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1.
Int J Chron Obstruct Pulmon Dis ; 18: 1919-1929, 2023.
Article in English | MEDLINE | ID: mdl-37671143

ABSTRACT

Introduction: Physical activity (PA) and sedentary behavior (SB) have attracted attention in chronic obstructive pulmonary disease (COPD), and there have been efforts to evaluate PA and SB separately. The factors associated with the characteristics of the four activity phenotypes defined by the durations of PA and SB are largely unknown. The aim of this study was to clarify the factors that could differentiate each activity phenotype. Materials and Methods: Study subjects were outpatients with stable COPD who were ≥40 years of age. We investigated the influence of 26 different factors on the activity phenotypes of COPD and extracted the factors that showed significant differences among the four activity phenotypes. Results: Two hundred sixteen patients were included in the analysis. Exercise capacity and dyspnea were determinants that distinguished the low PA groups from the high PA groups. The pulmonary function and desaturation during exercise were factors that distinguished the high PA with low SB group from the low PA with high SB group. BMI, grip strength, upper arm circumference and HbA1c were higher in the low PA and low SB group than in the low PA and high SB group. Conclusion: These factors could be the determinants discriminating activity phenotypes of patients with COPD.


Subject(s)
Pulmonary Disease, Chronic Obstructive , Humans , Dyspnea , Exercise , Hand Strength , Phenotype
2.
J Clin Med ; 11(19)2022 Sep 21.
Article in English | MEDLINE | ID: mdl-36233400

ABSTRACT

Physical activity is decreased in patients with chronic obstructive pulmonary disease, and decreased physical activity leads to a poor prognosis. To determine an individual's target step count from the measured step counts and predicted step counts, simple and detailed prediction equations for step count were developed. To verify the validity of the simple prediction equation, the validity of the simple equation was evaluated in a different cohort and the correlation between the step counts calculated by the simple equation and those by the detailed prediction equation were evaluated. When the step counts calculated by the simple prediction equation for all participants were compared with the measured step counts, a significant correlation was obtained among them, and the calculated values were found to be reproducible with the measured values in patients with a measured step count of <6500 by Bland−Altman plots. Furthermore, the values calculated by the simple prediction equation and those calculated by the detailed prediction equation showed a significant correlation. In conclusion, the simple prediction equation was considered reasonable.

3.
Adv Respir Med ; 2021 Dec 09.
Article in English | MEDLINE | ID: mdl-34881806

ABSTRACT

INTRODUCTION: Improving physical activity in patients with chronic obstructive pulmonary disease (COPD) is a very important issue; however, effective recommended targets for individual patients remain to be determined. MATERIAL AND METHODS: We developed a method for setting a target value for the step count for each patient using a measured value and the predicted step count. We then evaluated the effect of providing a pedometer or a pedometer with this target value for eight weeks on the step count in patients with COPD. RESULTS: Sixteen stable COPD patients were included in the analysis. Overall, no significant increase in the step count was obtained by providing the target value; however, when the patients were divided into two groups based on the median step count at baseline, a significant increase in the step count was observed in the low step-count group. In both the overall population and the low step-count group, there was a significant increase in the target achievement rate in patients who received a pedometer with a target value in comparison to patients who were given a pedometer without a target value. CONCLUSIONS: Physical activity may be improved by providing a newly developed individual target step count to COPD patients with a low step count at baseline.

4.
Int J Chron Obstruct Pulmon Dis ; 16: 3041-3053, 2021.
Article in English | MEDLINE | ID: mdl-34795478

ABSTRACT

BACKGROUND: To improve physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD), providing a target PA value based on the individual patient's condition may be a useful interventional strategy. However, to determine the target value, a predictive PA value for each patient is required. RESEARCH QUESTION: What is the reference equation consisting of PA-related factors to determine the predictive PA value for each patient with COPD? MATERIAL AND METHODS: In this prospective cross-sectional observational study, we measured the PA with a triaxial accelerometer and several other factors including demographic factors, pulmonary function, dyspnea, exercise capacity, muscle strength, nutrition, and indicators of several comorbidities in stable Japanese outpatients with COPD aged ≥40 years old and detected PA-related factors by a multiple regression analysis and stepwise method. We created reference equations for four indices of PA using multiple linear regression equations. RESULTS: Two hundred and twenty-seven patients were registered. The equations of duration at ≥2.0 metabolic equivalents (METs) and step count consisted of 4 factors: 6-minute walk distance, modified Medical Research Council dyspnea scale, anxiety score of the Hospital Anxiety and Depression Scale, and the forced expiratory volume in 1 second % of predicted value. Those of duration at ≥3.0 METs and total activity at ≥3.0 METs consisted of 5 factors: the above 4 factors and age or brain natriuretic peptide. There was no fixed bias or proportional bias between the measured and predictive values in patients with non-high measured PA values. CONCLUSION: We determined reference equations for four indicators of PA using PA-related factors in Japanese patients with COPD. The predictive values calculated using the equations could be useful for deciding target PA values for each patient. CLINICAL TRIAL REGISTRATION: UMIN-CTR; No.: UMIN000025459; URL: https://www.umin.ac.jp/ctr/index.htm.


Subject(s)
Pulmonary Disease, Chronic Obstructive , Adult , Cross-Sectional Studies , Exercise , Exercise Tolerance , Humans , Japan , Prospective Studies , Pulmonary Disease, Chronic Obstructive/diagnosis
5.
Clin Case Rep ; 9(4): 1964-1967, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33936623

ABSTRACT

The confirmation of the improvement of endobronchial lesions in addition to that of vascular lesions after bronchial artery embolization of primary racemose hemangioma could be important.

7.
Can Respir J ; 2018: 8343705, 2018.
Article in English | MEDLINE | ID: mdl-29849834

ABSTRACT

Background: Objective evaluation of the physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) is important. We validated a triaxial accelerometer, Active Style Pro HJA-750C® (HJA), and evaluated the necessary conditions for obtaining reproducible data. Methods: The PA measured by HJA was compared with that measured by two already validated accelerometers in 11 patients with COPD (age: 76.6 ± 6.9, FEV1% predicted: 57.6 ± 18.6). Then, the influence of weather and holidays on the PA and the required number of days to obtain repeatability were examined in 21 patients with COPD (age: 73.0 ± 8.0, FEV1% predicted: 58.7 ± 19.0). Results: The PA values measured by HJA and those by DynaPort Move Monitor® (DMM) or Actimarker® (AM) were significantly correlated at all intensities (p=0.024 at ≥4.0 METs by DMM and p < 0.0001 at the rest) except at ≥4.0 METs by AM, though the values measured by HJA were higher than those by AM which was reported to underestimate PA. The durations of PA on rainy days were significantly shorter than those on nonrainy days, but those on holidays were not different from those on weekdays. The values of ICC for 3, 4, or 5 days were higher than 0.8 at all intensities. The PA measured by HJA was correlated with the dyspnea scale FVC and age and tended to correlate with FEV1. Conclusions: The HJA was validated for evaluating the PA in patients with COPD. This trial is registered with UMIN000016363.


Subject(s)
Accelerometry/instrumentation , Exercise , Pulmonary Disease, Chronic Obstructive/physiopathology , Age Factors , Aged , Aged, 80 and over , Dyspnea/physiopathology , Female , Forced Expiratory Volume , Humans , Male , Reproducibility of Results , Vital Capacity
8.
Intern Med ; 55(24): 3641-3644, 2016.
Article in English | MEDLINE | ID: mdl-27980266

ABSTRACT

An 80-year-old man who had suffered from chronic lymphocytic leukemia (CLL) and achieved complete remission was admitted to our hospital due to right pleural effusion. Thoracentesis revealed that the effusion was chyle. Lymphoscintigraphy showed an obstruction of the thoracic duct below the sternum. CD45-gated flow cytometry of the pleural effusion showed elevated numbers of CD5- and CD23-positive lymphocytes and a high serum level of soluble interleukin-2 receptor. These results suggested that the chylothorax was caused by the obstruction of the thoracic duct by the sludging of either abnormal lymphocytes of CLL or transformed malignant lymphoma cells.


Subject(s)
Chylothorax/etiology , Chylothorax/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pleural Effusion/pathology , Thoracic Duct/pathology , Aged, 80 and over , Chylothorax/therapy , Flow Cytometry , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnostic imaging , Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology , Lymphocytes , Male , Pleural Effusion/complications , Remission Induction , Thoracic Duct/diagnostic imaging , Treatment Outcome
9.
Am J Physiol Heart Circ Physiol ; 311(2): H433-44, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27402666

ABSTRACT

Hypothalamic arcuate nucleus (ARCN) stimulation elicited increases in sympathetic nerve activity (IBATSNA) and temperature (TBAT) of interscapular brown adipose tissue (IBAT). The role of hypothalamic dorsomedial (DMN) and paraventricular (PVN) nuclei in mediating these responses was studied in urethane-anesthetized, artificially ventilated, male Wistar rats. In different groups of rats, inhibition of neurons in the DMN and PVN by microinjections of muscimol attenuated the increases in IBATSNA and TBAT elicited by microinjections of N-methyl-d-aspartic acid into the ipsilateral ARCN. In other groups of rats, blockade of ionotropic glutamate receptors by combined microinjections of D(-)-2-amino-7-phosphono-heptanoic acid (D-AP7) and NBQX into the DMN and PVN attenuated increases in IBATSNA and TBAT elicited by ARCN stimulation. Blockade of melanocortin 3/4 receptors in the DMN and PVN in other groups of rats resulted in attenuation of increases in IBATSNA and TBAT elicited by ipsilateral ARCN stimulation. Microinjections of Fluoro-Gold into the DMN resulted in retrograde labeling of cells in the ipsilateral ARCN, and some of these cells contained proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH), or vesicular glutamate transporter-3. Since similar projections from ARCN to the PVN have been reported by us and others, these results indicate that neurons containing POMC, α-MSH, and glutamate project from the ARCN to the DMN and PVN. Stimulation of ARCN results in the release of α-MSH and glutamate in the DMN and PVN which, in turn, cause increases in IBATSNA and TBAT.


Subject(s)
Adipose Tissue, Brown/drug effects , Arcuate Nucleus of Hypothalamus/drug effects , Dorsomedial Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/drug effects , Sympathetic Nervous System/drug effects , Thermogenesis/drug effects , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/pharmacology , Adipose Tissue, Brown/innervation , Animals , Arcuate Nucleus of Hypothalamus/physiology , Dorsomedial Hypothalamic Nucleus/physiology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Fluorescent Dyes , GABA-A Receptor Agonists/pharmacology , Glutamic Acid/metabolism , Immunohistochemistry , Male , Microinjections , Muscimol/pharmacology , N-Methylaspartate/pharmacology , Neural Inhibition , Paraventricular Hypothalamic Nucleus/physiology , Pro-Opiomelanocortin/metabolism , Quinoxalines/pharmacology , Rats , Rats, Wistar , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Stilbamidines , Sympathetic Nervous System/physiology , Temperature , Thermogenesis/physiology , Vesicular Glutamate Transport Proteins/metabolism , alpha-MSH/metabolism
10.
Clin Exp Hypertens ; 38(2): 209-17, 2016.
Article in English | MEDLINE | ID: mdl-26818039

ABSTRACT

We hypothesized that blockade of angiotensin II type 2 receptors (AT2Rs) in the rostral ventrolateral medullary pressor area (RVLM) may elicit sympathoexcitatory responses which are smaller in hypertensive rats compared to normotensive rats. This hypothesis was tested in urethane-anesthetized, artificially ventilated male 14-week-old spontaneously hypertensive rats (SHR). Age-matched male Wistar-Kyoto rats (WKY) and Wistar rats were used as controls. PD123319 (AT2R antagonist) was microinjected into the RVLM and mean arterial pressure (MAP), heart rate (HR) and greater splanchnic nerve activity (GSNA) were recorded. Increases in MAP, HR and GSNA elicited by unilateral microinjections of PD123319 into the RVLM were significantly smaller in SHR when compared with those in WKY and Wistar rats. Unilateral microinjections of l-glutamate (l-Glu) into the RVLM elicited greater increases in MAP and GSNA in SHR compared to those in WKY. AT2R immunoreactivity was demonstrated in the RVLM neurons which were retrogradely labeled from the intermediolateral cell column (IML) of the spinal cord. These results indicate that AT2Rs are present on the RVLM neurons projecting to the IML and their blockade results in sympathoexcitatory responses. Activation of AT2Rs has an inhibitory influence in the RVLM and these receptors are tonically active. Attenuation of the function of AT2Rs in the RVLM may play a role in genesis and/or maintenance of hypertension in SHR.


Subject(s)
Angiotensin II Type 2 Receptor Blockers/pharmacology , Arterial Pressure/drug effects , Glutamic Acid/pharmacology , Heart Rate/drug effects , Imidazoles/pharmacology , Medulla Oblongata/drug effects , Pyridines/pharmacology , Splanchnic Nerves/drug effects , Animals , Blood Pressure/drug effects , Hypertension , Immunohistochemistry , Male , Medulla Oblongata/metabolism , Microinjections , Neurons/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Receptor, Angiotensin, Type 2/metabolism , Spinal Cord Lateral Horn/metabolism
11.
Am J Physiol Heart Circ Physiol ; 309(1): H174-84, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25957221

ABSTRACT

We have previously reported that stimulation of the hypothalamic arcuate nucleus (ARCN) by microinjections of N-methyl-d-aspartic acid (NMDA) elicits tachycardia, which is partially mediated via inhibition of vagal inputs to the heart. The neuronal pools and neurotransmitters in them mediating tachycardia elicited from the ARCN have not been identified. We tested the hypothesis that the tachycardia elicited from the ARCN may be mediated by inhibitory neurotransmitters in the nucleus ambiguus (nAmb). Experiments were done in urethane-anesthetized, artificially ventilated, male Wistar rats. In separate groups of rats, unilateral and bilateral microinjections of muscimol (1 mM), gabazine (0.01 mM), and strychnine (0.5 mM) into the nAmb significantly attenuated tachycardia elicited by unilateral microinjections of NMDA (10 mM) into the ARCN. Histological examination of the brains showed that the microinjections sites were within the targeted nuclei. Retrograde anatomic tracing from the nAmb revealed direct bilateral projections from the ARCN and hypothalamic paraventricular nucleus to the nAmb. The results of the present study suggest that tachycardia elicited by stimulation of the ARCN by microinjections of NMDA is mediated via GABAA and glycine receptors located in the nAmb.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Heart/drug effects , Medulla Oblongata/metabolism , N-Methylaspartate/pharmacology , Receptors, GABA-A/metabolism , Receptors, Glycine/metabolism , Tachycardia/chemically induced , Animals , Arcuate Nucleus of Hypothalamus/drug effects , GABA Antagonists/pharmacology , GABA-A Receptor Agonists/pharmacology , Glycine Agents/pharmacology , Male , Medulla Oblongata/drug effects , Microinjections , Muscimol/pharmacology , Pyridazines/pharmacology , Rats, Wistar , Stimulation, Chemical , Strychnine/pharmacology , Tachycardia/metabolism
12.
Am J Physiol Heart Circ Physiol ; 306(3): H438-49, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24285114

ABSTRACT

Angiotensin (ANG)-(1-12) excites neurons via ANG II type 1 receptors (AT1Rs), which are present in the caudal ventrolateral medullary depressor area (CVLM). We hypothesized that microinjections of ANG-(1-12) into the CVLM may elicit decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity. This hypothesis was tested in urethane-anesthetized adult male Wistar rats. Microinjections of ANG-(1-12) into the CVLM elicited decreases in MAP, HR, and greater splanchnic nerve activity (GSNA). ANG-(1-12)-induced responses consisted of initial (first 1-8 min) and delayed (8-24 min) phases. Prior microinjections of losartan, A-779, and captopril into the CVLM blocked initial, delayed, and both phases of ANG-(1-12) responses, respectively. Blockade of GABA receptors in the rostral ventrolateral medullary pressor area (RVLM) attenuated cardiovascular responses elicited by microinjections of ANG-(1-12) into the ipsilateral CVLM. Microinjections of ANG-(1-12) into the CVLM potentiated the reflex decreases and attenuated the reflex increases in GSNA elicited by intravenous injections of phenylephrine and sodium nitroprusside, respectively. These results indicate that microinjections of ANG-(1-12) into the CVLM elicit decreases in MAP, HR, and GSNA. Initial and delayed phases of these responses are mediated via ANG II and ANG-(1-7), respectively; the effects of ANG II and ANG-(1-7) are mediated via AT1Rs and Mas receptors, respectively. Captopril blocked both phases of ANG-(1-12) responses, indicating that angiotensin-converting enzyme is important in mediating these responses. GABA receptors in the RVLM partly mediate the cardiovascular responses to microinjections of ANG-(1-12) into the CVLM. Microinjections of ANG-(1-12) into the CVLM modulate baroreflex responses.


Subject(s)
Adrenergic alpha-1 Receptor Agonists/pharmacology , Angiotensinogen/pharmacology , Baroreflex , Medulla Oblongata/physiology , Peptide Fragments/pharmacology , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacology , Animals , Antihypertensive Agents/pharmacology , Blood Pressure , Captopril/pharmacology , Heart Rate , Losartan/pharmacology , Male , Medulla Oblongata/drug effects , Nitroprusside/pharmacology , Phenylephrine/pharmacology , Rats , Rats, Wistar , Vasomotor System/drug effects , Vasomotor System/physiology
13.
Am J Physiol Heart Circ Physiol ; 305(6): H885-93, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23832700

ABSTRACT

Melanocortin receptors (MCRs) are present in the intermediolateral cell column of the spinal cord (IML). We tested the hypothesis that activation of MCRs in the IML elicits cardioacceleratory responses and the source of melanocortins in the IML may be the melanocortin-containing neurons in the hypothalamic arcuate nucleus (ARCN). Experiments were done in urethane-anesthetized, artificially ventilated adult male Wistar rats. Microinjections (50 nl) of α-melanocyte stimulating hormone (α-MSH) (0.4-2 mM) and adrenocorticotropic hormone (ACTH) (0.5-2 mM) into the right IML elicited increases in heart rate (HR). These tachycardic responses were blocked by microinjections of melanocortin receptor 4 (MC4R) antagonists [SHU9119 (0.25 mM) or agouti-related protein (AGRP, 0.1 mM)] into the right IML. Stimulation of right ARCN by microinjections (30 nl) of N-methyl-d-aspartic acid (NMDA, 10 mM) elicited increases in HR. Blockade of MC4Rs in the ipsilateral IML at T1-T3 using SHU9119 (0.25 mM) attenuated the tachycardic responses elicited by subsequent microinjections of NMDA into the ipsilateral ARCN. ARCN neurons retrogradely labeled by microinjections of Fluoro-Gold into the right IML showed immunoreactivity for proopiomelanocortin (POMC), α-MSH, and ACTH. Fibers immunoreactive for POMC, α-MSH, and ACTH were present in the IML at T1-T3. These results indicated that activation of MC4Rs in the right IML elicited tachycardia and one of the sources of melanocortins in the IML is the ARCN. Melanocortin levels are elevated in stress and ARCN neurons are activated during stress. Our results allude to the possibility that cardiac effects of stress may be mediated via melanocortin containing ARCN neurons that project to the IML.


Subject(s)
Action Potentials , Heart/physiopathology , Hypothalamus/physiopathology , Neurons/metabolism , Receptor, Melanocortin, Type 4/metabolism , Spinal Cord/physiopathology , Tachycardia/physiopathology , Animals , Heart/innervation , Male , Neural Pathways/physiopathology , Rats , Rats, Wistar , Thoracic Vertebrae/physiopathology
14.
Hypertension ; 62(2): 281-7, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23774228

ABSTRACT

We tested the hypothesis that tonic γ-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus (ARCN) modulates blood pressure control and attenuation of this inhibitory activity contributes to hypertension in the spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA) were recorded in urethane-anesthetized, artificially ventilated, adult male SHR and Wistar-Kyoto rats (WKY). Microinjections of gabazine into the ARCN elicited significantly smaller increases in MAP, HR, and GSNA in baroreceptor-intact SHR compared with baroreceptor-intact WKY. Attenuation of the responses to gabazine in SHR persisted, despite lowering of their baseline MAP to levels of WKY or barodenervation. Microinjections of N-methyl-d-aspartic acid (NMDA) into the ARCN elicited decreases in MAP and GSNA and increases in HR in baroreceptor-intact WKY. However, after microinjections of gabazine into the ARCN, microinjections of NMDA into the same nucleus elicited pressor responses in baroreceptor-intact WKY. In barodenervated WKY, increases in MAP and GSNA were elicited by ARCN stimulation by NMDA and the increases in HR were exaggerated. In baroreceptor-intact SHR, ARCN stimulation by NMDA elicited increases in MAP, GSNA, and HR which persisted, despite lowering of baseline MAP or barodenervation. Increases in MAP and GSNA elicited by ARCN stimulation by NMDA in barodenervated SHR were significantly greater than corresponding increases in barodenervated WKY. These results indicated that attenuated γ-aminobutyric acid-ergic activity in the ARCN and impaired baroreflex function may contribute to increases in blood pressure and sympathetic nerve activity after ARCN stimulation by NMDA and elevation of baseline blood pressure in SHR.


Subject(s)
Arcuate Nucleus of Hypothalamus/physiopathology , Hypertension/physiopathology , gamma-Aminobutyric Acid/physiology , Animals , Arterial Pressure/drug effects , Baroreflex , Denervation , Dose-Response Relationship, Drug , Heart Rate/drug effects , Male , N-Methylaspartate/pharmacology , Neuropeptide Y/physiology , Pyridazines/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred WKY
15.
Am J Physiol Heart Circ Physiol ; 305(2): H182-91, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23686711

ABSTRACT

The presence of urocortins (UCNs) and corticotropin-releasing factor (CRF) receptors has been reported in the hypothalamic arcuate nucleus (ARCN). We have previously reported that UCNs are involved in central cardiovascular regulation. Based on this information, we hypothesized that the ARCN may be one of the sites where UCNs exert their central cardiovascular actions. Experiments were done in artificially ventilated, adult male Wistar rats anesthetized with urethane. Unilateral microinjections (30 nl) of UCN1 (0.12-2 mM) elicited decreases in mean arterial pressure (MAP) and heart rate (HR). Maximum cardiovascular responses were elicited by a 1 mM concentration of UCN1. Microinjections of UCN2 and UCN3 (1 mM each) into the ARCN elicited similar decreases in MAP and HR. UCN1 was used as a prototype for the other experiments described below. HR responses elicited by UCN1 were significantly attenuated by bilateral vagotomy. Prior microinjections of NBI-27914 (CRF-1 receptor antagonist) and astressin (CRF-1 receptor and CRF-2 receptor antagonist) (1 mM each) into the ARCN significantly attenuated the cardiovascular responses elicited by UCN1 microinjections at the same site. Microinjections of UCN1 into the ARCN decreased efferent renal sympathetic nerve activity. It was concluded that microinjections of UCN1, UCN2, and UCN3 into the ARCN elicited decreases in MAP and HR. Decreases in MAP, HR, and renal sympathetic nerve activity elicited by UCN1 microinjections into the ARCN were mediated via CRF receptors. Bradycardic responses to UCN1 were mediated via the activation of vagus nerves, and decreases in MAP may be mediated via decreases in sympathetic nerve activity.


Subject(s)
Arcuate Nucleus of Hypothalamus/drug effects , Cardiovascular System/drug effects , Cardiovascular System/innervation , Hemodynamics/drug effects , Sympathetic Nervous System/drug effects , Urocortins/administration & dosage , Vagus Nerve/drug effects , Anesthesia, General , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Arterial Pressure/drug effects , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/administration & dosage , Heart Rate/drug effects , Hormone Antagonists/administration & dosage , Kidney/drug effects , Kidney/innervation , Male , Microinjections , Narcotic Antagonists/administration & dosage , Rats , Rats, Wistar , Receptors, Corticotropin-Releasing Hormone/drug effects , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Ionotropic Glutamate/drug effects , Receptors, Ionotropic Glutamate/metabolism , Respiration, Artificial , Vagotomy , Vagus Nerve/surgery
16.
Exp Physiol ; 98(1): 94-108, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22707504

ABSTRACT

The rostral ventrolateral medullary pressor area (RVLM) is known to be critical in the regulation of cardiovascular function. In this study, it was hypothesized that the RVLM may be one of the sites of cardiovascular actions of a newly discovered angiotensin, angiotensin-(1-12) [Ang-(1-12)]. Experiments were carried out in urethane-anaesthetized, artificially ventilated, adult male Wistar rats. The RVLM was identified by microinjections of L-glutamate (5 mM). The volume of all microinjections into the RVLM was 100 nl. Microinjections of Ang-(1-12) (0.1-1.0 mM) into the RVLM elicited increases in mean arterial pressure and heart rate. Maximal cardiovascular responses were elicited by 0.5 mM Ang-(1-12); this concentration was used in the other experiments described. Microinjections of Ang-(1-12) increased greater splanchnic nerve activity. The tachycardic responses to Ang-(1-12) were not altered by bilateral vagotomy. The cardiovascular responses elicited by Ang-(1-12) were attenuated by microinjections of an angiotensin II type 1 receptor (AT(1)R) antagonist (losartan), but not an AT(2)R antagonist (PD123319), into the RVLM. Combined inhibition of angiotensin-converting enzyme and chymase in the RVLM abolished Ang-(1-12)-induced responses. Angiotensin-(1-12)-immunoreactive cells were present in the RVLM. Angiotensin II type 1 receptors and phenylethanolamine-N-methyl-transferase were present in the RVLM neurons retrogradely labelled by microinjections of Fluoro-Gold into the intermediolateral cell column of the thoracic spinal cord. Angiotensin-(1-12)-containing neurons in the hypothalamic paraventricular nucleus did not project to the RVLM. These results indicated that: (1) microinjections of Ang-(1-12) into the RVLM elicited increases in mean arterial pressure, heart rate and greater splanchnic nerve activity; (2) both angiotensin-converting enzyme and chymase were needed to convert Ang-(1-12) into angiotensin II; and (3) AT(1)Rs, but not AT(2)Rs, in the RVLM mediated the Ang-(1-12)-induced responses.


Subject(s)
Angiotensinogen/pharmacology , Medulla Oblongata/physiology , Peptide Fragments/pharmacology , Angiotensin II/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors , Animals , Arterial Pressure/drug effects , Captopril/pharmacology , Chymases/antagonists & inhibitors , Imidazoles/pharmacology , Losartan/pharmacology , Male , Medulla Oblongata/drug effects , Oligopeptides/pharmacology , Paraventricular Hypothalamic Nucleus/metabolism , Peptidyl-Dipeptidase A/drug effects , Phenylethanolamine N-Methyltransferase/metabolism , Pyridines/pharmacology , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1/drug effects , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiology
17.
PLoS One ; 7(9): e45180, 2012.
Article in English | MEDLINE | ID: mdl-23028831

ABSTRACT

The mechanism of cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus (ARCN) was studied in urethane-anesthetized adult male Wistar rats. At the baseline mean arterial pressure (BLMAP) close to normal, ARCN stimulation elicited decreases in MAP and sympathetic nerve activity (SNA). The decreases in MAP elicited by ARCN stimulation were attenuated by either gamma-aminobutyric acid (GABA), neuropeptide Y (NPY), or beta-endorphin receptor blockade in the ipsilateral hypothalamic paraventricular nucleus (PVN). Combined blockade of GABA-A, NPY1 and opioid receptors in the ipsilateral PVN converted the decreases in MAP and SNA to increases in these variables. Conversion of inhibitory effects on the MAP and SNA to excitatory effects following ARCN stimulation was also observed when the BLMAP was decreased to below normal levels by an infusion of sodium nitroprusside. The pressor and tachycardic responses to ARCN stimulation at below normal BLMAP were attenuated by blockade of melanocortin 3/4 (MC3/4) receptors in the ipsilateral PVN. Unilateral blockade of GABA-A receptors in the ARCN increased the BLMAP and heart rate (HR) revealing tonic inhibition of the excitatory neurons in the ARCN. ARCN stimulation elicited tachycardia regardless of the level of BLMAP. ARCN neurons projecting to the PVN were immunoreactive for glutamic acid decarboxylase 67 (GAD67), NPY, and beta-endorphin. These results indicated that: 1) at normal BLMAP, decreases in MAP and SNA induced by ARCN stimulation were mediated via GABA-A, NPY1 and opioid receptors in the PVN, 2) lowering of BLMAP converted decreases in MAP following ARCN stimulation to increases in MAP, and 3) at below normal BLMAP, increases in MAP and HR induced by ARCN stimulation were mediated via MC3/4 receptors in the PVN. These results provide a base for future studies to explore the role of ARCN in cardiovascular diseases.


Subject(s)
Arcuate Nucleus of Hypothalamus/drug effects , Cardiovascular System/drug effects , Paraventricular Hypothalamic Nucleus/drug effects , Sympathetic Nervous System/drug effects , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Arterial Pressure/drug effects , Arterial Pressure/physiology , Cardiovascular System/metabolism , Glutamate Decarboxylase/metabolism , Heart Rate/drug effects , Injections, Intraventricular , Male , N-Methylaspartate/pharmacology , Narcotic Antagonists , Neuropeptide Y/pharmacology , Nitroprusside/pharmacology , Paraventricular Hypothalamic Nucleus/metabolism , Rats , Rats, Wistar , Receptor, Melanocortin, Type 3 , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Receptor, Melanocortin, Type 4/metabolism , Receptors, GABA-A/metabolism , Receptors, Melanocortin/antagonists & inhibitors , Receptors, Melanocortin/metabolism , Receptors, Neuropeptide Y/agonists , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Receptors, Opioid/agonists , Receptors, Opioid/metabolism , Stimulation, Chemical , Sympathetic Nervous System/metabolism , beta-Endorphin/pharmacology
18.
Am J Physiol Regul Integr Comp Physiol ; 303(10): R1023-30, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-23019211

ABSTRACT

The presence of urocortin 3 (UCN3) and CRF2 receptors (CRF2R) has been demonstrated in brain tissue. Nucleus ambiguus (nAmb) is the predominant brain area providing parasympathetic innervation to the heart. On the basis of these reports, it was hypothesized that activation of CRF2Rs in the nAmb may elicit cardiac effects. Experiments were carried out in urethane-anesthetized, artificially ventilated, and adult male Wistar rats. Microinjections of l-glutamate (l-GLU, 5 mM) were used to identify the nAmb. Different concentrations of UCN3 (0.031, 0.062, 0.125, 0.25, and 0.5 mM) microinjected into the nAmb elicited decreases in heart rate (HR) (5.3 ± 1, 22 ± 3.3, 38 ± 4.9, 45.7 ± 2.7, and 27.3 ± 2.3 bpm, respectively). The volume of all microinjections was 30 nl. Blood pressure changes concomitant with decreases in HR were not observed. Bradycardia elicited by microinjections of UCN3 (0.25 mM; maximally effective concentration) into the nAmb was significantly (P < 0.05) attenuated by microinjections of selective CRF2R antagonists (K41498, 0.5 mM, and astressin 2B, 0.25 mM) at the same site. Bilateral vagotomy abolished the bradycardic responses to UCN3. These results indicated that activation of CRF2Rs in the nAmb by UCN3 elicited bradycardia, which was vagally mediated. UCNs have been reported to exert cardioprotective effects in heart failure and ischemia/reperfusion injury. In this situation, centrally induced bradycardia by UCN3 would be beneficial. The results of the present investigation provide a platform for future studies on the role of CRF2Rs in the nAmb in pathological states such as heart failure.


Subject(s)
Bradycardia/chemically induced , Medulla Oblongata/drug effects , Urocortins/pharmacology , Animals , Glutamic Acid/pharmacology , Heart Rate/drug effects , Lethal Dose 50 , Male , Parasympathetic Nervous System/drug effects , Rats , Rats, Wistar , Urocortins/administration & dosage , Vagotomy
19.
PLoS One ; 7(12): e53111, 2012.
Article in English | MEDLINE | ID: mdl-23300873

ABSTRACT

We have previously reported that chemical stimulation of the hypothalamic arcuate nucleus (ARCN) in the rat elicited increases as well as decreases in blood pressure (BP) and sympathetic nerve activity (SNA). The type of response elicited from the ARCN (i.e., increase or decrease in BP and SNA) depended on the level of baroreceptor activity which, in turn, was determined by baseline BP in rats with intact baroreceptors. Based on this information, it was hypothesized that baroreceptor unloading may play a role in the type of response elicited from the ARCN. Therefore, the effect of barodenervation on the ARCN-induced cardiovascular and sympathetic responses and the neurotransmitters in the hypothalamic paraventricular nucleus (PVN) mediating the excitatory responses elicited from the ARCN were investigated in urethane-anesthetized adult male Wistar rats. Bilateral barodenervation converted decreases in mean arterial pressure (MAP) and greater splanchnic nerve activity (GSNA) elicited by chemical stimulation of the ARCN with microinjections of N-methyl-D-aspartic acid to increases in MAP and GSNA and exaggerated the increases in heart rate (HR). Combined microinjections of NBQX and D-AP7 (ionotropic glutamate receptor antagonists) into the PVN in barodenervated rats converted increases in MAP and GSNA elicited by the ARCN stimulation to decreases in MAP and GSNA and attenuated increases in HR. Microinjections of SHU9119 (a melanocortin 3/4 receptor antagonist) into the PVN in barodenervated rats attenuated increases in MAP, GSNA and HR elicited by the ARCN stimulation. ARCN neurons projecting to the PVN were immunoreactive for proopiomelanocortin, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). It was concluded that increases in MAP and GSNA and exaggeration of tachycardia elicited by the ARCN stimulation in barodenervated rats may be mediated via release of alpha-MSH and/or ACTH and glutamate from the ARCN neurons projecting to the PVN.


Subject(s)
Arcuate Nucleus of Hypothalamus/physiopathology , Blood Pressure/physiology , Cardiovascular System/innervation , Heart Rate/physiology , Pressoreceptors/physiopathology , Splanchnic Nerves/physiopathology , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/pharmacology , Adrenocorticotropic Hormone/metabolism , Animals , Arcuate Nucleus of Hypothalamus/drug effects , Arcuate Nucleus of Hypothalamus/metabolism , Blood Pressure/drug effects , Cardiovascular System/drug effects , Denervation , Excitatory Amino Acid Antagonists/pharmacology , Heart Rate/drug effects , Male , Melanocyte-Stimulating Hormones/pharmacology , Paraventricular Hypothalamic Nucleus/metabolism , Pro-Opiomelanocortin/metabolism , Quinoxalines/pharmacology , Rats , Rats, Wistar , Receptors, Corticotropin/antagonists & inhibitors , Splanchnic Nerves/drug effects , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiopathology , alpha-MSH
20.
Am J Physiol Heart Circ Physiol ; 296(2): H325-32, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19060121

ABSTRACT

Urocortin 3 (Ucn3) is a new member of the corticotropin-releasing factor (CRF) peptide family and is considered to be a specific and endogenous ligand for CRF type 2 receptors (CRF2Rs). The presence of CRF(2)Rs has been reported in the nucleus tractus solitarius (NTS) of the rat. It was hypothesized that the activation of CRF2Rs in the medial NTS (mNTS) may play a role in cardiovascular regulation. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of Ucn3 (0.03, 0.06, 0.12, and 0.25 mM) into the mNTS of anesthetized rats elicited decreases in mean arterial pressure (MAP: 5.0 +/- 1.0, 21.6 +/- 2.6, 20.0 +/- 2.8, and 12.7 +/- 3.4 mmHg, respectively) and heart rate (HR: 7.8 +/- 2.6, 46.2 +/- 9.3, 34.5 +/- 8.4, and 16.6 +/- 4.9 beats/min, respectively). Microinjections of artificial cerebrospinal fluid (100 nl) into the mNTS did not elicit cardiovascular responses. Maximum decreases in MAP and HR were elicited by 0.06 mM concentration of Ucn3. Cardiovascular responses to Ucn3 were similar in unanesthetized midcollicular decerebrate rats. A bilateral vagotomy completely abolished Ucn3-induced bradycardia. The decreases in MAP and HR elicited by Ucn3 (0.06 mM) were completely blocked by astressin (1 mM; nonselective CRFR antagonist) and K41498 (5 mM; selective CRF2R antagonist). Microinjections of Ucn3 (0.06 mM) into the mNTS decreased the efferent greater splanchnic nerve activity. After the blockade of CRF2Rs in the mNTS, a Ucn3-induced decrease in the efferent sympathetic nerve discharge was abolished. These results indicate that Ucn3 microinjections into the mNTS exerted excitatory effects on the mNTS neurons via CRF2Rs, leading to depressor and bradycardic responses.


Subject(s)
Blood Pressure , Heart Rate , Heart/innervation , Solitary Nucleus/metabolism , Urocortins/metabolism , Amphibian Proteins/pharmacology , Anesthesia, General , Animals , Blood Pressure/drug effects , Bradycardia/chemically induced , Bradycardia/physiopathology , Corticotropin-Releasing Hormone/pharmacology , Decerebrate State , Dose-Response Relationship, Drug , Heart Rate/drug effects , Hypotension/chemically induced , Hypotension/physiopathology , Male , Microinjections , Peptide Fragments/pharmacology , Peptide Hormones/pharmacology , Rats , Rats, Wistar , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone/metabolism , Respiration, Artificial , Solitary Nucleus/drug effects , Splanchnic Nerves/drug effects , Urocortins/administration & dosage , Vagotomy
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