M. Wiemann et al., Selective inhibition of the Na+/H+ exchanger type 3 activates CO2/H+-sensitive medullary neurones, PFLUG ARCH, 438(3), 1999, pp. 255-262
Hypercapnia as well as lowered intracellular pH (pH(i)) increase the bioele
ctric activity of CO2/H+-sensitive neurones (VLNcs) of the ventrolateral me
dulla oblongata. Here we describe that immunoreactive Na+/H+ exchanger (NHE
3) 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 S16
11 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 mu mol/l) suitable for selective inhibition of NHE3.
The changes in bioelectric activity strongly resembled the responses to hy
percapnia (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 acidificat
ion was similar to that evoked by hypercapnia. All drug effects were sustai
ned and readily reversible upon washing, Non-CO2/H+-responsive medullary ne
urones as well as hippocampal CA3 neurones were unaffected by up to 20 mu m
ol/l S1611. It is concluded that the selective inhibition of NHE3 acidifies
and activates CO2/H+-sensitive neurones within the ventrolateral medulla o
blongata.