The long-term objectives are to understand the physiology of central chemoreceptor (CCR) function and of cerebrospinal fluid (CFS) acid-based regulation and how they interact. These problems are relevant to acid-base and ventilatory control disorders and chronic lung diseases in which ventilatory control plays a role. The work planned for this project period will use a conscious rabbit model in which 1) measurements of ventilation and blood and CSF chemistry can be made, 2) drugs and solutions can be infused intravenously (iv) and/or via the cerebral ventricles and 3) the peripheral chemoreceptors (PCR) can be removed by carotid body denervation (PCR-). The first project deals with how the regulation of large cavity CSF acid-base balance in metabolic acidemia takes place and how it affects CCR function. The mechanisms of the PCO2 dependent CSF Cl- (and HCO3-) changes in metabolic acidemia will be examined by using the disulfonic stilbene anion transport inhibitors DIDS and SITS, the inhibitors of bulk CSF production, ouabain and acetazolamide, and a modified ventriculo-cisternal perfusion technique to separate bulk flow from non-bulk flow processes. Whether or not this PCO2 dependent large cavity CSF acid-base regulation effects a secondary modulation of the initial ventilatory response to metabolic acidemia will be examined by time course studies correlating ventilation with blood and CSF acid-base changes in intact and PCR- rabbits. Careful CSF pH measurements in chronic metabolic acidemia (greater than 9h) will be used to determine if large cavity CSF pH does or does not change. The second project will build on past work involving the use of different acids, HCl, Hlactate, Hacetate, HNO3, to examine the role of the acid anion in CSF acid-base regulation and CCR function. The role of the acetate anion per se in the greater ventilatory response to Hacetate acidosis will be examined using iv and ICM (intra cisterna magna) Naacetate infusion in intact and PCR- rabbits. Evaluation of the accessibility of Hacetate vs HCl to CCR will be made using IV and ICM infusion in PCR- rabbits. The mechanism of entry of these anions into CSF will be examined as in the experiments concerning the PCO2 dependent C1- mechanism above. The final project involves the relative roles of PCR and CCR in the response to metabolic acidosis. Experiments using intact and PCR rabbgits and iv and/or ICM acid administration will examine CCR sensitivity at various times after PCR denervation, the effect of CCR excitation or inhibition on PCR sensitivity and the effect of PCR excitation or inhibition on CCR sensitivity.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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Dartmouth College
Schools of Medicine
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Barrett, Karlene T; Dosumu-Johnson, Ryan T; Daubenspeck, J Andrew et al. (2016) Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development. J Neurosci 36:3943-53
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Li, Ningjing; Nattie, Eugene; Li, Aihua (2014) The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats. PLoS One 9:e103585
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