Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla

Ciriello, John; Li, Zhaohui; Oliveira, Cleusa V.R. de

doi:10.1016/j.brainres.2003.08.008

Cited by 71 publications

(58 citation statements)

References 42 publications

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“…25 Indeed, orexin is capable of increasing HR by indirect vagal inhibition. 26 However, it is unclear from the present findings, how much of the bradycardic effect of almorexant in BPH/2J mice is because of a decrease in SNS activity compared with an increase in vagal activity.…”

Section: Effect Of Almorexant On Hrcontrasting

confidence: 54%

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

et al. 2016

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BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...

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Section: Effect Of Almorexant On Hrcontrasting

confidence: 54%

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

et al. 2016

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“…Another line of evidence comes from microinjection studies assessing the role of ORX in sympathetic regions, such as the rostro-ventrolateral medulla (RVLM) that is innervated with ORX-containing fibers and express ORX 1 and 2 receptors (Ferguson and Samson, 2003). Pressor responses, elicited by disinhibition of the DMH region containing ORX neurons, appear to be mediated via the RVLM (Fontes et al, 2001), and injecting ORX directly into the RVLM elicits tachycardia (Chen et al, 2000, Ciriello et al, 2003 and hypertension (Chen et al, 2000;Machado et al, 2002, Ciriello et al, 2003.…”

Section: Orx's Role In Hypercapnia-induced Pressor Responsesmentioning

confidence: 99%

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Johnson

Samuels

Fitz

et al. 2012

Neuropsychopharmacol

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Acute hypercapnia (elevated arterial CO 2 /H + ) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO 2 /H + , and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood-brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of COPD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO 2 /normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO 2 challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as COPD.

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“…When administered intracisternally or directly into the ventrolateral medulla, orexin dose dependently increases blood pressure and heart rate in the anesthetized rat Ciriello et al, 2003a). It was shown in these experiments that orexin-A and its receptor were present in the areas of the ventrolateral medulla that yielded the largest cardioacceleratory responses (Ciriello et al, 2003a).…”

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confidence: 96%

Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function

2005

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Orexin-expressing neurons in the hypothalamus project throughout the neuraxis and are involved in regulation of the sleep/wake cycle, food intake, and autonomic functions. Here we specifically analyze the anatomical organization of orexin projections to the dorsal vagal complex (DVC) and raphe pallidus and effects on ingestive behavior and autonomic functions of local orexin-A administration in nonanesthetized rats. Retrograde tracing experiments revealed that as many as 20% of hypothalamic orexin neurons project to the DVC, where they form straight varicose axon profiles, some of which are in close anatomical apposition with tyrosine hydroxylase (TH)-, glucagon-like peptide-1-, gamma-aminobutyric acid-, and nitric oxide synthase-immunoreactive neurons in a nonselective manner. Similar contacts were frequently observed with neurons of the nucleus of the solitary tract whose activation by gastrointestinal food stimuli was demonstrated by the expression of nuclear c-Fos immunoreactivity. Orexin-A administration to the fourth ventricle induced significant Fos-expression throughout the DVC compared with saline control injections, with about 20-25% of TH-ir neurons among the stimulated ones. Fourth ventricular orexin injections also significantly stimulated chow and water intake in nonfood-deprived rats. Direct bilateral injections of orexin into the DVC increased intake of palatable high-fat pellets. Orexin-ir fibers also innervated raphe pallidus. Fourth ventricular orexin-A (1 nmol) activated Fos expression in the raphe pallidus and C1/A1 catecholaminergic neurons in the ventral medulla and increased body temperature, heart rate, and locomotor activity. The results confirm that hypothalamomedullary orexin projections are involved in a variety of physiological functions, including ingestive behavior and sympathetic outflow.

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Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla

Cited by 71 publications

References 42 publications

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function

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