11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Hypothalamic Paraventricular Nucleus Modulates Sympathetic Excitation

Zhang, Zhihua; Kang, Yu‐Ming; Yu, Yang; Wei, Shun-Guang; Schmidt, Thomas J.; Johnson, Alan Kim; Felder, Robert B.

doi:10.1161/01.hyp.0000224296.96235.dd

Cited by 70 publications

(57 citation statements)

References 43 publications

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“…Inhibition of 11b-HSD2 by carbenoxolone was shown to enhance the heart rate in rats (Zhang et al 2006). Furthermore, urinary catecholamine levels were double in 11b-Hsd2 K/K mice (Bailey et al 2008).…”

Section: Discussionmentioning

confidence: 96%

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

Lauterburg¹,

Escher²,

Dick³

et al. 2012

Journal of Endocrinology

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Renal allograft donors are at risk of developing hypertension. Here, we hypothesized that this risk is at least in part explained by an enhanced intracellular availability of 11b-hydroxyglucocorticoids due to an increased 11b-hydroxysteroid dehydrogenase type 1 enzyme (11b-HSD1), an intracellular prereceptor activator of biologically inactive 11-ketocorticosteroids in the liver, and/or a diminished 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2), an inactivator of 11b-hydroxyglucocorticoids in the kidney. To test this hypothesis, uninephrectomized (UNX) (nZ9) and sham-operated (nZ10) adult SpragueDawley rats were investigated. Mean arterial blood pressure and heart rate were measured continuously by telemetry for 6 days in week 5 after UNX. The mRNA of 11b-Hsd1 and 11b-Hsd2 in liver and kidney tissues were assessed by RT-PCR and the 11b-HSD activities were directly quantified in their corresponding tissues by determining the ratios of (tetrahydrocorticosteroneC5a-tetrahydrocorticosterone)/ tetrahydrodehydrocorticosterone ((THBC5a-THB)/THA) and of corticosterone/dehydrocorticosterone (B/A) by gas chromatography-mass spectrometry. The apparent total body activities of 11b-HSD1 and 11b-HSD2 were estimated using the urinary and plasma ratios of (THBC5a-THB)/THA and B/A. Mean arterial blood pressure was increased after UNX when compared with sham operation. Hepatic mRNA content of 11b-Hsd1 and hepatic, plasma, and urinary ratios of (THBC5a-THB)/THA were decreased after UNX, indicating diminished access of glucocorticoids to its receptors. In renal tissue, 11b-Hsd2 mRNA was reduced and B/A ratios measured in kidney, plasma, and urine were increased, indicating reduced 11b-HSD2 activity and enhanced access of glucocorticoids to mineralocorticoid receptors. Both 11b-HSD1 and 11b-HSD2 are downregulated after UNX in rats, a constellation considered to induce hypertension.

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Section: Discussionmentioning

confidence: 96%

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

Lauterburg¹,

Escher²,

Dick³

et al. 2012

Journal of Endocrinology

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“…3,18,27 There are reports suggesting that ROS in the brain might mediate the Ang II-induced pressor effect. 8 -12,18,19,26 11-␤-hydroxysteroid dehydrogenase type 2 28 and the epithelial sodium channel, etc, could be involved in sympathoexcitation in salt-sensitive hypertension. 26 However, the involvement and interaction of these factors have not been established.…”

Section: Discussionmentioning

confidence: 99%

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

et al. 2007

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Abstract-Central sympathoexcitation is involved in the pathogenesis of salt-sensitive hypertension. We have suggested that oxidative stress in the brain modulates the sympathetic regulation of arterial pressure. Thus, we investigated whether oxidative stress could mediate central sympathoexcitation in salt-sensitive hypertension. Five-to 6-week-old male Dahl salt-sensitive rats and salt-resistant rats were fed with a normal (0.3%) or high-(8%) salt diet for 4 weeks. In urethane-anesthetized and artificially ventilated rats, arterial pressure, renal sympathetic nerve activity, and heart rate decreased in a dose-dependent fashion, when 20 or 40 mol of tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. The same degree of reduction was noted in salt-sensitive and salt-resistant rats without salt loading. Salt loading significantly increased central tempol-induced reductions in arterial pressure (Ϫ29.1Ϯ4.8% versus Ϫ10.6Ϯ3.3% at 40 mol; PϽ0.01), sympathetic nerve activity (Ϫ18.7Ϯ2.0% versus Ϫ7.1Ϯ1.8%; PϽ0.01), and heart rate (Ϫ10.7Ϯ2.8% versus Ϫ2.0Ϯ0.7%; PϽ0.05) in salt-sensitive rats but not in salt-resistant rats. Intracerebroventricular diphenyleneiodonium, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, also elicited significantly greater reduction in each parameter in salt-loaded salt-sensitive rats. Moreover, salt loading increased reduced nicotinamide-adenine dinucleotide phosphate-dependent superoxide production in the hypothalamus in salt-sensitive rats but not in salt-resistant rats. In addition, reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits p22 phox , p47 phox , and gp91 phox mRNA expression significantly increased in the hypothalamus of salt-loaded salt-sensitive rats. In conclusion, in salt-sensitive hypertension, increased oxidative stress in the brain, possibly via activation of reduced nicotinamide-adenine dinucleotide phosphate oxidase, may elevate arterial pressure through central sympathoexcitation. Key Words: salt-sensitive hypertension Ⅲ oxidative stress Ⅲ brain Ⅲ hypertension Ⅲ salt Ⅲ sympathetic nervous system Ⅲ Dahl rat S ubstantial findings indicate that abnormal modulation of the sympathetic nervous system may be involved in salt-induced development of hypertension in humans 1 and animals. [2][3][4][5][6] In our previous study, 2 salt loading impaired the arterial baroreceptor reflex associated with abnormal central properties in spontaneously hypertensive rats (SHRs); the sympathetic nerve activity (SNA) was less inhibited by stimulation of the aortic depressor nerve in salt-loaded SHRs. However, salt loading did not affect the SNA in Wistar-Kyoto rats. Similarly, the SNA was augmented with salt loading in Dahl salt-sensitive rats (DSs), but not in Dahl salt-resistant rats (DRs). 3 Intracerebroventricular (ICV) infusion of sodium caused sympathoexcitatory and pressor responses to a greater degree in DSs than in DRs. 4 Thus, central sympathetic activation may be involved in salt-sensitive ...

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“…Aldosterone and corticosterone can be synthesized in the brain (11,12,24). Aldosterone and corticosterone bind MR with equal affinity (3), but the presence of the corticosterone-inactivating enzyme 11␤-HSD-2 enhances aldosterone selectivity of the MR in brain regions where it is expressed, such as the paraventricular nucleus of the hypothalamus (34).…”

mentioning

confidence: 99%

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

Huang¹,

White²,

Jeng³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [Na ϩ ] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ϳ35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ϳ65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [Na ϩ ]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dahl S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension.brain; corticosterone; high-salt diet IN DAHL SALT-SENSITIVE (S) rats, high salt intake increases cerebrospinal fluid (CSF) Na ϩ concentration ([Na ϩ ]) and causes sympathetic hyperactivity and hypertension (19). Saltinduced sympathetic hyperactivity and hypertension can be prevented by central blockade of steroid biosynthesis by the steroid synthase 3␤-hydroxysteroid dehydrogenase (HSD) inhibitor trilostane (14) or central blockade of mineralocorticoid receptors (MR) (13).The agonist binding to the MR in the central nervous system (CNS) has not been defined, nor has its origin, i.e., whether it is derived from the circulation or locally produced, been determined. Inasmuch as central infusion of trilostane has antihypertensive effects (14), it appears that local production of a steroid in the CNS plays a major role. However, trilostane blocks the synthesis not only of the mineralocorticoid hormone aldosterone but also of the glucocorticoid hormone corticosterone (14, 24). Aldosterone and corticosterone can be synthesized in the brain (11,12,24). Aldosterone and corticosterone bind MR with equal affinity (3), but the presence of the corticosterone-inactivating enzyme 11␤-HSD-2 enhances aldosterone selectivity of the MR in brain regions where it is expressed, such as the paraventricular nucleus of the hypothalamus (34).There is no evidence that, in Dahl S rats, high salt intake actually increases aldosterone or corticosterone production and release in brain regions implicated in sympathetic regulation or, alternatively, causes changes in MR or 11␤-HSD-2 expression. FAD286 is a specific aldosterone synthase (CYP11B2) blocker that appears to have no effects on corticosterone synthesis (25). Oral administration...

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11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Hypothalamic Paraventricular Nucleus Modulates Sympathetic Excitation

Cited by 70 publications

References 43 publications

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

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