Effects of Low-Dose Methazolamide on the Control of Breathing in Cats

Abstract

Inhibitors of carbonic anhydrase (CA) have complex effects on respiration. Many cells and tissues that are involved in the control of breathing contain various isoforms of CA, e.g., red cells, carotid bodies, lung and brain capillary endothelial cells, muscle and neurons closely associated with central chemoreceptors (1-9). In human and cats, low intravenous doses of acetazolamide have both stimulatory and inhibitory effects on the control of breathing. (10, 11). One of the inhibitory effects applies to the peripheral chemoreceptors because acetazolamide has been shown to reduce the hypoxic response and also the O2-CO2 interaction that is known to reside the carotid bodies (10,12,13). The mechanism by which this occurs is unclear: however, due to its physical-chemical properties acetazolamide does not easily cross biological membranes (1, 2) so that at low dose this inhibiting effect is unlikely due to inhibition of an intracellular isoform of CA in the carotid bodies. Methazolamide, another CA inhibitor with an about equal affinity for sulfonamide-sensitive CA isoforms is much more lipophilic and rapidly permeates into cells (1, 2). Therefore, this agent would be a suitable tool to study the effect to intracellular CA inhibition on carotid body-mediated responses. Another difference between acetazolamide and methazolamide refers to their effects on large-conductance Cadependent potassium (BK) channels: while acetazolamide specifically opens these channels, methazolamide is without any stimulating effect on them (14). Because BK channels may play a crucial role in the hypoxic response of type-I carotid body cells (15), it is therefore interesting to compare the effects of both agents on the carotid body responses to both hypoxia and hypercapnia. Dynamic end-tidal CO2 forcing (DEF) is a suitable means to study the separate effects of pharmacological agents on the CO2 sensitivity of the peripheral and central chemoreflex loops (16). In this study we have applied this technique to study the effects of low-dose methazolamide on the control of breathing in the cat.