Selective inhibition of the Na + /H + exchanger type 3 activates CO 2 /H + -sensitive medullary neurones

Abstract

Hypercapnia as well as lowered intracellular pH (pHi) increase the bioelectric activity of CO2/H+-sensitive neurones (VLNcs) of the ventrolateral medulla oblongata. Here we describe that immunoreactive Na+/H+ exchanger (NHE3) is present in ventrolateral neurones from medullary organotypic cultures (obex level). To test whether VLNcs can be acidified and thereby activated by inhibition of NHE3, we used the novel high-affinity NHE3-inhibitors S1611 and S3226. Both drugs raised the firing rates of VLNcs to at least 150% of the control values, and depolarized membrane potential by up to 15 mV at concentrations (0.5-1 micromol/l) suitable for selective inhibition of NHE3. The changes in bioelectric activity strongly resembled the responses to hypercapnia (PCO2: 60-100 mmHg). In BCECF-AM-loaded cultures a subfraction of ventrolateral VLNcs was found to be intracellularly acidified by 0.05-0.1 pH units following treatment with S1611; the time course of this acidification was similar to that evoked by hypercapnia. All drug effects were sustained and readily reversible upon washing. Non-CO2/H+-responsive medullary neurones as well as hippocampal CA3 neurones were unaffected by up to 20 micromol/l S1611. It is concluded that the selective inhibition of NHE3 acidifies and activates CO2/H+-sensitive neurones within the ventrolateral medulla oblongata.

Na+-H+Exchange Activity in Taste Receptor Cells

“…15) (Lyall et al , 2002a. Sustained changes in pH i seem to be a common feature of chemosensory cells dedicated to CO 2 /H ϩ sensing (Buckler et al 1991a;Ritucci et al 1998;Wiemann et al 1999). The sustained changes in pH i in chemosensitive neurons (Ritucci et al 1998;Wiemann et al 1999) are related to the acid-induced inhibition of pH recovery mechanisms.…”

Inhibition of Na+/H+ Exchanger Type 3 Reduces Duration of Apnea Induced by Laryngeal Stimulation in Piglets

“…Furthermore, amiloride, which is a 30 to 40 times less potent blocker of NHE3 than either NHE1 or NHE2 (29), did not affect ventilatory response to CO 2 in rabbits (30). Therefore, the effect of blockade of NHE3 is confined to the medullary chemosensory neurons, as it did not affect non-CO 2 / H ϩ -responsive medullary neurons or hippocampal CA3 neurons (13,29).…”

“…They are probably also involved in the control of excitability via changes of cell volume or pHi (25)(26)(27). NHE3 is present in ventrolateral neurons from medullary organotypic cultures, and blockade of this exchanger using high-affinity inhibitors caused a drop in pHi and potentiated the response of these cells to CO 2 (13). The NHE3 inhibitor S8218 was found to activate CO 2 /H ϩ -sensitive neurons in vitro (12) and to potentiate the CO 2 ventilatory response and decrease the apneic threshold in rabbits (28).…”

“…Recent studies showed that selective inhibition of NHE3 activates CO 2 /H ϩ -sensitive neurons within the ventrolateral medulla oblongata, resembling the responses evoked by hypercapnic stimuli (12,13). This raised the hypothesis that NHE3 inhibitors may reduce reflexly mediated respiratory depression and duration of apnea in the neonatal period.…”

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

“…11 There is also evidence that NHE3 may regulate the respiratory drive. 12 There is abundant expression of NHE4 in gastric parietal cells, where it is involved in regulating gastric acid secretion. 13 NHE5 is expressed in brain and sperm and cycles between the plasma membrane and intracellular endosomes; it regulates dendritic spine growth.…”