Humans experience chronic intermittent hypoxia (CIH) as a consequence of recurrent apneas and develop autonomic morbidity. It has been proposed that carotid chemoreceptors trigger CIH-induced cardio-respiratory abnormalities. Our studies showed that CIH induces long lasting chemoreceptor activation (i.e., sensory long-term facilitation LTF), which in turn may trigger reflex increase in sympathetic tone, and hypertension. The goal of the current proposal is to identify the mechanisms associated with CIH-induced sensory LTF and assess the significance of sensory LTF in evoking autonomic abnormalities. We hypothesize that sensory LTF is due to recruitment of certain transmitter/modulators by CIH, which otherwise play either a minor or no role in normal carotid body function. Specifically, the role of 5-hydroxytryptamine (5-HT) and subsequent activation of NADPH oxidase in CIH-induced sensory LTF will be examined. Experiments will be performed on rats as well as genetically engineered mice. An integrated approach with a repertoire of techniques including measurements of carotid body sensory activity, cardio-respiratory variables, neurotransmitters and second messenger pathways will be employed. Experiments in AIM 1 test the hypothesis that frequency of the hypoxic exposure regimen plays an important role in determining the magnitude of CIH-evoked sensory LTF. Studies in AIM 2 test the hypotheses that: a) 5- HT acting via 5-HT2 receptors plays a critical role in CIH evoked sensory LTF and b) CIH recruits IP-3 receptor mechanisms in eliciting 5-HT release from the carotid body. Protocols in AIM 3 test the hypothesis that CIH-evoked sensory LTF requires activation of NADPH oxidase by 5-HT2 receptors and subsequent generation of O2.- in the carotid body. Experiments in AIM 4 test the hypothesis that blockade of 5-HT and NADPH oxidase in the carotid body attenuate or abolish CIH-evoked long-lasting cardio- respiratory changes. The proposed studies assessing the role of transmitter(s) in CIH- induced sensory LTF of the carotid body and assessing the physiological significance of sensory LTF is of importance in developing novel therapeutic strategies for alleviating and/or retarding autonomic abnormalities associated with CIH. Experimental Animals: Rats and Mice NARRATIVE: Sleep disordered breathing leading recurrent apneas is a major cause of morbidity and mortality in U.S. population. Major advance in the field is the identification that chronic intermittent hypoxia (CIH) is the major contributor to the cardio-respiratory morbidity associated with apneas. Carotid bodies, the principal sensory organs for detecting arterial blood oxygen mediate CIH-induced morbidity. The current proposal proposes to investigate the role of neurotransmitters in altered carotid body function by CIH in experimental models that may lead to novel therapeutic strategies that help preventing or retarding the deleterious consequences of CIH associated with sleep-disordered breathing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086493-05
Application #
8261922
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2008-09-26
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$347,490
Indirect Cost
$124,740
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Prabhakar, Nanduri R; Peers, Chris (2014) Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology (Bethesda) 29:49-57
Nanduri, Jayasri; Prabhakar, Nanduri R (2013) Developmental programming of O(2) sensing by neonatal intermittent hypoxia via epigenetic mechanisms. Respir Physiol Neurobiol 185:105-9
Yuan, Guoxiang; Peng, Ying-Jie; Reddy, Vaddi Damodara et al. (2013) Mutual antagonism between hypoxia-inducible factors 1? and 2? regulates oxygen sensing and cardio-respiratory homeostasis. Proc Natl Acad Sci U S A 110:E1788-96
Prabhakar, Nanduri R (2013) Sensing hypoxia: physiology, genetics and epigenetics. J Physiol 591:2245-57
Peng, Ying-Jie; Nanduri, Jayasri; Raghuraman, Gayatri et al. (2013) Role of oxidative stress-induced endothelin-converting enzyme activity in the alteration of carotid body function by chronic intermittent hypoxia. Exp Physiol 98:1620-30
Prabhakar, Nanduri R; Semenza, Gregg L (2012) Gaseous messengers in oxygen sensing. J Mol Med (Berl) 90:265-72
Nanduri, Jayasri; Makarenko, Vladislav; Reddy, Vaddi Damodara et al. (2012) Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proc Natl Acad Sci U S A 109:2515-20
Khan, Shakil A; Nanduri, Jayasri; Yuan, Guoxiang et al. (2011) NADPH oxidase 2 mediates intermittent hypoxia-induced mitochondrial complex I inhibition: relevance to blood pressure changes in rats. Antioxid Redox Signal 14:533-42
Peng, Ying-Jie; Nanduri, Jayasri; Khan, Shakil A et al. (2011) Hypoxia-inducible factor 2? (HIF-2?) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci U S A 108:3065-70
Yuan, Guoxiang; Khan, Shakil A; Luo, Weibo et al. (2011) Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol 226:2925-33

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