Esteban Moya | University of California, San Diego (original) (raw)

Papers by Esteban Moya

American Journal of Respiratory Cell and Molecular Biology

Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hep... more Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte hypoxia inducible factor-1 (HIF-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling OSA would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a (Hif1a-/-hep) and wild-type (Hif1aF/F) controls were fed a high trans-fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half to intermittent air. Glucose tolerance test was performed prior to sacrifice. Liver collagen and triglycerides were determined. Mitochondrial efficiency was assessed in fresh liver tissue at sacrifice. Hepatic malondialdehyde concentration and pro-inflammatory cytokine levels were assessed, and genes of collagen and fatty acid metabolism were queried. Hif1a-/-hep mice gained less weight than Hif1aF/F mice (-2.3 grams, p=0.029). There was also a genotype-independent effect of IH on body weight, with less weight gain in IH (p=0.003). Fasting glucose, HOMA-IR, and glucose tolerance test were all improved in Hif1a-/-hep mice. Liver collagen was increased in IH (p=0.033), and reduced in Hif1a-/-hep mice (p<0.001), without any significant exposure/genotype interaction. Liver TNF-α and IL-1β were significantly increased in IH, and decreased in Hif1a-/-hep. We conclude that HIF-1 signaling worsens the metabolic profile and hastens NAFLD progression, and that IH may worsen liver fibrosis. These effects are plausibly mediated by hepatic inflammatory stress.

Cardiopulmonary Monitoring

The FASEB Journal, Apr 1, 2020

The Journal of Physiology

We hypothesized that hypoxia inducible factor 1α (HIF‐1α) in CNS respiratory centres is necessary... more We hypothesized that hypoxia inducible factor 1α (HIF‐1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time‐dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF‐1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild‐type mice with CH. Conditional deletion of HIF‐1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO2, and there were no changes in the HVR in normoxic mice. HIF‐1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH.

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2018

Chronic intermittent hypoxia (CIH), main feature of obstructive sleep apnea, produces nitro-oxida... more Chronic intermittent hypoxia (CIH), main feature of obstructive sleep apnea, produces nitro-oxidative stress, which contributes to potentiate carotid body (CB) chemosensory discharges and sympathetic-adrenal-axis activity, leading to hypertension. The MnSOD enzymatic activity, a key enzyme on oxidative stress control, is reduced by superoxide-induced nitration. However, the effects of CIH-induced nitration on MnSOD enzymatic activity in the CB and adrenal gland are not known. We studied the effects of CIH on MnSOD protein and immunoreactive (MnSOD-ir) levels in the CB, adrenal gland and superior cervical ganglion (SCG), and on 3-nitrotyrosine (3-NT-ir), CuZnSOD (CuZnSOD-ir), MnSOD nitration, and its enzymatic activity in the CB and adrenal gland from male Sprague-Dawley rats exposed to CIH for 7 days. CIH increased 3-NT-ir in CB and adrenal gland, whereas MnSOD-ir increased in the CB and in adrenal cortex, but not in the whole adrenal medulla or SCG. CIH nitrated MnSOD in the CB and...

The Journal of Physiology

Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal mus... more Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal muscles remain unexplored. Two hours of hypoxia caused significant down-regulation of extracellular matrix genes followed by a shift at 6 h to altered expression of genes associated with the nuclear lumen while respiratory and blood gases were stabilized. Enrichment analysis of mRNAs classified by stability rates suggests an attenuation of post-transcriptional regulation within hours of hypoxic exposure, where PI3K-Akt signalling was suggested to have a nodal role by pathway analysis. Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2 h of hypoxic exposure might deactivate RNA-binding protein BRF1, hence resulting in the selective degradation of mRNAs. The effects of acute hypoxia have been widely studied, but there are few studies of transcriptional responses to hours of hypoxia in vivo, especially in hypoxia-tolerant tissues like skeletal muscles. We used RNA-seq to analyse gene expression in plantaris muscles while monitoring respiration, arterial blood gases, and blood glucose in mice exposed to 8% O2 for 2 or 6 h. Rapid decreases in blood gases and a slower reduction in blood glucose suggest stress, which was accompanied by widespread changes in gene expression. Early down-regulation of genes associated with the extracellular matrix was followed by a shift to genes associated with the nuclear lumen. Most of the early down-regulated genes had mRNA half-lives longer than 2 h, suggesting a role for post-transcriptional regulation. These transcriptional changes were enriched in signalling pathways in which the PI3K-Akt signalling pathway was identified as a hub. Our analyses indicated that gene targets of PI3K-Akt but not HIF were enriched in early transcriptional responses to hypoxia. Among the PI3K-Akt targets, 75% could be explained by a deactivation of adenylate-uridylate-rich element (ARE)-binding protein BRF1, a target of PI3K-Akt. Consistent decreases in the phosphorylation of Akt and BRF1 were experimentally confirmed following 2 h of hypoxia. These results suggest that the PI3K-Akt signalling pathway might play a role in responses induced by acute hypoxia in skeletal muscles, partially through the dephosphorylation of ARE-binding protein BRF1.

The Journal of Physiology

The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with th... more The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID-19 patients have been labelled with 'happy hypoxia' , in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

Eur Resp J, 2010

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic resp... more Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.

Advances in Experimental Medicine and Biology, 2010

The obstructive sleep apnea (OSA) syndrome, characterized by repeated episodes of intermittent hy... more The obstructive sleep apnea (OSA) syndrome, characterized by repeated episodes of intermittent hypoxia is recognized as an independent risk factor for hypertension. One potential contributing mechanism to the OSA-induced hypertension is the potentiation of the carotid body chemosensory responses to hypoxia, which is responsible for the augmented sympathetic modulation of heart rate variability (HRV) and the enhanced ventilatory response to hypoxia found in OSA patients and animal exposed to chronic intermittent hypoxia (CIH). However, it is not known if the cardiorespiratory alterations may precede the hypertension. Thus, we studied the effects of CIH on arterial pressure, HRV and ventilatory response to acute hypoxia in rats exposed to CIH (5% O(2), 12 times/h per 8 h) or sham condition for 7-21 days. Exposure of rats to CIH for 14 days enhanced the ventilatory response to hypoxia and produced a significant shift of the HRV power spectrum, with a predominance of the sympathetic modulation. These cardiorespiratory alterations occurred without noticeable changes in arterial blood pressure, until 21 days of CIH exposure. Thus, our results support the idea that the hypertension induced by CIH was preceded by alterations in the autonomic balance of HRV, associated with an enhance chemoreflex ventilatory reactivity in normotensive animals.

Auton Neurosci Basic Clin, 2011

Backgroud: The dorsal hippocampus (DH) is involved with aversive responses in rats. Local HD nitr... more Backgroud: The dorsal hippocampus (DH) is involved with aversive responses in rats. Local HD nitric oxide (NO)/cGMP pathway is able to modulate aversive responses. Finally, during the inhibition of the area occur both autonomic and behavioral changes. Aim: To investigate the possible involvement of local DH NO/cGMP pathway on behavioral (freezing), autonomic, increase of mean arterial pressure (MAP), heart rate (HR) and drop cutaneous temperature (CT).

Advances in Experimental Medicine and Biology, 2009

It has been proposed that histamine is an excitatory transmitter between the glomus cells of the ... more It has been proposed that histamine is an excitatory transmitter between the glomus cells of the carotid body (CB) and the nerve endings of the petrosal ganglion (PG) neurons. The histamine biosynthetic pathway and the presence of histamine H1, H2 and H3 receptors have been reported in the CB. Thus, histamine meets some of the criteria to be regarded as a transmitter. However, there is no evidence that glomus cells contain histamine, or whether its application produces chemosensory excitation. Therefore, we studied its immunocytochemical localization on cat CB and its effects on chemosensory activity. Using perfused and superfused in vitro CB and PG preparations, we assessed the effects of histamine hydrochloride on chemosensory discharges and of histamine H1, H2 and H3 receptor blockers. We found the presence of histamine immunoreactivity in dense-core vesicles in glomus cells. In an in vitro CB preparation we performed pharmacological experiments to characterize histamine effects. The application of histamine hydrochloride (0.5-1,000 microg) to the CB produces a dose-dependent increase in the carotid sinus nerve activity. The H1 receptor blockade with pyrilamine 500 nM produces partial decrease of the histamine-induced response, whereas the H2 receptor blockade (ranitidine 100microM) fail to abolish the histamine excitatory effects. Antagonism of the H3 receptor results in an increase in carotid body chemosensory activity. On the other hand, application of histamine to the isolated PG had no effect on the carotid nerve discharge. Our results suggest that histamine is a modulator of the carotid body chemoreception through H1 and H3 receptor activation.

Advances in Experimental Medicine and Biology, 2009

It has been proposed that chronic intermittent hypoxia (CIH) contributes to generate hypertension... more It has been proposed that chronic intermittent hypoxia (CIH) contributes to generate hypertension in patients with obstructive sleep apnea syndrome and animal models, due to an enhanced sympathetic outflow. A possible contributing mechanism to the CIH-induced hypertension is a potentiation of carotid body (CB) chemosensory responses to hypoxia, but early changes that precede the CIH-induced hypertension are not completely known. Since the variability of heart rate (HRV) has been used as an index of autonomic influences on cardiovascular system, we studied the effects of short and long-term CIH exposure on HRV in animals with or without hypertension. In cats exposed to CIH (PO 2 ∼75 Torr, 10 times/hr during 8 hr) for 4 days, the ventilatory response to acute hypoxia was potentiated, the arterial pressure remained unchanged, but the HRV power spectrum showed a shift towards the low frequency band. Exposure of rats to CIH (PO 2 ∼37.5 Torr, 12 times/hr during 8 hr) for 12 days enhanced the ventilatory response to acute hypoxia, but did not increase the arterial pressure. After 21 days of CIH, we found a significant increase of arterial pressure and a shift of the HRV power spectrum towards the low frequency band. Thus, our results support the idea that hypertension induced by long-term CIH was preceded by alterations in the autonomic balance of HRV, associated with an enhance CB chemoreflex sensitivity to hypoxia. Therefore, few days of CIH are enough to enhance the CB reactivity to hypoxia, which contribute to the augmented ventilatory response to hypoxia, and to the early alterations in the autonomic balance of HRV.

Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid bo... more Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid body (CB) chemosensory discharges. NO modulates the chemoreception process by several mechanisms, indirectly by modifying the vascular tone and oxygen delivery, and directly through the modulation of the excitability of glomus cells and petrosal neurons. In addition to the inhibitory effect, at high concentrations NO has a dual dose-dependent effect on CB chemoreception that depends on the P O 2 . In hypoxic conditions, NO is primarily an inhibitory modulator of CB chemoreception, while in normoxia NO increases the chemosensory discharges. In this review, we will examine new evidence supporting the idea that NO is involved in the CB chemosensory potentiation induced by congestive heart failure (CHF) and chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA). Evidence from patients and experimental animal models indicates that CHF and OSA, as well as CIH, potentiate the carotid hypoxic chemoreflexes, contributing to enhance the sympathetic tone. Moreover, animals exposed to CIH or to pacing-induced CHF showed enhanced baseline CB discharges in normoxia and potentiated chemosensory responses to acute hypoxia. Several molecules and pathways are altered in CHF, OSA and CIH, but the available evidence suggests that a reduced NO production in the CB plays an essential role in both diseases, contributing to enhance the CB chemosensory discharges.

European Respiratory Journal, 2010

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic resp... more Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.

American Journal of Respiratory Cell and Molecular Biology

Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hep... more Obstructive sleep apnea (OSA) is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte hypoxia inducible factor-1 (HIF-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling OSA would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a (Hif1a-/-hep) and wild-type (Hif1aF/F) controls were fed a high trans-fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half to intermittent air. Glucose tolerance test was performed prior to sacrifice. Liver collagen and triglycerides were determined. Mitochondrial efficiency was assessed in fresh liver tissue at sacrifice. Hepatic malondialdehyde concentration and pro-inflammatory cytokine levels were assessed, and genes of collagen and fatty acid metabolism were queried. Hif1a-/-hep mice gained less weight than Hif1aF/F mice (-2.3 grams, p=0.029). There was also a genotype-independent effect of IH on body weight, with less weight gain in IH (p=0.003). Fasting glucose, HOMA-IR, and glucose tolerance test were all improved in Hif1a-/-hep mice. Liver collagen was increased in IH (p=0.033), and reduced in Hif1a-/-hep mice (p<0.001), without any significant exposure/genotype interaction. Liver TNF-α and IL-1β were significantly increased in IH, and decreased in Hif1a-/-hep. We conclude that HIF-1 signaling worsens the metabolic profile and hastens NAFLD progression, and that IH may worsen liver fibrosis. These effects are plausibly mediated by hepatic inflammatory stress.

Cardiopulmonary Monitoring

The FASEB Journal, Apr 1, 2020

The Journal of Physiology

We hypothesized that hypoxia inducible factor 1α (HIF‐1α) in CNS respiratory centres is necessary... more We hypothesized that hypoxia inducible factor 1α (HIF‐1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time‐dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF‐1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild‐type mice with CH. Conditional deletion of HIF‐1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO2, and there were no changes in the HVR in normoxic mice. HIF‐1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH.

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2018

Chronic intermittent hypoxia (CIH), main feature of obstructive sleep apnea, produces nitro-oxida... more Chronic intermittent hypoxia (CIH), main feature of obstructive sleep apnea, produces nitro-oxidative stress, which contributes to potentiate carotid body (CB) chemosensory discharges and sympathetic-adrenal-axis activity, leading to hypertension. The MnSOD enzymatic activity, a key enzyme on oxidative stress control, is reduced by superoxide-induced nitration. However, the effects of CIH-induced nitration on MnSOD enzymatic activity in the CB and adrenal gland are not known. We studied the effects of CIH on MnSOD protein and immunoreactive (MnSOD-ir) levels in the CB, adrenal gland and superior cervical ganglion (SCG), and on 3-nitrotyrosine (3-NT-ir), CuZnSOD (CuZnSOD-ir), MnSOD nitration, and its enzymatic activity in the CB and adrenal gland from male Sprague-Dawley rats exposed to CIH for 7 days. CIH increased 3-NT-ir in CB and adrenal gland, whereas MnSOD-ir increased in the CB and in adrenal cortex, but not in the whole adrenal medulla or SCG. CIH nitrated MnSOD in the CB and...

The Journal of Physiology

Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal mus... more Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal muscles remain unexplored. Two hours of hypoxia caused significant down-regulation of extracellular matrix genes followed by a shift at 6 h to altered expression of genes associated with the nuclear lumen while respiratory and blood gases were stabilized. Enrichment analysis of mRNAs classified by stability rates suggests an attenuation of post-transcriptional regulation within hours of hypoxic exposure, where PI3K-Akt signalling was suggested to have a nodal role by pathway analysis. Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2 h of hypoxic exposure might deactivate RNA-binding protein BRF1, hence resulting in the selective degradation of mRNAs. The effects of acute hypoxia have been widely studied, but there are few studies of transcriptional responses to hours of hypoxia in vivo, especially in hypoxia-tolerant tissues like skeletal muscles. We used RNA-seq to analyse gene expression in plantaris muscles while monitoring respiration, arterial blood gases, and blood glucose in mice exposed to 8% O2 for 2 or 6 h. Rapid decreases in blood gases and a slower reduction in blood glucose suggest stress, which was accompanied by widespread changes in gene expression. Early down-regulation of genes associated with the extracellular matrix was followed by a shift to genes associated with the nuclear lumen. Most of the early down-regulated genes had mRNA half-lives longer than 2 h, suggesting a role for post-transcriptional regulation. These transcriptional changes were enriched in signalling pathways in which the PI3K-Akt signalling pathway was identified as a hub. Our analyses indicated that gene targets of PI3K-Akt but not HIF were enriched in early transcriptional responses to hypoxia. Among the PI3K-Akt targets, 75% could be explained by a deactivation of adenylate-uridylate-rich element (ARE)-binding protein BRF1, a target of PI3K-Akt. Consistent decreases in the phosphorylation of Akt and BRF1 were experimentally confirmed following 2 h of hypoxia. These results suggest that the PI3K-Akt signalling pathway might play a role in responses induced by acute hypoxia in skeletal muscles, partially through the dephosphorylation of ARE-binding protein BRF1.

The Journal of Physiology

The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with th... more The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID-19 patients have been labelled with 'happy hypoxia' , in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

Eur Resp J, 2010

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic resp... more Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.

Advances in Experimental Medicine and Biology, 2010

The obstructive sleep apnea (OSA) syndrome, characterized by repeated episodes of intermittent hy... more The obstructive sleep apnea (OSA) syndrome, characterized by repeated episodes of intermittent hypoxia is recognized as an independent risk factor for hypertension. One potential contributing mechanism to the OSA-induced hypertension is the potentiation of the carotid body chemosensory responses to hypoxia, which is responsible for the augmented sympathetic modulation of heart rate variability (HRV) and the enhanced ventilatory response to hypoxia found in OSA patients and animal exposed to chronic intermittent hypoxia (CIH). However, it is not known if the cardiorespiratory alterations may precede the hypertension. Thus, we studied the effects of CIH on arterial pressure, HRV and ventilatory response to acute hypoxia in rats exposed to CIH (5% O(2), 12 times/h per 8 h) or sham condition for 7-21 days. Exposure of rats to CIH for 14 days enhanced the ventilatory response to hypoxia and produced a significant shift of the HRV power spectrum, with a predominance of the sympathetic modulation. These cardiorespiratory alterations occurred without noticeable changes in arterial blood pressure, until 21 days of CIH exposure. Thus, our results support the idea that the hypertension induced by CIH was preceded by alterations in the autonomic balance of HRV, associated with an enhance chemoreflex ventilatory reactivity in normotensive animals.

Auton Neurosci Basic Clin, 2011

Backgroud: The dorsal hippocampus (DH) is involved with aversive responses in rats. Local HD nitr... more Backgroud: The dorsal hippocampus (DH) is involved with aversive responses in rats. Local HD nitric oxide (NO)/cGMP pathway is able to modulate aversive responses. Finally, during the inhibition of the area occur both autonomic and behavioral changes. Aim: To investigate the possible involvement of local DH NO/cGMP pathway on behavioral (freezing), autonomic, increase of mean arterial pressure (MAP), heart rate (HR) and drop cutaneous temperature (CT).

Advances in Experimental Medicine and Biology, 2009

It has been proposed that histamine is an excitatory transmitter between the glomus cells of the ... more It has been proposed that histamine is an excitatory transmitter between the glomus cells of the carotid body (CB) and the nerve endings of the petrosal ganglion (PG) neurons. The histamine biosynthetic pathway and the presence of histamine H1, H2 and H3 receptors have been reported in the CB. Thus, histamine meets some of the criteria to be regarded as a transmitter. However, there is no evidence that glomus cells contain histamine, or whether its application produces chemosensory excitation. Therefore, we studied its immunocytochemical localization on cat CB and its effects on chemosensory activity. Using perfused and superfused in vitro CB and PG preparations, we assessed the effects of histamine hydrochloride on chemosensory discharges and of histamine H1, H2 and H3 receptor blockers. We found the presence of histamine immunoreactivity in dense-core vesicles in glomus cells. In an in vitro CB preparation we performed pharmacological experiments to characterize histamine effects. The application of histamine hydrochloride (0.5-1,000 microg) to the CB produces a dose-dependent increase in the carotid sinus nerve activity. The H1 receptor blockade with pyrilamine 500 nM produces partial decrease of the histamine-induced response, whereas the H2 receptor blockade (ranitidine 100microM) fail to abolish the histamine excitatory effects. Antagonism of the H3 receptor results in an increase in carotid body chemosensory activity. On the other hand, application of histamine to the isolated PG had no effect on the carotid nerve discharge. Our results suggest that histamine is a modulator of the carotid body chemoreception through H1 and H3 receptor activation.

Advances in Experimental Medicine and Biology, 2009

It has been proposed that chronic intermittent hypoxia (CIH) contributes to generate hypertension... more It has been proposed that chronic intermittent hypoxia (CIH) contributes to generate hypertension in patients with obstructive sleep apnea syndrome and animal models, due to an enhanced sympathetic outflow. A possible contributing mechanism to the CIH-induced hypertension is a potentiation of carotid body (CB) chemosensory responses to hypoxia, but early changes that precede the CIH-induced hypertension are not completely known. Since the variability of heart rate (HRV) has been used as an index of autonomic influences on cardiovascular system, we studied the effects of short and long-term CIH exposure on HRV in animals with or without hypertension. In cats exposed to CIH (PO 2 ∼75 Torr, 10 times/hr during 8 hr) for 4 days, the ventilatory response to acute hypoxia was potentiated, the arterial pressure remained unchanged, but the HRV power spectrum showed a shift towards the low frequency band. Exposure of rats to CIH (PO 2 ∼37.5 Torr, 12 times/hr during 8 hr) for 12 days enhanced the ventilatory response to acute hypoxia, but did not increase the arterial pressure. After 21 days of CIH, we found a significant increase of arterial pressure and a shift of the HRV power spectrum towards the low frequency band. Thus, our results support the idea that hypertension induced by long-term CIH was preceded by alterations in the autonomic balance of HRV, associated with an enhance CB chemoreflex sensitivity to hypoxia. Therefore, few days of CIH are enough to enhance the CB reactivity to hypoxia, which contribute to the augmented ventilatory response to hypoxia, and to the early alterations in the autonomic balance of HRV.

Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid bo... more Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid body (CB) chemosensory discharges. NO modulates the chemoreception process by several mechanisms, indirectly by modifying the vascular tone and oxygen delivery, and directly through the modulation of the excitability of glomus cells and petrosal neurons. In addition to the inhibitory effect, at high concentrations NO has a dual dose-dependent effect on CB chemoreception that depends on the P O 2 . In hypoxic conditions, NO is primarily an inhibitory modulator of CB chemoreception, while in normoxia NO increases the chemosensory discharges. In this review, we will examine new evidence supporting the idea that NO is involved in the CB chemosensory potentiation induced by congestive heart failure (CHF) and chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA). Evidence from patients and experimental animal models indicates that CHF and OSA, as well as CIH, potentiate the carotid hypoxic chemoreflexes, contributing to enhance the sympathetic tone. Moreover, animals exposed to CIH or to pacing-induced CHF showed enhanced baseline CB discharges in normoxia and potentiated chemosensory responses to acute hypoxia. Several molecules and pathways are altered in CHF, OSA and CIH, but the available evidence suggests that a reduced NO production in the CB plays an essential role in both diseases, contributing to enhance the CB chemosensory discharges.

European Respiratory Journal, 2010

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic resp... more Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.