Immunohistochemical Changes in 5 Respiratory Nuclei after Bilateral Carotid Body Denervation (CBD) in Sprague Dawley Rats

Erythropoietin (EPO) regulates respiration under conditions of normoxia and hypoxia through interaction with the respiratory centers of the brainstem. Here we investigate the dose-dependent impact of EPO in the CB response to hypoxia and hypercapnia. We show, in isolated “en bloc” carotid body (CB) preparations containing the carotid sinus nerve (CSN) from adult male Sprague Dawley rats, that EPO acts as a stimulator of CSN activity in response to hypoxia at concentrations below 0.5 IU/ml. Under hypercapnic conditions, EPO did not influence the CSN response. EPO concentrations above 0.5 IU/ml decreased the response of the CSN to both hypoxia and hypercapnia, reaching complete inhibition at 2 IU/ml. The inhibitory action of high-dose EPO on the CSN activity might result from an increase in nitric oxide (NO) production. Accordingly, CB preparations were incubated with 2 IU/ml EPO and the unspecific NO synthase inhibitor (L-NAME), or the neuronal-specific NO synthase inhibitor (7NI). Both NO inhibitors fully restored the CSN activity in response to hypoxia and hypercapnia in presence of EPO. Our results show that EPO activates the CB response to hypoxia when its concentration does not exceed the threshold at which NO inhibitors masks EPO’s action.

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Long-term captopril treatment restores natriuresis after carotid baroreceptor activation in the SHR

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.1.r70 ◽

1997 ◽

Vol 273 (1) ◽

pp. R70-R79

Author(s):

J. P. Valentin ◽

S. A. Mazbar ◽

M. H. Humphreys

Keyword(s):

Renal Plasma Flow ◽

Renal Nerves ◽

Sprague Dawley ◽

Wky Rats ◽

Sprague Dawley Rats ◽

Long Term Treatment ◽

Bilateral Carotid ◽

Wistar Kyoto ◽

Captopril Treatment

In anesthetized Sprague-Dawley rats, intermittent bilateral carotid artery traction (BilCAT) caused a transient decrease in mean arterial pressure (MAP) of 28 +/- 3 mmHg and led to a progressive increase in sodium excretion (UNaV) that nearly doubled 45-90 min after initiation of the repetitive application of BilCAT (P < 0.001). This natriuresis was accompanied by an increase in glomerular filtration rate (GFR) from 2.70 +/- 0.3 to 3.2 +/- 0.3 ml/min (P < 0.001), no change in renal plasma flow [clearance of p-aminohippurate (PAH)], and an increase in the fractional excretion of lithium. Rats with bilateral renal denervation exhibited neither natriuresis nor an increase in GFR in response to BilCAT despite similar vasodepression caused by the maneuver. Normotensive Wistar-Kyoto (WKY) rats responded to BilCAT like Sprague-Dawley rats, whereas spontaneously hypertensive rats (SHR) exhibited an exaggerated vasodepressor response to BilCAT (-51 +/- 3 mmHg) without increasing either UNaV or GFR. Separate groups of WKY and SHR were treated from 4 wk of age with captopril added to the drinking water at a concentration of 1 g/l. At 12-14 wk, both groups had lower MAP compared with untreated animals. Captopril treatment did not alter either the natriuretic response or the increase in GFR seen in untreated WKY after BilCAT, and the maneuver produced equivalent degrees of vasodepression as in controls. However, treated SHR now responded to BilCAT with increases in both UNaV and GFR that closely resembled the responses seen in Sprague-Dawley and WKY rats. These results suggest that BilCAT produces natriuresis through a pathway dependent on the renal nerves. This pathway does not function in untreated SHR despite similar vasodepression. Long-term treatment with captopril restores this reflex pathway in SHR, lending support to the concept that angiotensin II is critically linked to heightened sympathetic nerve activity and abnormal sodium metabolism in this strain.

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Abstract 17082: Carotid Body Denervation Improves Autonomic Balance and Prevents the Worsening of Heart Failure in Rats After Large Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.17082 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Keita Saku ◽

Takuya Kishi ◽

Akiko Nishizaki ◽

Kana Fujii ◽

Takuya Akashi ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Carotid Body ◽

High Frequency ◽

Diastolic Pressure ◽

Plasma Norepinephrine ◽

Autonomic Balance ◽

Sprague Dawley ◽

Lung Weight ◽

Carotid Body Denervation

Introduction: Carotid body denervation (CBD) abolishes the carotid body hypersensitivity induced sympathoexcitatory hypertension. Since the carotid body hypersensitivity is a salient feature and predicts poor outcome of chronic heart failure (CHF), we hypothesized that CBD restores normal autonomic balance, thus improves CHF in rats after large myocardial infarction (MI). Methods: We created MI in 8 weeks Sprague-Dawley rats. Surviving rats at 2 weeks after MI were randomized into CBD (n=11) and sham-operated (Sham; n=13) groups. We removed the tissues around the carotid bifurcation and established CBD. In some rats (Sham; n=5, CBD; n=5), we telemetrically recorded heart rate (HR). One month after CBD, we compared physiological, histological and immunochemical findings between CBD and Sham. Results: CBD significantly reduced HR (337±15 vs. 364±12 bpm, p<0.05). CBD markedly increased the power spectral density of HR in the high frequency range (81.0±9.5 vs. 29.0±8.2 n.u., p<0.05) and decreased that of the low frequency/high frequency ratio (0.6±0.2 vs. 1.8±0.5, p<0.05) indicating the restoration of autonomic balance. CBD significantly reduced biventricular weight (3.1±0.3 vs. 3.7±0.3 g/kg, p<0.05) and left ventricle (LV) end-diastolic pressure (22±5 vs. 33±5 mmHg, p<0.01) and increased maximum LV dp/dt (5118±809 vs. 4217±472 mmHg/sec, p<0.05). CBD reduced lung weight (a marker of pulmonary edema) (6.8±2.0 vs. 12.4±1.5 g/kg, p<001). Furthermore, CBD reduced plasma brain natriuretic peptide (70±43 vs. 166±71 pg/ml, p<0.01) and plasma norepinephrine as an index of sympathetic drive (384±202 vs. 1048±997 pg/ml, p<0.05). CBD significantly reduced the number of inflammatory macrophages (345±45 vs. 474±73 counts/mm2, p<0.05) in the LV and the plasma concentration of interleukin-1β (14.3±4.7 vs. 24.5±11.8 pg/ml, p<0.05) indicating that CBD also suppressed the inflammatory response in CHF. Conclusions: CBD restores normal autonomic balance and prevents the worsening of heart failure in rats after large myocardial infarction. CBD may serve as a novel neuro-modulatory therapy for CHF patients.

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Chronic hypoxia abolishes posthypoxia frequency decline in the anesthetized rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00033.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. R1322-R1330 ◽

Cited By ~ 10

Author(s):

Oleg Ilyinsky ◽

Gleb Tolstykh ◽

Steve Mifflin

Keyword(s):

Phrenic Nerve ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Sprague Dawley ◽

Burst Frequency ◽

Anesthetized Rats ◽

Sprague Dawley Rats ◽

Bilateral Carotid ◽

Central Network ◽

Nerve Discharge

In anesthetized rats, increases in phrenic nerve amplitude and frequency during brief periods of hypoxia are followed by a reduction in phrenic nerve burst frequency [posthypoxia frequency decline (PHFD)]. We investigated the effects of chronic exposure to hypoxia on PHFD and on peripheral and central O2-sensing mechanisms. In Inactin-anesthetized (100 mg/kg) Sprague-Dawley rats, phrenic nerve discharge and arterial pressure responses to 10 s N2 inhalation were recorded after exposure to hypoxia (10 ± 0.5% O2) for 6-14 days. Compared with rats maintained at normoxia, PHFD was abolished in chronic hypoxic rats. Because of inhibition of PHFD, the increased phrenic burst frequency and amplitude after N2 inhalation persisted for 1.8-2.8 times longer in chronic hypoxic (70 s) compared with normoxic (25-40 s) rats ( P < 0.05). After acute bilateral carotid body denervation, N2 inhalation produced a short depression of phrenic nerve discharge in both chronic hypoxic and normoxic rats. However, the degree and duration of depression of phrenic nerve discharge was smaller in chronic hypoxic compared with normoxic rats ( P < 0.05). We conclude that after exposure to chronic hypoxia, a reduction in PHFD contributes to an increased duration of the acute hypoxic ventilatory response in anesthetized rats. Furthermore, after exposure to chronic hypoxia, the central network responsible for respiration is more resistant to the depressant effects of acute hypoxia in anesthetized rats.

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Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/9802136 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Esteban A. Moya ◽

Paulina Arias ◽

Carlos Varela ◽

María P. Oyarce ◽

Rodrigo Del Rio ◽

...

Keyword(s):

Carotid Body ◽

Reactive Nitrogen Species ◽

Intermittent Hypoxia ◽

Acute Hypoxia ◽

Systemic Hypertension ◽

Chronic Intermittent Hypoxia ◽

Sprague Dawley ◽

Arterial Blood ◽

Sprague Dawley Rats ◽

Obstructive Sleep

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO−scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2(266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO−formation.

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Hypoxia potentiates, oxygen attenuates deflation-induced reflex tracheal constriction

Journal of Applied Physiology ◽

10.1152/jappl.1985.59.3.941 ◽

1985 ◽

Vol 59 (3) ◽

pp. 941-946 ◽

Cited By ~ 12

Author(s):

E. H. Vidruk

Keyword(s):

Carotid Body ◽

Stretch Receptor ◽

Partial Denervation ◽

Bilateral Carotid ◽

Lung Deflation ◽

Pulmonary Stretch Receptor ◽

Carotid Body Denervation

The reflex tracheomotor responses of in situ isolated segments of the extrathoracic trachea of anesthetized, paralyzed, and ventilated dogs were monitored. Reflex tracheal constriction was evoked by passive lung deflation. The purpose of this study was to determine whether the prevailing state of oxygenation altered the magnitude of this reflex. Compared with the magnitude of the response during normoxia [arterial O2 tension (PaO2) = 78 Torr], that during hypoxia (PaO2 = 44 Torr) was nearly threefold larger while that during hyperoxia (PaO2 greater than 250 Torr) was about 50% smaller. The isocapnic changes in oxygenation by themselves usually had no effect on tracheomotor tone. The deflation-induced reflex tracheal constriction was eliminated by complete denervation of the tracheal segment but usually only diminished by partial denervation. Bilateral vagotomies or bilateral carotid body denervation also usually decreased the magnitude of the reflex. It appears that the magnitude of this reflex is dependent on the prevailing state of oxygenation and that a pulmonary stretch receptor-carotid body chemoreceptor interaction accounts for the exaggerated reflex tracheal constriction during hypoxia and the attenuated response during hyperoxia.

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Renin and ACTH responses to hypercapnia and hypoxia after chronic carotid chemodenervation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.3.r412 ◽

1984 ◽

Vol 247 (3) ◽

pp. R412-R417 ◽

Cited By ~ 3

Author(s):

H. Raff ◽

J. Shinsako ◽

M. F. Dallman

Keyword(s):

Blood Pressure ◽

Partial Pressure ◽

Carotid Body ◽

Plasma Renin ◽

Angiotensin I ◽

Co2 Partial Pressure ◽

O2 Partial Pressure ◽

Bilateral Carotid ◽

Hypercapnic Hypoxia ◽

Carotid Body Denervation

We studied the effect of chronic carotid body denervation on renin (plasma renin activity, PRA), adrenocorticotropin (ACTH), blood pressure, and hematocrit responses to acute normocapnic (arterial CO2 partial pressure, PaCO2, 35 Torr) and hypercapnic (PaCO2, 65 Torr) hypoxia (arterial O2 partial pressure, PaO2, 31 Torr) in five anesthetized, artificially ventilated dogs. Animals were studied at least 3 days before and again at least 10 days after carotid body denervation (bilateral carotid sinus nerve resection). Increases in PRA during hypercapnic normoxia [21.8 +/- 6.4 ng angiotensin I (ANG I) X ml-1 X 3 h-1] and normocapnic hypoxia (13.3 +/- 4.2 ng ANG I X ml-1 X 3 h-1) were not attenuated by carotid body denervation. Increases in ACTH during normocapnic hypoxia (117 +/- 34 pg/ml) were attenuated but not eliminated by carotid body denervation; the increase in ACTH during hypercapnic hypoxia (295 +/- 93 pg/ml) was not attenuated by carotid body denervation. Both the blood pressure and hematocrit responses to normocapnic and hypercapnic hypoxia were attenuated by carotid body denervation. We concluded that 1) the renin response to hypercapnia and hypoxia is not a carotid chemoreflex, 2) the ACTH response to hypoxia is partially a carotid chemoreflex, and 3) blood pressure and hematocrit responses to hypoxia are primarily carotid chemoreflexes.

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