Na⁺/H⁺ exchanger type 3 (NHE3) is involved in central chemosensitivity and control of breathing. Inhibition of this exchanger acidifies intracellular pH and increases the firing rate of ventrolateral cultured neurons (Wiemann and Bingmann, 2001). In vivo, in anesthetized, vagotomized, and mechanically ventilated rabbits, NHE3 inhibition enhanced respiratory drive (Kiwull-Shöne et al., 2001). Recently, we showed that selective inhibition of NHE3 led to an activation of the rostral aspect of both the ventral respiratory complex and the parapyramidal region (Ribas-Salgueiro et al., 2006). The aim of the present study was to analyze the effect of selective inhibition of NHE3 on the respiratory response in the intact spontaneously-breathing anesthetized rat. For that purpose, respiratory measurements were made with a whole body, plethysmograph, before and after treatment with the selective NHE3 blocker AVE1599 (Aventis Pharma). Rats were intravenously infused during 10 min with AVE1599 (0.5 or 2 mg/kg) or phosphate buffer (control animals) and breathing was recorded for one hour. At the end, c-Fos immunohistochemistry was performed and positive-cells were counted along the brainstem.

Treatment with AVE 1599 (0.5 mg/kg) led to a significant 8% increase in breathing frequency after the drug administration as compared with control animals (ANOVA, p<0.05, n=10); whereas the amplitude remained unaffected. An increase in the number of c-Fos positive cells was also found in the lateral parabrachial nucleus (t test, p<0.05, n=4), an area related with cardiorespiratory control. Our results from both physiological and morphological experiments support the involvement of NHE3 in the central control of breathing.