scholarly journals AT1a dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia

2021 ◽  
Author(s):  
George E. Farmer ◽  
Joel T. Little ◽  
Alexandria B. Marciante ◽  
J. Thomas Cunningham
Keyword(s):  
Intermittent Hypoxia ◽  
Receptor Expression ◽  
Chronic Intermittent Hypoxia ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Spontaneous Action ◽  
Potential Activity ◽  
At1a Receptor

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with a shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH 8 h a day for 7 days. In vitro loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, MnPO KCC2 protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA mediated inhibition and CIH with AT1a knockdown produced GABAA mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA mediated inhibition in the MnPO contributing sustained hypertension.

Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries

2006 ◽  
Vol 100 (4) ◽  
pp. 1117-1123 ◽  
Author(s):  
Shane A. Phillips ◽  
E. B. Olson ◽  
Julian H. Lombard ◽  
Barbara J. Morgan
Keyword(s):  
Skeletal Muscle ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Physiological Salt Solution ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Sprague Dawley Rats ◽  
Resting Tone ◽  
Wall Distensibility

Although arterial dilator reactivity is severely impaired during exposure of animals to chronic intermittent hypoxia (CIH), few studies have characterized vasoconstrictor responsiveness in resistance arteries of this model of sleep-disordered breathing. Sprague-Dawley rats were exposed to CIH (10% inspired O2 fraction for 1 min at 4-min intervals; 12 h/day) for 14 days. Control rats were housed under normoxic conditions. Diameters of isolated gracilis muscle resistance arteries (GA; 120–150 μm) were measured by television microscopy before and during exposure to norepinephrine (NE) and angiotensin II (ANG II) and at various intraluminal pressures between 20 and 140 mmHg in normal and Ca2+-free physiological salt solution. There was no difference in the ability of GA to constrict in response to ANG II ( P = 0.42; not significant; 10−10–10−7 M). However, resting tone, myogenic activation, and vasoconstrictor responses to NE ( P < 0.001; 10−9–10−6 M) were reduced in CIH vs. controls. Treatment of rats with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol; 1 mM) in the drinking water restored myogenic responses and NE-induced constrictions of CIH rats, suggesting that elevated superoxide production during exposure to CIH attenuates vasoconstrictor responsiveness to NE and myogenic activation in skeletal muscle resistance arteries. CIH also leads to an increased stiffness and reduced vessel wall distensibility that were not correctable with oral tempol treatment.

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

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
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.

scholarly journals Chronic intermittent hypoxia increases blood pressure and expression of FosB/ΔFosB in central autonomic regions

2011 ◽  
Vol 301 (1) ◽  
pp. R131-R139 ◽  
Author(s):  
W. David Knight ◽  
Joel T. Little ◽  
Flavia R. Carreno ◽  
Glenn M. Toney ◽  
Steven W. Mifflin ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Renin Angiotensin System ◽  
Brain Regions ◽  
Ventrolateral Medulla ◽  
Chronic Intermittent Hypoxia ◽  
Preoptic Nucleus ◽  
Sprague Dawley ◽  
Angiotensin System ◽  
Sprague Dawley Rats ◽  
Obstructive Sleep

Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7–10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/ΔFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 ± 1; CIH: 34 ± 3 cells/section), subfornical organ (CON: 7 ± 2; CIH: 31 ± 3), median preoptic nucleus (CON 15 ± 1; CIH: 38 ± 3), nucleus of the solitary tract (CON: 9 ± 2; CIH: 28 ± 4), A5 (CON: 3 ± 1; CIH: 10 ± 1), and rostral ventrolateral medulla (CON: 5 ± 1; CIH: 17 ± 2). In the paraventricular nucleus, FosB/ΔFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/ΔFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/ΔFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA.

scholarly journals Potential of Hibiscus sabdariffa linn. in managing Fgf21 resistance in diet-induced-obesity rats via miR-34a regulation

2020 ◽  
Author(s):  
Neng Tine Kartinah ◽  
Nisa Komara ◽  
Nuraini Diah Noviati ◽  
Syarifah Dewi ◽  
Sophie Yolanda ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Receptor Expression ◽  
Hibiscus Sabdariffa ◽  
Sprague Dawley ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Sprague Dawley Rats ◽  
Equivalent Expression ◽  
Potential Activity

Abstract Background Obesity is a cause of Fgf21 resistance, which affects the browning and thermogenesis process of the adipose tissue. Decreased receptor expression is influenced by microRNA 34a (miR-34a), whose expression is increased in obesity. While Fgf21-based therapies have been widely investigated, the potential activity of Hibiscus sabdariffa Linn extract (HSE) against Fgf21 resistance is unknown. This study aims to determine the effects of HSE on the expression of miR-34a and Fgf21 receptors in white adipose tissue. Methods This experimental study used 24 male Sprague-Dawley rats and divided into four groups: Control (N); diet-induced-obesity rats (DIO); DIO rats with HSE 200 mg/kgBW/day and DIO rats with HSE 400 mg/kgBW/day. Rats were fed a high-fat diet for 17 weeks. HSE was administered daily for five weeks. The administration of HSE 400 mg/kg BW/day resulted in the equivalent expression of miR-34a to that of the control (p > 0.05). Results Fgfr1 receptor expression was also similar to controls (p > 0.05). Beta-klotho expression was significantly lower than that of Control (p < 0.05) but equivalent to that of DIO rats (p < 0.05). Conclusions H. sabdariffa has the potential to reduce Fgf21 resistance in DIO rats through the suppression of miR-34a expression and an increase in the number of Fgfr1 and beta-klotho receptors in adipose tissue.

Angiotensin receptors and angiotensin I-converting enzyme in rat intestine

1989 ◽  
Vol 257 (4) ◽  
pp. G504-G510 ◽  
Author(s):  
K. A. Duggan ◽  
F. A. Mendelsohn ◽  
N. R. Levens
Keyword(s):  
Binding Sites ◽  
Subsequent Development ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Sprague Dawley ◽  
Rat Intestine ◽  
Angiotensin I Converting Enzyme ◽  
Sprague Dawley Rats

The purpose of this study was to map the distribution of angiotensin II (ANG II) receptors and ANG I-converting enzyme (ACE) in rat intestine. ANG II binding sites were visualized by in vitro autoradiography using iodinated [Sar1, Ile8]ANG II. The distribution of ACE was mapped using an iodinated derivative of lisinopril. Male Sprague-Dawley rats were killed and the interior of the whole intestine washed with ice-cold saline. Segments of duodenum, jejunum, ileum, and colon were quickly frozen in a mixture of isopentane and dry ice. Twenty-micron frozen sections were thaw-mounted onto gelatin-coated slides, incubated with either ligand, and exposed to X-ray film. After exposure and subsequent development, the films were quantitated by computerized densitometry. ANG II receptors were most dense in the colon, followed by the ileum, duodenum, and jejunum. Within each segment of intestine, specific ANG II binding sites were localized exclusively to the muscularis. In contrast, ACE was present in both the mucosa and the muscularis. The colocalization of ANG II receptors and ACE may suggest a role for locally generated ANG II in the control of intestinal function. The luminal orientation of ACE in the mucosa of the small intestine may suggest that at this site ACE serves primarily to hydrolyze dietary peptides.

Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats

2003 ◽  
Vol 95 (4) ◽  
pp. 1499-1508 ◽  
Author(s):  
Michelle McGuire ◽  
Yi Zhang ◽  
David P. White ◽  
Liming Ling
Keyword(s):  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Freely Behaving ◽  
Long Term Facilitation ◽  
Awake Rats

This study examined the effect of chronic intermittent hypoxia (CIH: 5 min 11-12% O2/5 min air, 12 h/night, 7 nights) on ventilatory long-term facilitation (LTF) and determined the persistence period of this CIH effect in awake rats. LTF, elicited by 5 or 10 episodes of 5 min 12% O2, was measured four times in the same Sprague-Dawley rats by plethysmography, before and 8 h, 3 days, and 7 days after CIH treatment. Resting ventilation was unchanged after CIH. Five episodes of 12% O2 did not initially elicit LTF but elicited LTF (23.5 ± 1.4% above baseline) 8 h after CIH, which partially remained at 3 days (11.4 ± 2.2%, P < 0.05) and disappeared at 7 days. Ten episodes initially elicited LTF (17.7 ± 1.1%, 45-min duration) and elicited an enhanced LTF (29.1 ± 1.5%, 75 min) 8 h after CIH. These results demonstrated that CIH enhanced ventilatory LTF in conscious, freely behaving rats in two ways: 1) a previously ineffective protocol induced LTF; and 2) LTF magnitude was increased and LTF duration prolonged, and this CIH effect on LTF persisted for at least 3 days.

Chronic intermittent hypoxia-induced vascular enlargement and VEGF upregulation in the rat carotid body is not prevented by antioxidant treatment

2011 ◽  
Vol 301 (5) ◽  
pp. L702-L711 ◽  
Author(s):  
Rodrigo Del Rio ◽  
Cristian Muñoz ◽  
Paulina Arias ◽  
Felipe A. Court ◽  
Esteban A. Moya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ascorbic Acid ◽  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Vessel Diameter ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Antioxidant Treatment ◽  
Sprague Dawley Rats ◽  
Vascular Area

Chronic intermittent hypoxia (CIH), a characteristic of sleep obstructive apnea, enhances carotid body (CB) chemosensory responses to hypoxia, but its consequences on CB vascular area and VEGF expression are unknown. Accordingly, we studied the effect of CIH on CB volume, glomus cell numbers, blood vessel diameter and number, and VEGF immunoreactivity (VEGF-ir) in male Sprague-Dawley rats exposed to 5% O2, 12 times/h for 8 h or sham condition for 21 days. We found that CIH did not modify the CB volume or the number of glomus cells but increased VEGF-ir and enlarged the vascular area by increasing the size of the blood vessels, whereas the number of the vessels was unchanged. Because oxidative stress plays an essential role in the CIH-induced carotid chemosensory potentiation, we tested whether antioxidant treatment with ascorbic acid may impede the vascular enlargement and the VEGF upregulation. Ascorbic acid, which prevents the CB chemosensory potentiation, failed to impede the vascular enlargement and the increased VEGF-ir. Thus present results suggest that the CB vascular enlargement induced by CIH is a direct effect of intermittent hypoxia and not secondary to the oxidative stress. Accordingly, the subsequent capillary changes may be secondary to the mechanisms involved in the neural chemosensory plasticity induced by intermittent hypoxia.

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