Intrapulmonary chemoreceptors (IPC) are CO(2)-sensitive sensory neurons that innervate the lungs of birds, help control the rate and depth of breathing, and require carbonic anhydrase (CA) for normal function. We tested whether the CA enzyme is located intracellularly or extracellularly in IPC by comparing the effect of a CA inhibitor that is membrane permeable (iv acetazolamide) with one that is relatively membrane impermeable (iv benzolamide). Single cell extracellular recordings were made from vagal filaments in 16 anesthetized, unidirectionally ventilated mallards (Anas platyrhynchos). Without CA inhibition, action potential discharge rate was inversely proportional to inspired PCO(2) (-9.0 +/- 0.8 s(-1). lnTorr(-1); means +/- SE, n = 16) and exhibited phasic responses to rapid PCO(2) changes. Benzolamide (25 mg/kg iv) raised the discharge rate but did not alter tonic IPC PCO(2) response (-9.8 +/- 1.6 s(-1). lnTorr(-1), n = 8), and it modestly attenuated phasic responses. Acetazolamide (10 mg/kg iv) raised IPC discharge, significantly reduced tonic IPC PCO(2) response to -3.5 +/- 3.6 s(-1). lnTorr(-1) (n = 6), and severely attenuated phasic responses. Results were consistent with an intracellular site for CA that is less accessible to benzolamide. A model of IPC CO(2) transduction is proposed.
R1551-R1559, 2003. First published February 20, 2003 10.1152/ajpregu.00519.2002Avian intrapulmonary chemoreceptors (IPC) are vagal respiratory afferents that are inhibited by high lung PCO 2 and excited by low lung PCO 2. Previous work suggests that increased CO 2 inhibits IPC by acidifying intracellular pH (pHi) and that pH i is determined by a kinetic balance between the rate of intracellular carbonic anhydrase-catalyzed CO 2 hydration/dehydration and transmembrane extrusion of acids and/or bases by various exchangers. Here, the role of amiloride-sensitive Na ϩ /H ϩ exchange (NHE) in the IPC CO2 response was tested by recording single-unit action potentials from IPC in anesthetized ducks, Anas platyrhynchos. For each of the IPC tested, blockade of the NHE using dimethyl amiloride (DMA) elicited a marked (Ͼ50%) dose-dependent decrease in mean IPC discharge (P Ͻ 0.05), suggesting that NHE is important for pH i regulation and CO2 transduction in IPC. In addition, activation of the NHE using 12-O-tetradecanoylphorbol 13-acetate stimulated six of the seven IPC tested, although the overall effect was not statistically significantly (P ϭ 0.07). Taken together, these findings suggest that CO 2 transduction in IPC is dependent on transmembrane NHE although it is likely to be much slower than carbonic anhydrase-catalyzed hydration-dehydration of CO2. carbon dioxide chemosensitivity; intracellular pH regulation; respiratory control; neuron; acid; base BIRDS HAVE INTRAPULMONARY chemoreceptors (IPC) that monitor lung PCO 2 and exert reflex effects on the pattern of breathing (9,15,16,36,37,43,45). These IPC have afferent axons in the vagus nerves, cell bodies in the nodose ganglia, and sensory endings in the parabronchial tissue of the lungs (9, 25, 34). The action potential discharge of IPCs responds to both rapidly changing (i.e., phasic) and sustained (or tonic) levels of intrapulmonary PCO 2 , thereby encoding information about the temporal relationships between ventilation, perfusion, and metabolism (4,9,15,16,19,24,34). IPC sensory feedback helps terminate inspiration by sensing CO 2 washout from the lung, helps maintain arterial homeostasis in response to moderate inspired hypercapnia (35,37,45), and helps adjust breathing to metabolic demands (4,9,19,24,50).IPC are unusual respiratory chemoreceptors because their action potential discharge rate is inversely proportional to intrapulmonary PCO 2 . Low PCO 2 stimulates IPC firing, and high PCO 2 inhibits firing (9, 15, 16); thus the IPC response is backward compared with that of traditional respiratory chemoreceptors like the carotid bodies (18, 29), many presumptive central chemoreceptors (40), and snail pneumostome ganglia chemoreceptors (13,14). Many presumptive chemoreceptor neurons located in the mammalian medullary raphe, however, have also been shown to be inhibited by high PCO 2 (41, 54), as are reptilian IPC, mammalian pulmonary stretch receptors, and mammalian laryngeal CO 2 chemoreceptors (10,32,39,44). Thus the inverse CO 2 response (discharge rate inhi...
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