Is central chemoreceptor sensitive to intracellular rather than extracellular pH?

Abstract

Summary. The chemosensitive area on the ventral surface of the brain stem responds to local acidosis by eliciting hyperventilation and to local alkalosis by hypoventilation. The stimulus is conventionally thought to be the hydrogen ion concentration in the area's extracellular fluid. It is pointed out, however, that the elegant studies by Loeschcke & Ahmad have demonstrated that [pH]_c and [pH]_i are normally tightly and rapidly coupled (Loeschcke & Ahmad, 1980). For this reason, the stimulus might just as well be the intracellular hydrogen ion concentration in the chemoreceptor area. The administration of acetazolamide allows the dissociation of [pH]_c from [pH]_i. With acetazolamide a sharp acid shift of CSF pH ([pH]_c) is measured and in consonance with this shift a marked increase in CBF is seen. Comparing these two reactions to that obtained with CO₂ breathing, it is apparent that 7% CO₂ causes about the same decrease in [pH]_c and the same increase in CBF. In other words CBF acidosis can quantitatively account for the CBF increase induced by acetazolamide. But CO₂ and acetazolamide influence [pH]_i quite differently, as CO₂ drops [pH], to almost the same extent as [pH]_i, while two recent studies by MR spectroscopy have shown that acetazolamide does not drop [pH]_i measurably, if tissue hypercapnia is prevented in artificially ventilated rabbits or by the mild spontaneous hyperventilation caused by acetazolamide in normal man. The lack of measurable intracellular acidosis with acetazolamide accords with the very mild hyperventilation seen in man: the very high gain of the chemoreceptor response means namely that the approximate 10% drop in end-expiratory Pco₂ seen in man should result from a local acid shift of only 0·002 pH units, a shift much too small to be measurable by the technique used. If, on the other hand, [pH]_c were the chemoreceptor stimulus, then it is surprising that 2 g of acetazolamide did not cause the same many-fold increase in alveolar ventilation as 7% CO₂, as the [pH]_c acid shift is practically the same for the two stimuli. The [pH]_c and [pH]_i values referred to stem from global measurements. But the data regarding blood flow and Pco₂ of the chemoreceptor area combined with histological evidence suggest that the acid-base balance extra- and intracellularly of the area is just as for the brain as a whole. Therefore, the simplest hypothesis explaining the dissociation of the responses to CO₂ and acetazolamide with respect to ventilation and to [pH]_i is to assume that it is [pH]_i and not [pH]_c that is the chemoreceptor stimulus.