MVD for Neurogenic Hypertension: A Review

Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.

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Brain-Selective Overexpression of Human Angiotensin-Converting Enzyme Type 2 Attenuates Neurogenic Hypertension

Circulation Research ◽

10.1161/circresaha.109.208645 ◽

2010 ◽

Vol 106 (2) ◽

pp. 373-382 ◽

Cited By ~ 134

Author(s):

Yumei Feng ◽

Huijing Xia ◽

Yanhui Cai ◽

Carmen M. Halabi ◽

Lenice K. Becker ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Neurogenic Hypertension

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Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00317.2013 ◽

2013 ◽

Vol 305 (3) ◽

pp. H403-H409 ◽

Cited By ~ 9

Author(s):

Amanda L. Sharpe ◽

Mary Ann Andrade ◽

Myrna Herrera-Rosales ◽

Steven L. Britton ◽

Lauren G. Koch ◽

...

Keyword(s):

Sleep Apnea ◽

Aerobic Capacity ◽

Intermittent Hypoxia ◽

Chronic Intermittent Hypoxia ◽

Neurogenic Hypertension ◽

Body Weights ◽

Aerobic Exercise Capacity ◽

Chemical Inhibition ◽

Ganglionic Transmission ◽

Selection Of

Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14–16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity.

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Abstract 73: Nanoformulated Copper/Zinc Superoxide Dismutase: Alternative Therapeutic Strategy for Angiotensin II-dependent Neurogenic Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a73 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Krupa K Savalia ◽

Devika S Manickam ◽

Erin G Rosenbaugh ◽

Jun Tian ◽

Iman Ahmad ◽

...

Keyword(s):

Superoxide Dismutase ◽

Angiotensin Ii ◽

Therapeutic Potential ◽

Therapeutic Option ◽

In Vivo Studies ◽

Neuronal Uptake ◽

Neurogenic Hypertension ◽

Copper Zinc Superoxide Dismutase ◽

Zinc Superoxide Dismutase ◽

Copper Zinc

Excessive production of superoxide (O2•-) in the central nervous system has been widely implicated in the pathogenesis of angiotensin II (AngII)-dependent neurogenic hypertension (HTN). Our group has tried to overcome the failed therapeutic potential of currently available antioxidants by utilizing nanoformulated copper/zinc superoxide dismutase (SOD1), so-called SOD1 nanozymes, that specifically scavenges intracellular O2•-. These nanozymes consist of SOD1 protein wrapped with cationic block copolymers followed by covalent cross-linking of the polycation template (cl-nano). We hypothesize that cl-nano delivers active SOD1 protein to neurons and can effectively decrease blood pressure in a mouse model of AngII-dependent neurogenic HTN. As determined by electron paramagnetic resonance (EPR) spectroscopy, cl-nano retains SOD1 activity and scavenges O2•- to levels comparable with native SOD1 protein in a cell-free environment (EPR arbitrary units: vehicle 1.12e6 ± 1.79e5; native SOD1 protein 4.45e4 ± 3.00e3; cl-nano 6.78e4 ± 1.74e3, p<0.05 vs. vehicle). Experiments to examine neuronal uptake of cl-nano, analyzed by western blot and SOD1 activity assays, reveal that cl-nano delivers active SOD1 to central neurons in culture (CATH.a neurons) more efficiently than native SOD1 protein following 1 hour treatment (SOD1 activity in units/mg protein: vehicle 336; native SOD1 protein 313; cl-nano 718). Furthermore, in vivo studies demonstrate that HTN established by chronic subcutaneous infusion of AngII (400 ng/kg/min) is significantly attenuated following a single intracerebroventricular (ICV) injection of cl-nano for up to 7 days (mean arterial pressure (MAP) in mmHg: pre-AngII 87 ± 3; 9 days post-AngII 138 ± 6; 7 days post-ICV injection of cl-nano 112 ± 4, p<0.05 vs. pre-ICV injection). These data provide evidence for the efficacy of nanoformulated SOD1 in counteracting excessive O2•- and decreasing MAP in AngII-dependent hypertensive mice when injected directly into the brain. Although further experiments must be performed with more clinically relevant routes of cl-nano administration, such as intravenous injection, this study supports the further development of cl-nano with SOD1 as an alternative therapeutic option for HTN.

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Urinary Kallikrein Excretion in Neurogenic Hypertension in the Dogs : Possible Relationship between Kallikrein Excretion and Catecholamines

Advances in Experimental Medicine and Biology - Kinins V ◽

10.1007/978-1-4615-9546-5_72 ◽

1989 ◽

pp. 437-442

Author(s):

Philippe Valet ◽

Jean-Loup Bascands ◽

Christiane Pécher ◽

Jean-Pierre Moatti ◽

Jean-Louis Montastruc ◽

...

Keyword(s):

Urinary Kallikrein ◽

Neurogenic Hypertension ◽

Urinary Kallikrein Excretion

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Effect of Baroreceptor Deafferentation on Central Catecholamines in the Rat

Clinical Science ◽

10.1042/cs057221s ◽

1979 ◽

Vol 57 (s5) ◽

pp. 221s-223s ◽

Cited By ~ 1

Author(s):

Margaret A. Petty ◽

J. P. Chalmers ◽

M. Brown ◽

J. L. Reid

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Tyrosine Hydroxylase ◽

Brain Stem ◽

Hydroxylase Activity ◽

Methyltransferase Activity ◽

Neurogenic Hypertension ◽

Noradrenaline Synthesis ◽

Noradrenaline And Adrenaline ◽

Sympathetic Efferent Activity

1. Sinoaortic deafferentation in the rat leads to increased blood pressure and heart rate. 2. Early increases in tyrosine hydroxylase activity both in brain stem and hypothalamus suggest that increased noradrenaline synthesis may contribute to the development of neurogenic hypertension. 3. After 4 weeks, phenylethanolamine-N-methyltransferase activity was reduced in the hypothalamus. 4. Noradrenaline- and adrenaline, but not dopamine-containing neurones may participate in regulation of sympathetic efferent activity.

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