The proposed research is designed to gain a better understanding of the regulation of central nervous system (CNS) acid-base and electrolyte homeostasis. The CNS acid-base status, in turn, has an important effect on the central chemical ventilatory drive. In studies of regulation of [HCO3-] in the CNS, our preliminary data show that active regulation of cerebrospinal fluid (CSF) [Cl-] is critical to establishing the level of [HCO3-]. Regulation of the CSF [Cl-] concentration thus plays a key role in CNS acid-base homeostatis, yet the mechanisms underlying its control remain uncertain. The role of net flux of chloride will be evaluated by studying the CSF electrolyte and acid-base composition following administration of chloride transport inhibitors and/or acid-base disturbances in anesthetized dogs. Quantitative estimates of the individual unindirectional fluxes of radiolabelled chloride between blood, CSF, brain ECF in anesthetized dogs will be made. The use of 38 Cl-, a short half-lived isotope, will allow multiple studies to be performed in a given animal, permitting each animal to serve as its own control. By studying the effects of chloride transport inhibitors and acid-base disturbances on unidirectional fluxes, as well as on the CSF electrolyte and acid-base status, and good understanding of the role of chloride movements in CNS acid-base regulation will be gained. Brain intracellular acid-base and high-energy phosphate metabolism and their relation to ventilation will be evaluated in unanesthetized rats. Thirty one phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy will be used to measure brain intracellular pH, ATP, and phosphocreatine levels. NMR allows both steady and nonsteady state noninvasive measurements of these variables simultaneously, in the intact, unanesthetized animal. Alterations of inspired CO2, O2 and changes in systemic chloride concentration will induce CNS acid-base stress. In this way, the intracellular homeostatic mechanisms will be evaluated. Thirteen carbon (13C) NMR will be used to follow intracellular CO2 metabolism. These studies will provide a basis for the non-invasive measurement of intracellular adaptations to acid-base stress and the relation between brain intracellular events and ventilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001166-05
Application #
3081694
Study Section
(SRC)
Project Start
1983-07-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
O'Neill, A V; Johnson, D C (1991) Transition from exercise to rest. Ventilatory and arterial blood gas responses. Chest 99:1145-50
Masjedi, M R; Kazemi, H; Johnson, D C (1990) Effects of passive smoking on the pulmonary function of adults. Thorax 45:27-31
Johnson, D C; Nishimura, M; Okunieff, P et al. (1989) Effects of hypothermia on rat brain pHi and phosphate metabolite regulation by 31P-NMR. J Appl Physiol 67:2527-34
King, D K; Thompson, B T; Johnson, D C (1989) Wheezing on maximal forced exhalation in the diagnosis of atypical asthma. Lack of sensitivity and specificity. Ann Intern Med 110:451-5
Nishimura, M; Johnson, D C; Hitzig, B M et al. (1989) Effects of hypercapnia on brain pHi and phosphate metabolite regulation by 31P-NMR. J Appl Physiol 66:2181-8
Nishimura, M; Johnson, D C; Kazemi, H (1988) Effects of inhibitors on chloride outflux from cerebrospinal fluid. J Appl Physiol 64:2183-9
Okunieff, P; Ramsay, J; Tokuhiro, T et al. (1988) Estimation of tumor oxygenation and metabolic rate using 31P MRS: correlation of longitudinal relaxation with tumor growth rate and DNA synthesis. Int J Radiat Oncol Biol Phys 14:1185-95
Okunieff, P; McFarland, E; Rummeny, E et al. (1987) Effects of oxygen on the metabolism of murine tumors using in vivo phosphorus-31 NMR. Am J Clin Oncol 10:475-82
Johnson, D C; Singer, S; Hoop, B et al. (1987) Chloride flux from blood to CSF: inhibition by furosemide and bumetanide. J Appl Physiol 63:1591-600
Kazemi, H; Johnson, D C (1986) Regulation of cerebrospinal fluid acid-base balance. Physiol Rev 66:953-1037

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