Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid.

FENCL, V., T. B. MILLER, AND J. R. PAPPENHEIMER. Studies on the respiratory response to distwbances of acid-base balance, with deductions concerning the ionic cornposition of cerebral interstitial @id. Am. J. Physiol. 2 I o(3) : 459-472, I g66.-Respiratory responses to inhaled (202 were studied on five unanesthetized goats during chronic metabolic acidosis or alkalosis. Measurements were made of alveolar ventilation, pH, [HCOa-1, and [Cl-] of arterial plasma and CSF during each steady-state period of CO2 inhalation at each level of acidosis or alkalosis, Net transependymal fluxes of HCOaand Clwere determined. Results lead to the following principal conclusions: I) Resting ventilation is a single function of [H*] in cerebral interstitial fluid during inhalation of COZ, perfusion of the ventriculocisternal system with varying [HCOa-1, and during all degrees of chronic metabolic acidosis or alkalosis consistent with life at normal Pao,. 2) Respiratory adaptations to chronic acidosis or alkalosis are accounted for quantitatively by observed changes in ion transport between blood and CSF. 3) Concentrations of Hf, HCO~-, and Clin cerebral interstitial fluid are equal to those in CSF, even when large differences in concentration between plasma and CSF are maintained by the blood-brain barrier. the over-all response. The unified theory of Winterstein (35, 36), ascribing all changes of ventilation to changes in [H+] within the central nervous system, gave way to the multiple factor theory advanced by Gray (IO) following Nielsen’s (22) demonstration that arterial CO2 and [H+] apparently exerted independent actions on respiration during chronic metabolic acidosis. In recent years the interpretation of respiratory responses in terms of the composition of arterial blood has been questioned, owing largely to the demonstration by Leusen (I 7) that changes in the composition of fluid perfusing the cerebral ventricles could alter ventilation independently of the composition of arterial blood, Extensions of Leusen’s experiments by Loeschcke and others (x8, 20) have led to the hypothesis that ventilation may be controlled by the [H+] in CSF bathing a chemoreceptive area at the surface of the medulla. This hypothesis has recently been rendered untenable, at least in its simplest form, by our own observations on unanesthetized goats (24) showing that no one of the three related variables in CSF perfusate, Pco~, [HCOS-1, or [H+] was uniquely responsible for regulation of breathing. Large changes of ventilation could be produced by varying PCQ and [HCOS-] at constant pH or alternatively by varying Pco? and pH at constant [HCOZ-1. Pulmonary ventilation became a single function of pH only when the pH was referred to a locus part way along the concentration gradient of HCOSbetween CSF-perfusate and interstitial fluid close to cerebral capillaries taking part in the exchange of HCOS-. The absolute values of pH or [HCOS-] in interstitial fluid could not be determined from our data, which were consistent with several possible concentration profiles between CSF and cerebral capillaries. Two hypothetical profiles were discussed which led to unique relations between ventilation and pH; in hypothesis A, the normal concentration difference of HC03between blood and CSF was assumed to be maintained. by an ion pump located at the blood-brain barrier and in this case the ventilation was a single function of interstitial fluid pH in the range 7.32-7.24 at all values of [HCOa-] and Pcoz in CSF perfusate; in hypathesis B, the ion pump was assumed to be located at the ependymal cerebrospinal fluid; regulation of respiration; chronic acidosis, alkalosis; respiration in goat; cerebral HCOatransport; brain tissue fluid pH; blood-brain barrier