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

Soto‐Piña, Alexandra Estela; Franklin, Cynthia; Rani, C. S. Sheela; Gottlieb, Helmut; Hinojosa‐Laborde, Carmen; Strong, Randy

doi:10.1124/jpet.116.234005

Cited by 12 publications

(8 citation statements)

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“…Dexamethasone (Dex) is a synthetic glucocorticoid that has been widely used to treat various diseases such as autoimmune diseases and asthma [5,6]. Hypertension is a common side effect of chronic Dex usage [7]. Dex administration could induce hypertension via multiple mechanisms such as induction of oxidative stress, downregulation of cationic amino acid transporter-1, downregulation of eNOS and reduction of NO [8].…”

Section: Introductionmentioning

confidence: 99%

Piper sarmentosum attenuates dexamethasone-induced hypertension by stimulating endothelial nitric oxide synthase

Ugusman¹,

Fadze²,

Hamid³

et al. 2020

jrp

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Reduced endothelial nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) in the vasculature is a feature of endothelial dysfunction. Dexamethasone causes secondary hypertension by inhibiting eNOS activity. Piper sarmentosum is an herb with anti-hypertensive effect. The aim of this study was to evaluate the antihypertensive effect of aqueous extract of P. sarmentosum (AEPS) in dexamethasone (Dex)-induced hypertensive rats. A total of 30 male Sprague Dawley rats were divided into five groups including control, AEPS (500 mg/kg/day, orally), Dex (20 μg/kg/day, subcutaneously), Dex (20 μg/kg/day) + AEPS (500 mg/kg/day) and Dex (20 μg/kg/day) + captopril (40 mg/kg/day, orally). Blood pressure was measured using tail-cuff method at baseline and fortnightly thereafter. The rats were sacrificed and the serum was collected to quantify the amount of NO after 28 days of treatment. Aortic samples were homogenized for measurement of eNOS mRNA expression, protein level and activity. Treatment of Dex-induced hypertensive rats with AEPS lowered systolic blood pressure (P < 0.001) and diastolic blood pressure (P < 0.01), increased eNOS mRNA expression (P < 0.01), eNOS protein (P < 0.01), eNOS activity (P < 0.05) and NO level (P < 0.05). In conclusion, AEPS reduces the blood pressure of Dex-induced hypertensive rats as it shows positive effects on eNOS and NO production.

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Section: Introductionmentioning

confidence: 99%

Piper sarmentosum attenuates dexamethasone-induced hypertension by stimulating endothelial nitric oxide synthase

Ugusman¹,

Fadze²,

Hamid³

et al. 2020

jrp

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“…This experimental metabolic model is already well characterized as being associated with a decrease in body weight [ 10 ]; an increase of glycemia and insulinemia [ 11 , 12 ] which mark the presence of an insulin resistance; a loss in muscle mass associated with liver hypertrophy [ 10 ]; an alteration of protein [ 13 ]; and lipid profiles [ 14 ]. Besides metabolic changes, some cardiovascular alterations have also been described in this model such as arterial hypertension associated with an increased oxidative stress [ 15 , 16 ] and cardiac hypertrophy [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoglycemic Properties of the Aqueous Extract from the Stem Bark of Ceiba pentandra in Dexamethasone‐Induced Insulin Resistant Rats

Fofié

Nguelefack‐Mbuyo

Tsabang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Parts of Ceiba pentandra are wildly used in Africa to treat diabetes and previous works have demonstrated their in vivo antidiabetic effects on type 1 diabetes models. In addition, it has been recently shown that the decoction and the methanol extract from the stem bark of C. pentandra potentiate in vitro, the peripheral glucose consumption by the liver and skeletal muscle slices. But nothing is known about its effect on type II diabetes, especially on insulin resistance condition. We investigated herein the antihyperglycemic, insulin-sensitizing potential, and cardioprotective effects of the dried decoction from the stem bark of Ceiba pentandra (DCP) in dexamethasone-induced insulin resistant rats. DCP phytochemical analysis using LC-MS showed the presence of many compounds, including 8-formyl-7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4-naphthaquinone, 2,4,6-trimethoxyphenol, and vavain. Wistar rats were given intramuscularly (i.m.) dexamethasone (1 mg/kg/day) alone or concomitantly with oral doses of DCP (75 or 150 mg/kg/day) or metformin (40 mg/kg/day) for 9 days. Parameters such as body weight, glycemia, oral glucose tolerance, plasma triglycerides and cholesterol, blood pressure, and heart rate were evaluated. Moreover, cardiac, hepatic and aortic antioxidants (reduced glutathione, catalase, and superoxide dismutase), malondialdehyde level, and nitric oxide content were determined. DCP decreased glycemia by up to 34% and corrected the impairment of glucose tolerance induced by dexamethasone but has no significant effect on blood pressure and heart rate. DCP reduced the total plasma cholesterol and triglycerides as compared to animals treated only with dexamethasone. DCP also increased catalase, glutathione, and NO levels impaired by dexamethasone, without any effect on SOD and malondialdehyde. In conclusion, the decoction of the stem bark of Ceiba pentandra has insulin sensitive effects as demonstrated by the improvement of glucose tolerance, oxidative status, and plasma lipid profile. This extract may therefore be a good candidate for the treatment of type II diabetes.

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“…The radiotelemetry implant was performed as before (Soto-Piña et al, 2016) using an aseptic procedure. After the 5-day acclimation period, rats underwent inhaled anesthesia with (2% isoflurane in oxygen), the abdominal aorta was exposed and two clamps were made to prevent bleeding, one underneath the renal artery and another above the iliac arteries.…”

Section: Methodsmentioning

confidence: 99%

“…To date the role of the peripheral sympathetic nervous system in hypertension induced by synthetic GCs under chronic conditions is unknown. In a previous study, the administration of the TH inhibitor, alpha-methyl-para-tyrosine (αMPT), reduced the pressor effect of DEX in a model of hypertension induced by this GC (Soto-Piña et al, 2016). However, it was not clear whether the influence was on the adrenal medulla and/or sympathetic nerves.…”

Section: Introductionmentioning

confidence: 99%

“…As an alternative, we hypothesize that the adrenal medulla, which is a major source of plasma catecholamines, plays a role in DEX-induced hypertension. We recently showed that chronic DEX administration, in addition to increasing MAP, induces the transcription of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, in the rat adrenal medulla (Soto-Piña et al, 2016). At the molecular level, the mechanism of DEX regulation of TH transcription through the GR involves an atypical GC-responsive element in the TH promoter region (Rani et al, 2009, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves

et al. 2019

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Synthetic glucocorticoids (GCs) are widely used to treat inflammatory conditions. However, chronic use of GCs can lead to hypertension. The cause of this undesired side effect remains unclear. Previously, we developed an in vivo rat model to study the mechanisms underlying hypertension induced by the chronic administration of the potent synthetic GC, dexamethasone (DEX) and found that the catecholamine biosynthetic pathway plays an important role. In the current study, we used this model to investigate the role of the adrenal medulla, renal nerves, and other peripheral sympathetic nerves in DEX-induced hypertension. After 5 days of baseline telemetric recording of mean arterial pressure (MAP) and heart rate (HR), rats were subjected to one of the following treatments: renal denervation (RDNX), adrenal medullectomy (ADMX), 6-hydroxydopamine (6-OHDA, 20 mg/kg, i.p.) to induce chemical sympathectomy, or a combination of ADMX and 6-OHDA. On day 11, the animals received vehicle (VEH) or DEX in drinking water for 7 days, with the latter causing an increase in MAP in control animals. ADMX and RDNX by themselves exacerbated the pressor effect of DEX. In the chemical sympathectomy group, DEX still caused a rise in MAP but the response was lower (ΔMAP of 6-OHDA/DEX < VEH/DEX, p = 0.039). However, when ΔMAP was normalized to day 10, 6-OHDA + DEX did not show any difference from VEH + DEX, certainly not an increase as observed in DEX + ADMX or RDNX groups. This indicates that sympathetic nerves do not modulate the pressor effect of DEX. TH mRNA levels increased in the adrenal medulla in both VEH/DEX (p = 0.009) and 6-OHDA/DEX (p = 0.031) groups. In the 6-OHDA group, DEX also increased plasma levels of norepinephrine (NE) (p = 0.016). Our results suggest that the activation of catecholamine synthetic pathway could be involved in the pressor response to DEX in animals even under chemical sympathectomy with 6-OHDA.

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

Cited by 12 publications

References 70 publications

Piper sarmentosum attenuates dexamethasone-induced hypertension by stimulating endothelial nitric oxide synthase

Piper sarmentosum attenuates dexamethasone-induced hypertension by stimulating endothelial nitric oxide synthase

Hypoglycemic Properties of the Aqueous Extract from the Stem Bark of Ceiba pentandra in Dexamethasone‐Induced Insulin Resistant Rats

Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves

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