Inhibition of the sodium-proton exchanger subtype 3 (NHE3) by brain permeant drugs such as 8218 (Sanofi-Aventis) increased the firing frequency of chemosensitive neurons of the ventrolateral medulla oblongata. They also augmented the respiratory drive in rabbits.

In this investigation we used the novel NHE3 inhibitor 8713A which selectively inhibits NHE3 with an IC50 of <50 nM, whereas other neuronal NHE-subtypes are affected to a much lower degree (IC50 for NHE1, 2, and 5 were: 95, >100, and 33 mM, respectively). To test for the effect of 8713A on respiration of young adult rats (70-90g) we recorded phrenic nerve (PN) discharges using the working heart brainstem preparation (WHB) perfused with a hyperoxic saline to which 0.01-3 mM 8713A was added. 8713A dose-dependently and reversibly increased the frequency of PN (n=13) within 10-30 min. Most striking, a concentration of 0.3-1 mM 8713A qualitatively mimicked the response to CO2 (PCO2: 80-100 mmHg) in that it shortened PN discharges and increased their frequency. While 0.01-0.03 mM 8713A had no significant effect (n=6), the stimulation of PN by 3 mM was below the maximum (n=6).

We conclude that selective NHE3 inhibition stimulates central respiratory drive in rats.