The long-term objective of this proposal is to understand the role of brain hypoxia in ventilatory and cardiovascular control. This is a crucial and controversial question, as it impinges upon both our fundamental understanding of how hypoxia affects central ventilatory and cardiovascular control systems and upon the pathophysiology of these control systems, particularly as they relate to sleep disordered breathing, hypertension, respiratory failure, and environmental hypoxia. To address this question adequately, we must also investigate fundamental questions about the physiology of the carotid body. Much of our knowledge about the integrative aspects of carotid body physiology may be based on animal and human models that were not appropriate to the problem. Accordingly, this proposal has 3 specific aims: 1) How does specific CNS hypoxia affect the control of ventilation and blood pressure? 2) What are the relative contributions of carotid body and central chemoreceptors to the ventilatory response to hypercapnia? 3) Is tonic carotid body afferent input important to the total system response to other stimuli? To accomplish these goals we will use a unique unanesthetized canine model that allows separation of the circulation to the carotid bodies from that of the rest of the systemic circulation so that peripheral and CNS responses can be studied separately in a neurally intact, unanesthetized preparation that can be studied during normal wakefulness and sleep. To date, we have used our unanesthetized carotid body perfusion to obtain preliminary data suggesting that specific CNS hypoxia stimulates breathing, and carotid body hyperoxia can reduce or eliminate the hyperventilatory response to CNS hypoxia. We also have preliminary data suggesting that carotid body denervation causes time-dependent changes in the CNS response to hypercapnia and thus may not be an appropriate model for studies designed to assess relative contributions of central and peripheral chemoreceptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL050531-05
Application #
2751741
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1995-04-01
Project End
2003-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Smith, Curtis A; Blain, Grégory M; Henderson, Kathleen S et al. (2015) Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2. J Physiol 593:4225-43
Dempsey, Jerome A; Smith, Curtis A (2014) Pathophysiology of human ventilatory control. Eur Respir J 44:495-512
Dempsey, Jerome A; Veasey, Sigrid C; Morgan, Barbara J et al. (2010) Pathophysiology of sleep apnea. Physiol Rev 90:47-112
Smith, Curtis A; Forster, Hubert V; Blain, Gregory M et al. (2010) An interdependent model of central/peripheral chemoreception: evidence and implications for ventilatory control. Respir Physiol Neurobiol 173:288-97
Forster, H V; Smith, C A (2010) Contributions of central and peripheral chemoreceptors to the ventilatory response to CO2/H+. J Appl Physiol 108:989-94
Chenuel, Bruno J; Smith, Curtis A; Skatrud, James B et al. (2006) Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog. J Appl Physiol 101:76-83
Smith, C A; Rodman, J R; Chenuel, B J A et al. (2006) Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors. J Appl Physiol 100:13-9
Nakayama, Hideaki; Smith, Curtis A; Rodman, Joshua R et al. (2003) Carotid body denervation eliminates apnea in response to transient hypocapnia. J Appl Physiol 94:155-64
Rodman, J R; Curran, A K; Henderson, K S et al. (2001) Carotid body denervation in dogs: eupnea and the ventilatory response to hyperoxic hypercapnia. J Appl Physiol 91:328-35
Curran, A K; Rodman, J R; Eastwood, P R et al. (2000) Ventilatory responses to specific CNS hypoxia in sleeping dogs. J Appl Physiol 88:1840-52

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