The first major goal of this project is to examine ventilatory control mechanisms operating in prolonged exposure to hypoxia, i.e., ventilatory acclimatization to hypoxia (VAH) and deacclimatization upon return to normoxia. A second major goal is to better understand mechanism(s) of central-peripheral chemoreceptor interaction in the control of breathing . Two experimental approaches will be used: a) the awake goat carotid body (CB) perfusion model which allows separation and control of arterial blood gases reaching the CB from those reaching the brain, and b) the recording of single chemoreceptor fiber afferent activity from the CB of anesthetized goats and dogs and decerebrate dogs. The 1st specific aim is to determine if diminishing stimuli at the CB will produce VAH in the awake goat CB perfusion model and time-dependent increase in CB afferent activity as occurs with steady-state isocapnic-hypoxic stimulation. A 2nd aim is to determine what mechanisms contribute to the time-dependent, hypoxia-induced increasing CB activity observed in goats. We will measure afferent CB activity in goats and dogs before, during and after 4 hours of hypoxia to answer these questions: Is increasing CB activity during hypoxia a species specific phenomenon? Does CB dopamine depletion or increased responsiveness to CB stimuli other than hypoxia contribute to it? Does anesthesia or nerve degeneration confound these studies? We will also initiate studies of CB monoamine metabolism in VAH. A 3rd aim is to determine if central or peripheral chemoreceptor mechanisms or a combination of both, produce the maintained hyperventilation (decclimatization) occurring upon removal of CB (or whole animal) hypoxia? This question will be answered in part by studies described above under aim 2. We will also use the awake goat CB perfusion model to examine the role of central and peripheral chemoreceptors in deacclimatization by measuring separately the systemic hyperoxic-hypercapnic ventilatory response (central chemoreceptors) and the ventilatory response to CB hypercapnia before and after VAH induced by 4 hours of CB hypoxia. A 4th aim is to utilize the unique awake goat CB perfusion model to examine the interaction between central and peripheral chemoreceptors. The model avoids two major problems, anesthesia and brain hypoxia. The ventilatory response to systemic arterial hyperoxic-hypercapnia (central chemoreceptor stimulation) will be applied at three levels of CB stimulation. The proposed experiments will improve our understanding of ventilatory control in hypoxic states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL015473-14
Application #
3485420
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1977-12-01
Project End
1991-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Earth Sciences/Resources
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Herman, Jay K; O'Halloran, Ken D; Janssen, Patrick L et al. (2003) Dopaminergic excitation of the goat carotid body is mediated by the serotonin type 3 receptor subtype. Respir Physiol Neurobiol 136:1-12
Wang, Zun-Yi; Keith, Ingegerd M; Olson Jr, E Burt et al. (2002) Expression of 5-HT3 receptors in primary sensory neurons of the petrosal ganglion of adult rats. Auton Neurosci 95:121-4
Wang, Zun-Yi; Bisgard, Gerald E (2002) Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59:168-77
Herman, J K; O'Halloran, K D; Bisgard, G E (2001) Effect of 8-OH DPAT and ketanserin on the ventilatory acclimatization to hypoxia in awake goats. Respir Physiol 124:95-104
Herman, J K; O'Halloran, K D; Bisgard, G E (2001) Sustained moderate hyperoxia augments the acute hypoxic response in awake goats. Adv Exp Med Biol 499:325-30
Wang, Z Y; Herman, J K; O'Halloran, K D et al. (2001) Pharmacological and immunochemical evidence of the dopamine D3 receptor in the goat carotid body. Adv Exp Med Biol 499:49-53
Bisgard, G E (2000) Carotid body mechanisms in acclimatization to hypoxia. Respir Physiol 121:237-46
Herman, J K; O'Halloran, K D; Bisgard, G E (2000) Serotonin and the hypoxic ventilatory response in awake goats. Adv Exp Med Biol 475:559-69
Wang, Z Y; Keith, I M; Beckman, M J et al. (2000) 5-HT5a receptors in the carotid body chemoreception pathway of rat. Neurosci Lett 278:12-Sep
O'Halloran, K D; Herman, J K; Janssen, P L et al. (2000) Dopaminergic excitation in goat carotid body may be mediated by serotonin receptors. Adv Exp Med Biol 475:581-8

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