Methazolamide does not impair respiratory work performance in anesthetized rabbits.
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(2+)-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 = 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 (+/- SE) cumulative doses of 3.5 +/- 0.1 and 20.8 +/- 0.4 mg/kg. Similar to acetazolamide, low- and high-dose methazolamide enhanced baseline ventilation by 52 +/- 10% and 166 +/- 30%, respectively (P < 0.01) and lowered the base excess in a dose-dependent manner by up to 8.3 +/- 0.9 mmol/l (P < 0.001). The transmission of a CO(2)-induced rise in phrenic nerve activity into volume and/or pressure and, hence, respiratory work performance was 0.27 +/- 0.05 ml x kg(-1) x kPa x unit(-1) under control conditions, but remained unchanged upon low- or high-dose methazolamide, at 0.30 +/- 0.06 and 0.28 +/- 0.07 ml x kg(-1) x kPa x unit(-1), 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.
Kiwull-Schöne
Heidrun F
HF
Dept. of Physiology, Faculty of Medicine, Ruhr-Univ., 44780 Bochum, Germany. Heidrun.Kiwull-Schoene@rub.de
Li
Yi
Y
Kiwull
Peter J
PJ
Teppema
Luc J
LJ
D000768:Anesthesia, General; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006935:Hypercapnia / Q000503:physiopathology*; D008297:Male; D008704:Methazolamide / Q000494:pharmacology* / Q000633:toxicity; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism; D011312:Pressure; D012123:Pulmonary Ventilation / Q000187:drug effects*; D011817:Rabbits; D012132:Respiratory Muscles / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D013990:Tidal Volume / Q000187:drug effects; D014939:Work of Breathing / Q000187:drug effects*
D002257:Carbonic Anhydrase Inhibitors; D002245:Carbon Dioxide; D008704:Methazolamide