Patients with chronic obstructive pulmonary diseases (COPD) and/or central sleep apnea are sometimes treated with the carbonic anhydrase inhibitor acteazolamide to improve blood gas values. Studies have shown that this agent may have a complicated effect on lung ventilation, because carbonic anhydrase has a widespread distribution within the body, particularly in tissues involved in the control of breathing. To investigate whether acetazolamide may have (neuro)muscular effects on respiration, we measured the responses of ventilation, phrenic nerve activity, and transpulmonary pressure to changes in arterial PCO2 before and after intravenous administration of a low-dose (4.6 +/- 0.2 mg x kg(-1), mean +/- SEM) of this inhibitor in anesthetized spontaneously breathing rabbits. The agent decreased the mean resting end-tidal PCO2 by 1 kPa and increased ventilation from 258 +/- 15 to 292 +/- 14 ml x min(-1) x kg(-1) (p < or = 0.05). The ventilatory and tidal volume responses to CO2 were reduced, and the response curves were shifted to lower PCO2 values. At the level of phrenic activity, however, the response was shifted leftward without altering CO2 sensitivity. With an unchanged lung compliance, the slopes of the relationships between tidal volume and phrenic activity and that between the tidal change in transpulmonary pressure and phrenic amplitude were both reduced by about 40%, indicating an action of acetazolamide on (neuro)muscular level. The results raise the suggestion that treatment of some hypercapnic COPD patients with acetazolamide may have undesired clinical implications, particularly in those with already weakened respiratory muscles.

Cultured CO2-sensitive neurons from the ventrolateral medulla of newborn rats enhanced their bioelectric activity upon intracellular acidification induced by inhibition of the Na+/H+ exchanger type 3 (NHE3). Now we detected NHE3 also in the medulla oblongata of adult rabbits. Therefore, this animal model was employed to determine whether NHE3 inhibition also affects central respiratory chemosensitivity in vivo. Seven anesthetized (pentobarbital), vagotomized, paralyzed rabbits were artificially ventilated with O2-enriched air. From the phrenic nerve compound discharge, integrated burst amplitude (IPNA), respiratory rate (fR), and phrenic minute activity (IPNA. fR) were taken as measures of central respiratory rhythm and drive. Effects of potent NHE3 inhibition with the novel brain permeant substance S8218 were studied by comparing respiratory characteristics before and after up to 9.2 +/- 1.1 mg/kg cumulative drug application, yielding average plasma concentrations of 0.9 +/- 0.2 microg/ml. In response to S8218, the baseline level of IPNA. fR was significantly enhanced by an average of 51.0 +/- 6.4% (n = 27, p < 0.0001). The influence of NHE3 inhibition on the respiratory CO2 response was studied at plasma concentrations of S8218 maintained in the range of 0.3 microg/ml (10(-6) M). Although the metabolic acid-base status thereby remained widely unchanged, the group mean apneic threshold PaCO2 was significantly lowered by 0.45 +/- 0.11 kPa (n = 7, p < 0.01), whereby in four of seven animals even strong hyperventilation failed to suppress phrenic nerve rhythmicity completely. Likewise, S8218 significantly augmented IPNA. fR, in the range of PaCO2 between 1 and 6 kPa above threshold, by an average of 38.0 +/- 8.5% (n = 35, p < 0.0001). These in vivo results are compatible with the effects of NHE3 inhibition on chemosensitive brainstem neurons in vitro. Moreover, rhythmogenesis is supported through NHE3 inhibition by lowering the threshold PCO2 for central apnea.

Herbivore nutritional alkali-load elicited large rates of renal base excretion including precipitates, to which the urinary tract of the rabbits appeared to be adapted. Dietary base variations were more accurately reflected in the urine than by the blood acid-base status. A strongly base-deficient diet exerted maximum impact on renal base saving mechanisms, implying a critical precondition for growing susceptibility to metabolic acidosis also in the rabbit.

AbstractThe 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.