Enhanced c-Fos expression in the rostral ventral respiratory complex and rostral parapyramidal region by inhibition of the Na+/H+ exchanger type 3

Previous studies have shown that selective inhibition of Na+/H+ exchanger type 3 (NHE3) induces intracellular acidification and activates CO2/H+-sensitive medullary neurons, mimicking the responses evoked by hypercapnic stimuli. In addition, NHE3 blockers administration decreases the duration of apnoea induced by laryngeal stimulation, presumably by means of central chemoreceptor activation. To test the hypothesis that the central chemoreceptor network may be affected by NHE3 inhibition, brainstem c-Fos immunoreactive cell counting was performed after systemic administration of the NHE3 blocker AVE1599 (Aventis Pharma Deutschland GmbH) (2 mg/kg). The rostro-caudal quantitative c-Fos analysis showed a significant increase in the number of c-Fos positive cells in the rostral part of the ventral respiratory complex (VRC) as well as in the rostral part of the parapyramidal (Ppy) region. The VRC activated region (− 4.2 to − 3.2 mm interaural) included the pre-Bötzinger complex, the rostral ventral respiratory group and the rostral ventrolateral medulla, all of them involved in cardiorespiratory control. The activated Ppy region corresponded with the rostral chemosensitive area, which elicits the strongest ventilatory response upon ventral medullary surface stimulation with H+/CO2. Most cells activated in Ppy after NHE3 inhibition were serotonergic. Hence, systemic application of NHE3 blockers may induce central chemoreceptors activation and an increase in the respiratory network activity in a similar way to known physiological stimuli such as hypercapnia. On the other hand, selective NHE3 blockers could be excellent tools for treatment of pathological states where central chemoreceptor function is diminished or absent, such as central hypoventilation syndrome or sudden infant death syndrome.