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Nanduri R. Prabhakar - One of the best experts on this subject based on the ideXlab platform.
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role of olfactory receptor78 in carotid body dependent sympathetic activation and hypertension in murine models of Chronic Intermittent Hypoxia
Journal of Neurophysiology, 2021Co-Authors: Yingjie Peng, Jayasri Nanduri, Benjamin L Wang, Timothy David Matthews, Nanduri R. PrabhakarAbstract:Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with Chronic Intermittent Hypoxia (CIH) simulating blood O2 profiles dur...
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Chronic Intermittent Hypoxia alters local respiratory circuit function at the level of the prebotzinger complex
Frontiers in Neuroscience, 2016Co-Authors: Alfredo J Garcia, Nanduri R. Prabhakar, Shakil A Khan, Sebastien Zanella, Tatiana Dashevskiy, Maggie A Khuu, Janmarino RamirezAbstract:Chronic Intermittent Hypoxia (CIH) is a common state experienced in several breathing disorders, including obstructive sleep apnea (OSA) and apneas of prematurity. Unraveling how CIH affects the CNS, and in turn how the CNS contributes to apneas is perhaps the most challenging task. The preBotzinger complex (preBotC) is a pre-motor respiratory network critical for inspiratory rhythm generation. Here, we test the hypothesis that CIH increases irregular output from the isolated preBotC, which can be mitigated by antioxidant treatment. Electrophysiological recordings from brainstem slices revealed that CIH enhanced burst-to-burst irregularity in period and/or amplitude. Irregularities represented a change in individual fidelity among preBotC neurons, and changed transmission from preBotC to the hypoglossal motor nucleus (XIIn), which resulted in increased transmission failure to XIIn. CIH increased the degree of lipid peroxidation in the preBotC and treatment with the antioxidant, 5,10,15,20-Tetrakis (1-methylpyridinium-4-yl)-21H,23H-porphyrin manganese(III) pentachloride (MnTMPyP), reduced CIH-mediated irregularities on the network rhythm and improved transmission of preBotC to the XIIn. These findings suggest that CIH promotes a pro-oxidant state that destabilizes rhythmogenesis originating from the preBotC and changes the local rhythm generating circuit which in turn, can lead to Intermittent transmission failure to the XIIn. We propose that these CIH-mediated effects represent a part of the central mechanism that may perpetuate apneas and respiratory instability, which are hallmark traits in several dysautonomic conditions.
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Chronic Intermittent Hypoxia alters local respiratory circuit function at the level of the preBötzinger complex
Frontiers Media S.A., 2016Co-Authors: Alfredo J Garcia, Nanduri R. Prabhakar, Sebastien Ezanella, Tatiana Edashevskiy, Shakil Ekhan, Maggie Ekhuu, Jan-marino EramirezAbstract:Chronic Intermittent Hypoxia (CIH) is a common state experienced in several breathing disorders, including obstructive sleep apnea (OSA) and apneas of prematurity. Unraveling how CIH affects the CNS, and in turn how the CNS contributes to apneas is perhaps the most challenging task. The preBötzinger complex (preBötC) is a pre-motor respiratory network critical for inspiratory rhythm generation. Here, we test the hypothesis that CIH increases irregular output from the isolated preBötC, which can be mitigated by antioxidant treatment. Electrophysiological recordings from brainstem slices revealed that CIH enhanced burst-to-burst irregularity in period and/or amplitude. Irregularities represented a change in individual fidelity among preBötC neurons, and changed transmission from preBötC to the hypoglossal motor nucleus (XIIn), which resulted in increased transmission failure to XIIn. CIH increased the degree of lipid peroxidation in the preBötC and treatment with the antioxidant, 5,10,15,20-Tetrakis (1-methylpyridinium-4-yl)-21H,23H-porphyrin manganese(III) pentachloride (MnTMPyP), reduced CIH-mediated irregularities on the network rhythm and improved transmission of preBötC to the XIIn. These findings suggest that CIH promotes a pro-oxidant state that destabilizes rhythmogenesis originating from the preBötC and changes the local rhythm generating circuit which in turn, can lead to Intermittent transmission failure to the XIIn. We propose that these CIH-mediated effects represent a part of the central mechanism that may perpetuate apneas and respiratory instability, which are hallmark traits in several dysautonomic conditions
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neuromolecular mechanisms mediating the effects of Chronic Intermittent Hypoxia on adrenal medulla
Respiratory Physiology & Neurobiology, 2015Co-Authors: Ganesh K. Kumar, Yingjie Peng, Jayasri Nanduri, Nanduri R. PrabhakarAbstract:Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to Chronic Intermittent Hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathetic nervous system is a major contributor to CIH-induced hypertension. In this article, we present an overview of our current understanding on how CIH reconfigures AM function and highlight recent findings on the underlying cellular and molecular mechanisms.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
Jayasri Nanduri - One of the best experts on this subject based on the ideXlab platform.
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role of olfactory receptor78 in carotid body dependent sympathetic activation and hypertension in murine models of Chronic Intermittent Hypoxia
Journal of Neurophysiology, 2021Co-Authors: Yingjie Peng, Jayasri Nanduri, Benjamin L Wang, Timothy David Matthews, Nanduri R. PrabhakarAbstract:Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with Chronic Intermittent Hypoxia (CIH) simulating blood O2 profiles dur...
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neuromolecular mechanisms mediating the effects of Chronic Intermittent Hypoxia on adrenal medulla
Respiratory Physiology & Neurobiology, 2015Co-Authors: Ganesh K. Kumar, Yingjie Peng, Jayasri Nanduri, Nanduri R. PrabhakarAbstract:Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to Chronic Intermittent Hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathetic nervous system is a major contributor to CIH-induced hypertension. In this article, we present an overview of our current understanding on how CIH reconfigures AM function and highlight recent findings on the underlying cellular and molecular mechanisms.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:New findings • What is the central question of this study? What mechanisms mediate Chronic Intermittent Hypoxia-induced increases in endothelin-1 in the carotid body? • What is the main finding and its importance? Upregulation of endothelin-1 by Chronic Intermittent Hypoxia results from reactive oxygen species-dependent activation of endothelin-converting enzyme and is not the result of augmented endothelin-1 gene transcriptional activity. The resultant increased endothelin-1 acts via endothelin-1A receptors to induce hypoxic hypersensitivity of the carotid body but does not contribute to the sensory long-term facilitation observed in this condition. These findings provide mechanistic insight into how Chronic Intermittent Hypoxia alters carotid body function. Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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impairment of pancreatic β cell function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Ning Wang, Nanduri R. Prabhakar, Shakil A Khan, Jayasri NanduriAbstract:New Findings • What is the central question of this study? Periodic decreases in arterial blood O2 or Chronic Intermittent Hypoxia (CIH) is a hallmark feature of sleep apnoea patients. Despite a large body of clinical evidence linking sleep-disordered breathing with apnoeas to diabetes, the causal relationships between CIH and β-cell function and the underlying molecular mechanisms have not been established. • What is the main finding and its importance? In a rodent model, we show that mitochondrial oxidative stress generated by CIH leads to pancreatic β-cell dysfunction manifested by augmented basal insulin secretion, insulin resistance, defective proinsulin processing and impaired glucose-stimulated insulin secretion. The results of the present study provide evidence for direct effects of CIH on β-cell function, which may be an underlying molecular mechanism contributing to the development of type 2 diabetes among sleep apnoea patients. Breathing disorders with recurrent apnoea produce periodic decreases in arterial blood O2, i.e. Chronic Intermittent Hypoxia (CIH). Recurrent apnoea patients and CIH-exposed rodents exhibit several co-morbidities, including diabetes. However, the effects of CIH on pancreatic β-cell function are not known. In the present study, we investigated pancreatic β-cell function in C57BL6 mice exposed to 30 days of CIH. Compared with control animals, the CIH-exposed mice exhibited elevated levels of fasting plasma insulin but comparable glucose levels and higher homeostasis model assessment, indicating insulin resistance. Pancreatic β-cell morphology was unaltered in CIH-exposed mice. Insulin content was decreased in CIH-exposed β-cells, and this effect was associated with increased proinsulin levels. The mRNA and protein levels of the enzyme prohormone convertase 1, which converts proinsulin to insulin, were downregulated in CIH-treated islets. More importantly, glucose-stimulated insulin secretion was impaired in CIH-exposed mice and in isolated islets. Mitochondrial levels of reactive oxygen species (ROS) were elevated in CIH-exposed pancreatic islets. Treatment of mice with mito-tempol, a scavenger of mitochondrial ROS, during exposure to CIH prevented the augmented insulin secretion and restored the proinsulin and homeostasis model assessment values to control levels. These results demonstrate that CIH leads to pancreatic β-cell dysfunction, manifested by augmented basal insulin secretion, insulin resistance, defective proinsulin processing, impaired glucose-stimulated insulin secretion and increased mitochondrial ROS, which mediate the effects of CIH on pancreatic β-cell function.
Ganesh K. Kumar - One of the best experts on this subject based on the ideXlab platform.
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neuromolecular mechanisms mediating the effects of Chronic Intermittent Hypoxia on adrenal medulla
Respiratory Physiology & Neurobiology, 2015Co-Authors: Ganesh K. Kumar, Yingjie Peng, Jayasri Nanduri, Nanduri R. PrabhakarAbstract:Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to Chronic Intermittent Hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathetic nervous system is a major contributor to CIH-induced hypertension. In this article, we present an overview of our current understanding on how CIH reconfigures AM function and highlight recent findings on the underlying cellular and molecular mechanisms.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:New findings • What is the central question of this study? What mechanisms mediate Chronic Intermittent Hypoxia-induced increases in endothelin-1 in the carotid body? • What is the main finding and its importance? Upregulation of endothelin-1 by Chronic Intermittent Hypoxia results from reactive oxygen species-dependent activation of endothelin-converting enzyme and is not the result of augmented endothelin-1 gene transcriptional activity. The resultant increased endothelin-1 acts via endothelin-1A receptors to induce hypoxic hypersensitivity of the carotid body but does not contribute to the sensory long-term facilitation observed in this condition. These findings provide mechanistic insight into how Chronic Intermittent Hypoxia alters carotid body function. Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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sympatho adrenal activation by Chronic Intermittent Hypoxia
Journal of Applied Physiology, 2012Co-Authors: Nanduri R. Prabhakar, Ganesh K. Kumar, Yingjie PengAbstract:Recurrent apnea with Chronic Intermittent Hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to Hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by Hypoxia-inducible factor-1 and -2, respectively.
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nadph oxidase is required for the sensory plasticity of the carotid body by Chronic Intermittent Hypoxia
The Journal of Neuroscience, 2009Co-Authors: Yingjie Peng, Swetha Pendyala, Guoxiang Yuan, Jayasri Nanduri, Viswanathan Natarajan, Evan S Deneris, Ganesh K. Kumar, N. Wang, Nanduri R. PrabhakarAbstract:Respiratory motoneuron response to Hypoxia is reflex in nature and carotid body sensory receptor constitutes the afferent limb of this reflex. Recent studies showed that repetitive exposures to Hypoxia evokes long term facilitation of sensory nerve discharge (sLTF) of the carotid body in rodents exposed to Chronic Intermittent Hypoxia (CIH). Although studies with anti-oxidants suggested the involvement of reactive oxygen species (ROS)-mediated signaling in eliciting sLTF, the source of and the mechanisms associated with ROS generation have not yet been investigated. We tested the hypothesis that ROS generated by NADPH oxidase (NOX) mediate CIH-evoked sLTF. Experiments were performed on ex vivo carotid bodies from rats and mice exposed either to 10 d of CIH or normoxia. Acute repetitive Hypoxia evoked a ∼12-fold increase in NOX activity in CIH but not in control carotid bodies, and this effect was associated with upregulation of NOX2 mRNA and protein, which was primarily localized to glomus cells of the carotid body. sLTF was prevented by NOX inhibitors and was absent in mice deficient in NOX2. NOX activation by CIH required 5-HT release and activation of 5-HT2 receptors coupled to PKC signaling. Studies with ROS scavengers revealed that H2O2 generated from O2·− contributes to sLTF. Priming with H2O2 elicited sLTF of carotid bodies from normoxic control rats and mice, similar to that seen in CIH-treated animals. These observations reveal a novel role for NOX-induced ROS signaling in mediating sensory plasticity of the carotid body.
Yingjie Peng - One of the best experts on this subject based on the ideXlab platform.
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role of olfactory receptor78 in carotid body dependent sympathetic activation and hypertension in murine models of Chronic Intermittent Hypoxia
Journal of Neurophysiology, 2021Co-Authors: Yingjie Peng, Jayasri Nanduri, Benjamin L Wang, Timothy David Matthews, Nanduri R. PrabhakarAbstract:Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with Chronic Intermittent Hypoxia (CIH) simulating blood O2 profiles dur...
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neuromolecular mechanisms mediating the effects of Chronic Intermittent Hypoxia on adrenal medulla
Respiratory Physiology & Neurobiology, 2015Co-Authors: Ganesh K. Kumar, Yingjie Peng, Jayasri Nanduri, Nanduri R. PrabhakarAbstract:Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to Chronic Intermittent Hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathetic nervous system is a major contributor to CIH-induced hypertension. In this article, we present an overview of our current understanding on how CIH reconfigures AM function and highlight recent findings on the underlying cellular and molecular mechanisms.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:New findings • What is the central question of this study? What mechanisms mediate Chronic Intermittent Hypoxia-induced increases in endothelin-1 in the carotid body? • What is the main finding and its importance? Upregulation of endothelin-1 by Chronic Intermittent Hypoxia results from reactive oxygen species-dependent activation of endothelin-converting enzyme and is not the result of augmented endothelin-1 gene transcriptional activity. The resultant increased endothelin-1 acts via endothelin-1A receptors to induce hypoxic hypersensitivity of the carotid body but does not contribute to the sensory long-term facilitation observed in this condition. These findings provide mechanistic insight into how Chronic Intermittent Hypoxia alters carotid body function. Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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role of oxidative stress induced endothelin converting enzyme activity in the alteration of carotid body function by Chronic Intermittent Hypoxia
Experimental Physiology, 2013Co-Authors: Yingjie Peng, Jayasri Nanduri, Ganesh K. Kumar, Gayatri Raghuraman, Ning Wang, Nanduri R. PrabhakarAbstract:Chronic Intermittent Hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to Hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic Intermittent Hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, Hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with Hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to Hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
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sympatho adrenal activation by Chronic Intermittent Hypoxia
Journal of Applied Physiology, 2012Co-Authors: Nanduri R. Prabhakar, Ganesh K. Kumar, Yingjie PengAbstract:Recurrent apnea with Chronic Intermittent Hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to Hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by Hypoxia-inducible factor-1 and -2, respectively.
Gregg L Semenza - One of the best experts on this subject based on the ideXlab platform.
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ros signaling in systemic and cellular responses to Chronic Intermittent Hypoxia
Antioxidants & Redox Signaling, 2007Co-Authors: Nanduri R. Prabhakar, Jayasri Nanduri, Ganesh K. Kumar, Gregg L SemenzaAbstract:Chronic Intermittent Hypoxia (CIH) is a common and life-threatening condition that occurs in many different diseases, including sleep-disordered breathing manifested as recurrent apneas. Reactive oxygen species (ROS) have been identified as one of the causative factors in a variety of morbidities. The purpose of this article is to present a brief overview of recent studies implicating a critical role of ROS in evoking phenotypic adverse effects in experimental models of CIH and in patients with recurrent apneas. In experimental models, CIH activates ROS signaling that contributes to several systemic and cellular responses that include (a) altered carotid body function, the primary chemoreceptor for sensing changes in arterial blood O2; (b) elevated blood pressures; (c) enhanced release of transmitters and neurotrophic factors; (d) altered sleep and cognitive behaviors; and (e) activation of second-messenger pathways and transcriptional factors. Considerable evidence indicates elevated ROS levels in patien...
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hif 1 dependent respiratory cardiovascular and redox responses to Chronic Intermittent Hypoxia
Antioxidants & Redox Signaling, 2007Co-Authors: Gregg L Semenza, Nanduri R. PrabhakarAbstract:Sleep-disordered breathing with recurrent apnea is a major cause of morbidity and mortality. Affected individuals have increased risk of systemic hypertension. Sleep apnea results in Chronic Intermittent Hypoxia (CIH). Exposure of rodents to CIH is sufficient to induce hypertension by activation of the carotid body and sympathetic nervous system, leading to increased levels of circulating catecholamines. CIH induces increased levels of reactive oxygen species (ROS), and antioxidant treatment blocks CIH-induced hypertension. The transcriptional activator Hypoxia-inducible factor 1 (HIF-1) plays an essential role in O2 homeostasis. HIF-1 activity is induced when mice or cultured cells are subjected to CIH, an effect that is blocked by antioxidants. The carotid bodies from mice that are heterozygous for a null (knockout) allele at the locus encoding HIF-1 appear histologically normal but do not respond to continuous Hypoxia or CIH. In contrast to wild-type littermates, when heterozygous-null mice are subject...
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ros signaling in systemic and cellular responses to Chronic Intermittent Hypoxia
Antioxidants & Redox Signaling, 2007Co-Authors: Nanduri R. Prabhakar, Jayasri Nanduri, Ganesh K. Kumar, Gregg L SemenzaAbstract:Chronic Intermittent Hypoxia (CIH) is a common and life-threatening condition that occurs in many different diseases, including sleep-disordered breathing manifested as recurrent apneas. Reactive oxygen species (ROS) have been identified as one of the causative factors in a variety of morbidities. The purpose of this article is to present a brief overview of recent studies implicating a critical role of ROS in evoking phenotypic adverse effects in experimental models of CIH and in patients with recurrent apneas. In experimental models, CIH activates ROS signaling that contributes to several systemic and cellular responses that include (a) altered carotid body function, the primary chemoreceptor for sensing changes in arterial blood O2; (b) elevated blood pressures; (c) enhanced release of transmitters and neurotrophic factors; (d) altered sleep and cognitive behaviors; and (e) activation of second-messenger pathways and transcriptional factors. Considerable evidence indicates elevated ROS levels in patients experiencing CIH as a consequence of recurrent apneas. Antioxidants not only prevent many of the CIH-evoked physiologic and cellular responses in experimental settings, but more important, they also offer protection against certain phenotypic adverse effects in patients with recurrent apneas, suggesting their potential therapeutic value in alleviating certain morbidities associated with recurrent apneas.