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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
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
Prabhakar, Nanduri R; Kumar, Ganesh K; Peng, Ying-Jie (2012) Sympatho-adrenal activation by chronic intermittent hypoxia. J Appl Physiol (1985) 113:1304-10
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
Makarenko, Vladislav V; Nanduri, Jayasri; Raghuraman, Gayatri et al. (2012) Endogenous H2S is required for hypoxic sensing by carotid body glomus cells. Am J Physiol Cell Physiol 303:C916-23
Kumar, Prem; Prabhakar, Nanduri R (2012) Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol 2:141-219
Prabhakar, Nanduri R (2012) Hydrogen sulfide (H(2)S): a physiologic mediator of carotid body response to hypoxia. Adv Exp Med Biol 758:109-13

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