [7]
    L.J. Teppema, A. Dahan and C.N. Olievier: “Low-dose acetazolamide reduces the hypoxic ventilatory response in the anaesthetized cat”, Respir. Physiol. Neurobiol., Vol. 140, (2004), pp. 43–51.PubMedCrossRefGoogle Scholar
  8. [8]
    E.R. Swenson, K.L. Leatham, R.C. Roach, R.B. Schoene, W.J. Mills and P.H. Hackett: “Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing”, Respir. Physiol., Vol. 86, (1991) pp. 333–343.PubMedCrossRefGoogle Scholar
  9. [9]
    P.W. Jones and M. Greenstone: “Carbonic anhydrase inhibitors for hypercapnic ventilatory failure in chronic obstructive pulmonary disease”, Cochrane Database Syst. Rev., Vol. 1, (2001), CD002881.Google Scholar
  10. [10]
    J. Verbraecken, M. Willemen, W. De Cock, E. Coen, P. Van de Heyning and W. De Backer: “Central sleep apnea after interrupting longterm acetazolamide therapy”, Respir. Physiol., Vol. 112, (1998), pp. 59–70.PubMedCrossRefGoogle Scholar
  11. [11]
    H.F. Kiwull-Schöne, L.J. Teppema and P.J. Kiwull: “Low-dose acetazolamide does affect respiratory muscle function in spontaneously breathing anesthetized rabbits”, Am. J. Respir. Crit. Care Med., Vol. 163, (2001), pp. 478–483.PubMedGoogle Scholar
  12. [12]
    H. Kiwull-Schöne, L. Teppema, M. Wiemann and P. Kiwull: “Loop gain of respiratory control upon reduced activity of carbonic anhydrase or Na+/H+ exchange”, Adv. Exp. Med. Biol., Vol. 580, (2006), pp. 239–244.PubMedGoogle Scholar
  13. [13]
    W.F. Brechue, D.M. Koceja and J.M. Stager: “Acetazolamide reduces peripheral afferent transmission in humans”, Muscle Nerve, Vol. 20, (1997), pp. 1541–1548.PubMedCrossRefGoogle Scholar
  14. [14]
    L.A. Garske, M.G. Brown and S.C. Morrison: “Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions”, J. Appl. Physiol., Vol. 94, (2003), pp. 991–996.PubMedGoogle Scholar
  15. [15]
    L.J. Teppema, F. Rochette and M. Demedts: “Ventilatory effects of carbonic anhydrase inhibition in cats: effects of acetazolamide in intact vs. peripherally chemodenervated animals”, Respir. Physiol., Vol. 74, (1988), pp. 373–382.PubMedCrossRefGoogle Scholar
  16. [16]
    T.H. Maren: “Carbonic anhydrase: Chemistry, Physiology and inhibition”, Physiol. Rev. Vol. 47, (1967), pp. 595–781.Google Scholar
  17. [17]
    L.J. Teppema, F. Rochette and M. Demedts: “Effects of acetazolamide on medullary extracellular pH and PCO2 and on ventilation in peripherally chemodenervated cats”, Pflügers Arch., Vol. 415, (1990), pp. 519–525.PubMedGoogle Scholar
  18. [18]
    K. Kohshi, N. Konda, Y. Kinoshita, E. Tsuru and A. Yokota: “In situ arterial and brain tissue PaCO2 responses to acetazolamide in cats”, J. Appl. Physiol., Vol. 76, (1994), pp. 2199–2203.PubMedGoogle Scholar
  19. [19]
    Ph.E. Bickler, L. Litt, D.B. Banville and J.W. Severinghaus: “Effects of acetazolamide on cerebral acid-base balance”, J. Appl. Physiol., Vol. 65, (1988), pp. 422–427.PubMedGoogle Scholar
  20. [20]
    H. Kiwull-Schöne, H. Kalhoff, F. Manz, L. Diekmann and P. Kiwull: “Minimalinvasive approach to study pulmonary, metabolic and renal responses to acid-base changes in conscious rabbits”, Eur. J. Nutr., Vol. 40, (2001), pp. 255–259.PubMedCrossRefGoogle Scholar
  21. [21]
    R. Iturriagha: “Carotid body chemoreception: the importance of CO2-HCO3 and carbonic anhydrase (review)”, Biol. Res., Vol. 26, (1993), pp. 319–329.CrossRefGoogle Scholar
  22. [22]
    K. Taki, K. Oogushi, K. Hirahara, X. Gai, F. Nagashima and K. Tozuka: “Preferential acetazolamide-induced vasodilation based on vessel size and organ: Conformation of peripheral vasodilation with use of colored microspheres”, Angiology, Vol. 52, (2001), pp. 483–488.PubMedCrossRefGoogle Scholar
  23. [23]
    A. Dahl, D. Russell, K. Rootwelt, R. Nyberg-Hansen and E. Kerty: “Cerebral vasoreactivity assessed with transcranial Doppler and regional cerebral blood flow measurements. Dose, serum concentration, and time course of the response to acetazolamide”, Stroke, Vol. 26, (1995), pp. 2302–2306.PubMedGoogle Scholar
  24. [24]
    T.S. Lee: “End-tidal partial pressure of carbon dioxide does not accurately reflect PaCO2 in rabbits treated with acetazolamide during anaesthesia”, Br. J. Anaesthesiol., Vol. 73, (1994) pp. 225–226.Google Scholar
  25. [25]
    C. Geers and G. Gros: “Carbon dioxide transport and carbonic anhydrase in blood and muscle”, Physiol. Rev., Vol. 80, (2000), pp. 681–715.PubMedGoogle Scholar
  26. [26]
    M. Carmignani, C. Scopetta, F.O. Ranelletti and P. Tonali: “Adverse interaction between acetazolamide and anticholinesterase drugs at the normal and myasthenic neuromuscular junction level”, Int. J. Clin. Pharmacol. Therap. Toxicol., Vol. 22, (1984), pp. 140–144.Google Scholar
  27. [27]
    H. Westerblad, D.G. Allen and J. Lännergren: “Muscle fatigue: Lactic acid or inorganic phosphate the major cause?”, News Physiol. Sci., Vol. 17, (2002), pp. 17–21.PubMedGoogle Scholar
  28. [28]
    D. Tricarico, M. Barbieri, M. Mele, G. Carbonara and D. Conte Camerino: “Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats”, FASEB J., Vol. 18, (2004), pp. 760–761.PubMedGoogle Scholar
  29. [29]
    M. DeCramer, V. DeBock and R. Dom: “Functional and histologic picture of steroidinduced myopathy in chronic obstructive pulmonary disease”, Am. J. Respir. Crit. Care Med. Vol. 153, (1996), pp. 1958–1964.PubMedGoogle Scholar
  30. [30]
    G.S. Longobardo, B. Gothe, M.D. Goldman and N.S. Cherniack: “Sleep apnea considered as a control system instability”, Respir. Physiol., Vol. 50, (1982), pp. 311–333.PubMedCrossRefGoogle Scholar
  31. [31]
    M.C.K. Khoo: “Determinants of ventilatory instability and variability”, Respir. Physiol., Vol. 122, (2000), pp. 167–182.PubMedCrossRefGoogle Scholar
  32. [32]
    M. Younes, M. Ostrowski, W. Thompson, C. Leslie and W. Shewchuk: “Chemical control stability in patients with obstructive sleep apnea”, Am. J. Respir. Crit. Care Med., Vol. 163, (2001), pp. 1181–1190.PubMedGoogle Scholar
  33. [33]
    J.A. Dempsey, C.A. Smith, T. Przybylowski, B. Chenuel, A. Xie, H. Nakayama and J.B. Skatrud: “The ventilatory responsiveness to CO2 below eupnoea as a determinant of ventilatory stability in sleep”, J. Physiol. (Lond.), Vol. 560, (2004), pp. 1–11.CrossRefGoogle Scholar

Copyright information

© Versita Warsaw and Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Heidrun F. Kiwull-Schöne
    • 1
  • Luc J. Teppema
    • 2
  • Peter J. Kiwull
    • 1
  1. 1.Department of Physiology, Faculty of MedicineRuhr-UniversityBochumGermany
  2. 2.Department of Physiology and AnesthesiologyLeiden University Medical CenterRC LeidenThe Netherlands

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