Intracellular Acidosis and pH Regulation in Central Respiratory Chemoreceptors

Abstract

Dysfunctions of brainstem regions responsible for central CO2 chemoreception have been proposed as an underlying pathophysiology of Sudden Infant Death Syndrome (SIDS). We recorded respiratory motor output and intracellular pH (pHi) from chemosensitive neurons in an in vitro tadpole brainstem during normocapnia and hypercapnia. Flash photolysis of the H+ donor nitrobenzaldehyde was used to induce focal decreases in pHi alone. Hypercapnia and flash photolysis significantly decreased pHi from normocapnia. In addition, chemoreceptors did not regulate pHi during hypercapnia, but demonstrated significant pHi recovery when only pHi was reduced by flash photolysis. Respiration was stimulated by decreases in pHi (hypercapnia and flash photolysis) by decreases in burst cycle. These data represent our ability to load the brainstem with nitrobenzaldehyde without disrupting the respiration, to quantify changes in chemoreceptor pHi recovery, and to provide insights regarding mechanisms of human health conditions with racial/ethnic health disparities such as SIDS and Apnea of Prematurity (AOP).

Intracelluar pH (pHi) Measurements in the In Vitro Tadpole Brainstem: Direct Correlations between Changes in pHi and Ventilation

“…This adverse effect has been demonstrated in other preparations [1]. Therefore other methods of focal intracellular acidification which do not disrupt central respiratory rhythmicity and chemoreception, such as uncaging H + with ultraviolet light [38], should prove beneficial in further describing the correlation between respiratory motor output and pHi.…”

“…Studies in other animal preparations using pH-sensitive probes have also identified differences in the pHi regulatory processes of cells located in chemosensitiveand non-chemosensitive regions [34][35]. In addition, using BCECF in tadpole brainstem neurons to record pHi optically does not disrupt respiratory rhythmicity or central respiratory chemoreception [36][37][38]. The pHi regulatory responses to hypercapnic acidosis reported in this study are consistent with those reported in the snail [39] and rat [6,34,35], indicating the evolutionary conservation of pHi regulatory mechanisms, although the persistence of pHi regulation in non-chemosensory cells, as seen in all tadpole developmental stages, is observed only in preparations from neonatal mammals.…”

“…We recently adapted a technique to induce focal decreases in pHi alone while maintaining pHo to the tadpole brainstem preparation [38]. We bath applied the H + donor, nitrobenzaldehyde, to the tadpole brainstem and used flash photolysis to decrease only pHi to values similar to those observed with hypercapnia.…”

hERG1 channel subunit composition mediates proton inhibition of IKr in hiPSC-CMs

“…Extracellular acidosis is a major inhibitor of IKr (27), and occurs in a variety of pathological situations associated with cardiac dysfunction, including SIDS and myocardial ischemia (28-30). Consequently, a large body of work has explored the impact of extracellular protons on hERG1 (27,31-37).…”