Methazolamide does not impair respiratory work performance in anesthetized rabbits

Abstract

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...

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

“…Bijl et al 2006)note that only central CO 2 sensitivity was reduced); 14Kiwull-Schone et al (2009), this study;15 Gonzales and Scheuermann (2013).ª 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.…”

“…1996; Kiwull-Schone et al. 2009). An example of isocapnic response curves before and after drug administration in one animal is shown in Figure3.…”

“…This effect on respiratory muscle function surprisingly is not shared by MZ (Kiwull-Schone et al. 2006, 2009) and suggests that in the rabbit AZ acts independently of CA inhibition to weaken respiratory muscle function as it appears also to do also in humans (Gonzales and Scheuermann 2013). …”

“…Parameter A, ventilation in hyperoxia, did not change. In Table 2, note that NMA did not change the existing very small (<1 mmHg) and normal arterial-to end-tidal PCO 2 differences indicating the absence of erythrocytic CA inhibition, which generates very large and positive (>20 mmHg) gradients (Wagenaar et al 1996;Kiwull-Schone et al 2009). An example of isocapnic response curves before and after drug administration in one animal is shown in Figure 3.…”

“…When infused intravenously, it exerts specific actions on the peripheral chemoreceptors of the carotid bodies and respiratory muscles that partly account for a reduction in the hypoxic ventilatory response (HVR), the loss of the O 2 -CO 2 interaction at the peripheral chemoreceptors, and a decrease in ventilatory CO 2 sensitivity (Kiwull-Schone et al 2001, 2006Teppema and Dahan 2004;Teppema et al 2006b). 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).…”