Effect of chronic intracerebroventricular dexamethasone on blood pressure in normotensive rats

Tonolo, Giancarlo; Soro, A; Madeddu, Paolo; Troffa, Chiara; Melis, Maria Grazia; Patteri, G.; Parpaglia, Paolo Pinna; Sabino, Giuseppe; Maioli, Mario; Glorioso, Nicola

doi:10.1152/ajpendo.1993.264.6.e843

Cited by 17 publications

(17 citation statements)

References 22 publications

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“…This indicates that the long-term genomic effect of DEX on TH occurs mainly in the periphery, including adrenal medulla and other sympathetic nerve terminals. Had DEX crossed into the brain, its effects on blood pressure may have been opposite, based on the report that intracerebroventricular injection of DEX reduces blood pressure (Tonolo et al, 1993). We never observed a decrease in blood pressure during the entire period of DEX administration, consistent with peripheral, not central effects.…”

Section: Discussionsupporting

confidence: 47%

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

Soto‐Piña

Franklin

Rani

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, a-methyl-paratyrosine (a-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative realtime polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by 115.0 6 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and a-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine 40 ) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.

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Section: Discussionsupporting

confidence: 47%

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

Soto‐Piña

Franklin

Rani

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Several previous studies have investigated the contribution of centrally acting glucocorticoids to baseline arterial pressure regulation using acute microinjection and chronic infusion of receptor agonists or antagonists in the cerebral ventricals (15,49,51,53,54). In the brain, Cort binds to two primary receptor subtypes: the low-affinity but selective GR and the mineralocorticoid receptor (MR), which binds both glucocorticoids and mineralocorticoids with high affinity (10).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate

Bechtold¹,

Scheuer²

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Bechtold, Andrea G., and Deborah A. Scheuer. Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate. Am J Physiol Regul Integr Comp Physiol 290: R1003-R1011, 2006. First published November 3, 2005 doi:10.1152/ajpregu.00345.2005.-Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 Ϯ 2 mmHg) relative to both DHB Sham (108 Ϯ 3 mmHg) and Dura Cort rats (109 Ϯ 2 mmHg, P Ͻ 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 Ϯ 2 mmHg) compared with DHB Sham (105 Ϯ 2 mmHg) and Dura Cort animals (106 Ϯ 2 mmHg, P Ͻ 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 Ϯ 0.12 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 ) relative to DHB Sham and Dura Cort rats (3.51 Ϯ 0.28 and 3.37 Ϯ 0.27 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 , P Ͻ 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function. corticosterone; nucleus of the solitary tract; glucocorticoid receptors; brain; stress ELEVATED GLUCOCORTICOIDS INCREASE the risk for cardiovascular disease (13,20,46,58,59). Accumulating evidence further indicates that altered glucocorticoid activity or sensitivity, even in the absence of elevated plasma glucocorticoid levels, may play a role in the etiology of human essential hypertension, a primary risk factor for cardiovascular disease (27,47,56,57). Altered glucocorticoid activity has also been implicated in the pathogenesis of metabolic syndrome, a condition whose symptoms include obesity, elevated blood pressure, and insulin resistance or diabetes (55). Genetic factors appear to increase sensitivity to the adverse cardiovascular effects of glucocorticoids, since several recently identified polymorphisms of the human glucocorticoid receptor (GR) gene have been linked to hypertension and cardiovascular disease (25,26,34,35). Complementing the data from humans, a glucocorticoid-dependent mechanism of hypertension has been demonstrated in several rat strains, including s...

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“…The results from these experiments demonstrate that chronic elevations in DHB glucocorticoid levels increase arterial pressure and that chronic blockade of DHB GRs decreases arterial pressure in rats with glucocorticoid-induced elevations in blood pressure. Existing information regarding the effects of glucocorticoids on CNS regulation of blood pressure is sparse and is based almost entirely on the results of intracerebroventricular administration of glucocorticoid agonists and antagonists (21,58,60,64 (34), produced small reductions in arterial pressure of highly variable onset and duration (64). Our results are not in agreement with some of these previous studies that have suggested that activation of GRs in the CNS leads to a reduction in arterial pressure.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known regarding the effects of glucocorticoids on central nervous system (CNS) regulation of blood pressure. Several investigators have administered glucocorticoid agonists by intracerebroventricular infusion (21,60) or a single injection (58,64) and measured arterial pressure, but the results have been inconsistent. No studies have combined chronic delivery of glucocorticoids or GR antagonists to specific areas in the CNS with the measurement of blood pressure or heart rate.…”

mentioning

confidence: 99%

Glucocorticoids act in the dorsal hindbrain to increase arterial pressure

Scheuer¹,

Bechtold²,

Shank³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P Ͻ 0.05) mean arterial pressure (111 Ϯ 2 vs. 104 Ϯ 1 mmHg) and heart rate (355 Ϯ 9 vs. 326 Ϯ 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P Ͻ 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 Ϯ 2 vs. 108 Ϯ 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.corticosterone; nucleus of the solitary tract; brain; hypertension GLUCOCORTICOIDS ARE IMPORTANT for the maintenance of normal baseline arterial pressure in both rats and humans. Adrenal insufficiency or blockade of type II glucocorticoid receptors (GRs) can lower blood pressure (18,22,61). The effects of adrenalectomy to lower blood pressure can be reversed by glucocorticoid, but not mineralocorticoid, replacement (61). It is also established that elevated glucocorticoids produce doserelated increases in arterial pressure, and sufficiently high levels of glucocorticoids, due to either exogenous administration or endogenous overproduction, cause hypertension in both experimental animals and humans (22,43,44,54). Long-term administration of glucocorticoids, commonly prescribed because of their anti-inflammatory and immunosupressive therapeutic effects, results in a 20% incidence of iatrogenic hypertension (23). There is also increasing evidence that prolonged mild elevations in glucocorticoids or increased sensitivity to the actions of glucocorticoids promote the development and maintenance of essential hypertension. Several studies have reported elevations in plasma and/or urinary glucocorticoids in essential hyperte...

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Effect of chronic intracerebroventricular dexamethasone on blood pressure in normotensive rats

Cited by 17 publications

References 22 publications

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate

Glucocorticoids act in the dorsal hindbrain to increase arterial pressure

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