Central Regulation Of Blood Pressure Research Articles

Effects of AGT and AGTR1 Genetic Polymorphisms and Changes in Blood Pressure Over a Five-Year Follow-Up.

The renin-angiotensin system plays an important role in the central regulation of blood pressure (BP). Genetic variations of angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1) may increase susceptibility to elevated BP and hypertension. This study investigated the effects of AGT rs699 and AGTR1 rs5186 single nucleotide polymorphisms (SNPs) on BP at baseline and at a 5-year follow-up. The study population consisted of participants from the Electricity Generating Authority of Thailand cohort study (n=354); data were collected at baseline (2013) and 5 years later (2018). Genotyping of the two SNPs was performed using TaqMan® assay and statistical analyses were performed with SNPStats software. The frequencies of the two SNPs were within the Hardy-Weinberg equilibrium (p=0.22 for AGT rs699 and p=0.06 for AGTR1 rs5186). For each SNP, mutant genotypes were significantly associated with increased systolic BP and/or diastolic BP in the codominant and recessive models. Risk alleles of AGT rs699 and AGTR1 rs5186 were associated with increased odds of hypertension and hypertension with metabolic syndrome at follow-up. Overall, our results suggest that polymorphisms of genes in the renin-angiotensin system increase susceptibility to the development and progression of hypertension and the development of the metabolic syndrome.

Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats.

Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.

Monocular transcorneal electrical stimulation induces ciliary muscle thickening in contralateral eye

Transcorneal electrical stimulation (TES) is used as therapy for retinal diseases such as retinitis pigmentosa (RP) and was suggested for assessing retinal sensitivity by determining phosphene thresholds, subjective luminance impressions caused by retinal stimulation. Further applications concerned the accommodation process, revealing an improved accommodative amplitude in presbyopic eyes after TES treatment. The respective changes of the ciliary muscle (CM), the structure most important for near vision, during TES are yet unknown. In a pilot study, we aimed to assess whether monocular TES leads to morphological and functional CM changes and whether central accommodation control is affected. Ten healthy, near-emmetropic adults participated in the trial (4 females, age 26.3 ± 3.6 years). Using a wavefront and a stimulus generator, a biphasic square-wave stimulus (2 s positive and 6 s negative amplitude) of 0 μA average current was produced and transferred to the eye by means of a Dawson-Trick & Litzkow electrode. Prior to the stimulation, an individual determination of phosphene thresholds served to define individual TES current amplitudes, which ranged between 60 and 100 μA. Optical coherence tomography (OCT) imaging of the right eye's temporal ciliary muscle was performed before and during ipsi- as well as contralateral monocular TES in randomized order in the morning and afternoon of the same day. During imaging, subjects fixated a target at 4 m distance and refraction was simultaneously recorded via eccentric infrared photorefraction. OCT images were assessed using previously published custom-developed software, allowing the definition of selective CM thickness (CMT) readings, and plotting of continuous CMT profiles along the muscle border. CMT profiles revealed that both stimulations, on the ipsi- and contralateral eye, induced a thickening of the CM compared to the non-stimulated state. The selective CMT readings confirmed a significant increase with ipsi- (31 ± 30 μm; p = 0.010) and contralateral (25 ± 16 μm; p = 0.001) TES. However, refraction during far vision was not significantly affected by either stimulation (ipsilateral [n = 5]: median Δw/-w/o = 0 D; contralateral [n = 7]: Δw/-w/o = 0.13 D). Pupil size on average increased during TES, but without reaching significance (ipsilateral [n = 5] median Δw/-w/o = 0.23 mm, contralateral [n = 7] Δw/-w/o = 0.39 mm). Ipsilateral CM thickening could be explained by local changes within the stimulated ciliary muscle, such as increased blood flow or interstitial fluid rise induced by TES. However, the CMT increase in the right eye when TES was performed contralaterally, on the left eye, indicates an involvement of the central control circuit of accommodation. Further possible explanations for this finding are a synchronization of neuronal activities in the visual pathway, the release of vasoactive neuropeptides, or effects on the central blood pressure regulation. Given a neuromodulation effect on the CM function, TES might have implications for children with accommodation insufficiencies and as additional therapy in myopia control management, e.g. in combination with multifocal contact lens treatment. Our study is important for the clinical application of TES, and the outcome might add crucial knowledge to the current understanding of the accommodation process and inform research and treatment of both myopia and presbyopia.

SIRT1 exerts anti-hypertensive effect via FOXO1 activation in the rostral ventrolateral medulla

The rostral ventrolateral medulla (RVLM) is a pivotal region in the central regulation of blood pressure (BP). It has been documented that silent information regulator 2 homolog 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent multifunctional transcription regulatory factor, has many cardiovascular protective effects. However, the role and significance of SIRT1 in the central regulation of cardiovascular activity, especially in RVLM, remains unknown. Therefore, the aim of this study was to explore the role and underlying mechanism of SIRT1 in the central regulation of cardiovascular activity in hypertension. Spontaneously hypertensive rats (SHRs) were given resveratrol (RSV) via intracerebroventricular (ICV) infusion or injected with SIRT1-overexpressing lentiviral vectors into the RVLM. In vitro experiments, angiotensin II (Ang II)-induced rat pheochromocytoma cell line (PC12 cells) were transfected with forkhead box protein O1 (FOXO1) small interfering RNA (siRNA) before treatment with RSV. Our results showed that SIRT1 activation with RSV or overexpression in the RVLM significantly decreased BP and sympathetic outflow of SHRs. Furthermore, SIRT1 overexpression in the RVLM significantly decreased reactive oxygen species (ROS) production and facilitated the forkhead box protein O1 (FOXO1) activation, accompanied by upregulation of the ROS-detoxifying enzyme superoxide dismutases 1 (SOD1) in the RVLM of SHRs. In PC12 cells, it was found that Ang II could induce oxidative stress and downregulate the SIRT1-FOXO1-SOD1 signaling pathway, which indicated that the suppressed expression of SIRT1 in the RVLM of SHRs might relate to the elevated central Ang II level. Furthermore, the enhanced oxidative stress and decreased SIRT1-FOXO1-SOD1 axis induced by Ang II were restored by treatment with RSV. However, these favorable effects mediated by SIRT1 activation were blocked by FOXO1 knockdown. Based on these findings, we concluded that SIRT1 activation or overexpression in the RVLM exerts anti-hypertensive effect through reducing oxidative stress via SIRT1-FOXO1-SOD1 signaling pathway, which providing a new target for the prevention and intervention of hypertension.

Associations of circulating irisin with 24-h blood pressure, total and visceral fat, and metabolic parameters in young adult hypertensives.

Some experimental and clinical studies suggest a possible role of irisin in central and peripheral regulation of blood pressure. The purpose of the study was to assess the associations between serum irisin levels, total and visceral fat, metabolic parameters, and blood pressure pattern during 24-h monitoring (ABPM). In 206 patients with essential hypertension receiving standard antihypertensive treatments, we assessed anthropometric indices; serum irisin, blood lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), glucose and insulin; body composition including lean mass and total, visceral, android and gynoid fat using a dual-energy x-ray absorptiometry; ABPM; and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). Baseline irisin levels were within normal reference ranges and comparable between the genders. There were no significant correlations of irisin with age, anthropometric variables, lipids, HOMA-IR, body composition, as well as 24-h blood pressure and dipping status. In univariate analysis, age, fat mass and distribution, lipids and glucose, HOMA-IR, and nocturnal blood pressure fall were poor predictors of irisin levels. These neutral associations were not affected by age, gender, and treatment modality. In young adult hypertensives, serum concentration of irisin was within a normal range and not associated with total and regional fat, blood lipids, insulin resistance, as well as 24-h blood pressure and the magnitude of its nocturnal fall.

Brainstem networkconnectivity with mid-anterior insula predicts lower systolic blood pressure at rest in older adults with hypertension.

Central regulation of heart rate and blood pressureprovides the bases for a neurogenic mechanism of hypertension (HTN). Post menopause (PM) age coincides with changes inresting state functional brain connectivity (rsFC) as well as increased risk for HTN. Whether the neural networks underpinning cardioautonomic control differ between PM women with and without HTN is unclear. Phenotypic and functional neuroimaging data from the Nathan Kline Institute was first evaluated for group differences in intrinsic network connectivity between 22 HTN post menopausal women and 22 normotensive controls. Intrinsic rsFC of the midbrain-brainstem-cerebellar network with bilateral mid-anterior insula was lower in women withHTN (FWE-corrected, p < 0.05). Z-scores indicating rsFCof these regions were extracted from the 44 PMwomen and a cohortof 111 adults, not presenting with metabolic or neurodegenerative disease, and compared to in-office systolic and diastolic blood pressure. Lower rsFC of theleft (r = -0.17, p = 0.019) and right (r = -0.14, p = 0.048) mid-anterior insulawith brainstem nuclei was associated with higher systolic blood pressure in the combinedsample. The magnitude of thiseffect in men and women of post menopausal age supports a neurogenic mechanism for blood pressure regulation in older adultswith HTN.

Chronic L-Name-Treatment Produces Hypertension by Different Mechanisms in Peripheral Tissues and Brain: Role of Central eNOS.

The goal of our study was to analyze the time course of the effect of NG-nitro-L-arginine methyl ester (L-NAME) on nitric oxide synthase (NOS) isoforms and nuclear factor–κB (NF-κB) protein expression, total NOS activity, and blood pressure (BP) in rats. Adult 12-week-old male Wistar rats were subjected to treatment with L-NAME (40 mg/kg/day) for four and seven weeks. BP was increased after 4- and 7-week L-NAME treatments. NOS activity decreased after 4-week-L-NAME treatment; however, the 7-week treatment increased NOS activity in the aorta, heart, and kidney, while it markedly decreased NOS activity in the brainstem, cerebellum, and brain cortex. The 4-week-L-NAME treatment increased eNOS expression in the aorta, heart, and kidney and this increase was amplified after 7 weeks of treatment. In the brain regions, eNOS expression remained unchanged after 4-week L-NAME treatment and prolonged treatment led to a significant decrease of eNOS expression in these tissues. NF-κB expression increased in both peripheral and brain tissues after 4 weeks of treatment and prolongation of treatment decreased the expression in the aorta, heart, and kidney. In conclusion, decreased expression of eNOS in the brain regions after 7-week L-NAME treatment may be responsible for a remarkable decrease of NOS activity in these regions. Since the BP increase persisted after 7 weeks of L-NAME treatment, we hypothesize that central regulation of BP may contribute significantly to L-NAME-induced hypertension.

Interaction of Orexin A and Vasopressin in the Brain Plays a Role in Blood Pressure Regulation in WKY and SHR Rats.

BackgroundOrexin A (OXA) and vasopressin (AVP) exert a central hypertensive effect due to an increase in sympathetic nerve activity. To date, little is known about the interaction of these 2 neuropeptides in the central regulation of blood pressure. The present study compared the consequences of infusion into the left cerebral ventricle (ICV) of OXA on mean arterial blood pressure (MABP) in normotensive (WKY) and spontaneously hypertensive (SHR) rats, and explored whether the central pressor action of OXA in these 2 strains depends on activation of brain AVP V1a receptors (V1aR).Material/MethodsTen groups of experiments were performed on 12-week-old WKY and SHR rats implanted with ICV cannulas for infusion of OXA (3 nmol) and V1aR antagonist (V1aRANT, 500 ng), administered separately and together. Levels of V1aR and OXR in the medulla oblongata of WKY and SHR rats were compared in separate series.ResultsWe found that: 1) OXA significantly increased MABP only in WKY rats, 2) V1aRANT prevented an increase in MABP induced by OXA in WKY rats and decreased MABP in SHR rats, 3) OXA abolished the hypotensive action of V1aRANT in SHR rats, and 4) SHR rats had significantly higher levels of OX1R and V1aR proteins and OX1R mRNA in the brain medulla.ConclusionsThe present study shows that OXA and AVP can interact in the brain to affect blood pressure regulation, and that this interaction differs in normotension and hypertension.

839-P: Peripheral and Central Blood Pressure Regulation in Recently Diagnosed Prediabetes

Hypertension is found in up to 90% people with type 2 diabetes. The relationship between blood pressure (BP) (dys)regulation and prediabetes is much less clear. Fifty individuals (mean age [±SD] 42.7±13.1 years, BMI 29.2±7.3 kg/m2) with prediabetes (31 IFG; 19 IGT) and normal BP and 20 age- and BMI-matched healthy persons (40.8±9.6 years, BMI 27.9±6.6 kg/m2) were enrolled into the study. In all participants fasting plasma insulin, adiponectin and interleukin-8 (IL-8) were assessed; and 24-hour ambulatory BP monitoring (ABPM Monitor Schiller BR-102 Plus) and central BP assessment with the applanation tonometry method (SphygmoCor XCEL) were perfomed. ABPM results were similar in both groups: 24-hour systolic, diastolic, mean arterial pressure (MAP) and pulse pressure were 124.1±10.8 and 123.5±7.6; 74.3±7.9 and 74.3±7.0; 89.8±7.2 and 90.4±6.6; 50.5±7.9 i 48.6±5.3 mmHg, respectively (p&amp;gt;0.05). In daytime the respective values were 127.0±11.2 and 126.6±7.4; 75.7±6.5 and 77.2±7.0; 92.4±7.5 and 93.2±6.5; 50.9±8.0 and 48.9±5.5 mmHg, and at nighttime 109.1±21.8 and 109.8±10.5; 61.5±12.7 and 62.7±8.8; 77.1±15.4 and 78.1±9.0; 47.1±11.3 and 46.7±5.4 mmHg (p&amp;gt;0.05). Central systolic, diastolic, end systolic BP, central mean pressure, central pulse height, augmentation index and central stroke volume index were also similar in both groups: 109.3±13.7 and 112.1±14.4, 77.1±9.5 and 80.4±10.7, 99.0±11.7 and 102.1±13.0, 91.3±10.6 and 95.2±11.4, 32.1±9.7 and 31.9±9.4 mmHg, 16.7±13.2 and 15.5±14.3%, 149.5±25.3 and 144.2±29.2 (p&amp;gt;0.05). No significant diffferences in plasma insulin, adiponectin or IL-8 were found between the groups (30.4±25.3 and 26.5±28.8 µIU/ml; 4.86±2.56 and 6.28±3.48 µg/ml; and 25.6±2.58 and 27.9±9.76 pg/ml, respectively, p&amp;gt;0.05). In conclusion, recently diagnosed prediabetes is not associated with any blood pressure abnormalities. Vigorous prevention of diabetes in people with prediabetes should be encouraged as it may lead to maintaining cardiovascular health. Disclosure A. Bogaczewicz-Slowikowska: None. P. Abramczyk: None. K. Cienszkowska: None. E. Janeczko-Sosnowska: None. Z. Gaciong: None. L. Czupryniak: None.

The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet.

We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.

Abstract 087: Impaired Brain Cystathionine Beta-Synthase-Derived H 2 S Production is Associated With the Development of Neurogenic Hypertension

Hydrogen sulfide (H 2 S) is recognized as an important physiological signaling molecule for cardiovascular homeostasis. Decreased circulating H 2 S levels are associated with the development of hypertension, and central administration of H 2 S donors reduces blood pressure in animal models. Cystathionine β-synthase (CBS), one of the H 2 S producing enzymes, is highly expressed in the brain. However, little is known about the role of CBS and brain endogenous H 2 S in the regulation of blood pressure. We hypothesized that impaired brain H 2 S production is associated with the development of neurogenic hypertension. In the 1 st experiment, male C57/BL6/J mice (10-12 wks, n=7) were infused with Angiotensin-II (Ang-II, 600 ng/kg/min, sc, mini-osmotic pump; neurogenic hypertension model) or saline for 4 weeks. Plasma and brain H 2 S levels were measured using gas chromatography-chemiluminesence. Following 4 wks of Ang-II infusion, mean arterial blood pressure (MAP) under anesthesia (carotid artery catheter) was significantly higher in Ang-II compared to saline-infused mice (108.5 ± 8 vs. 77.1 ± 1 mmHg, p &lt; 0.01), confirming hypertension in the Ang-II group. Although plasma free H 2 S levels were not different between groups, brain free H 2 S level was significantly decreased in Ang-II-infused mice (3.3 ± 0.3 vs. 4.5 ± 0.4 pmol/mg, p &lt; 0.05), suggesting that brain H 2 S production is impaired during neurogenic hypertension. In the 2 nd experiment, Neuron-specific CBS knockout mice (NS-CBS KO) and CBS Flox controls (male, 10-12 wks, n=6) were implanted with telemetry probes for conscious blood pressure recording. Ang-II was infused after baseline recording. The basal level of MAP was not different between NS-CBSKO and CBS Flox mice (96.5 ± 3 vs. 99.3 ± 4 mmHg, p &lt; 0.05). After 1 wk of Ang-II infusion, MAP was significantly higher in NS-CBS KO compared to CBS Flox mice (126.6 ± 10 vs. 106.8 ± 5 mmHg, p &lt; 0.05). Taken together, these data suggest that CBS is involved in the central regulation of blood pressure, and impaired brain CBS-derived H 2 S production promotes the development of neurogenic hypertension. (Funding: NIH R01 HL146098-01; NIGMS P30GM106392)

Estrogen Receptor Beta and G‐Protein Coupled Estrogen Receptor are Located and Activated on Microglia by Estrogen

Upon menopause, women have an increased risk of cardiovascular disease, in part due to the decrease in estrogen production that occurs. While estrogen's cardioprotective effects have been known for many years, the exact mechanism of this protection is still under investigation. Estrogen receptors have been detected in locales in the central nervous system that are critical in the regulation of arterial pressure and sympathetic nervous activity, particularly the rostral ventrolateral medulla (RVLM) and paraventricular nucleus (PVN) of the hypothalamus. Animal models of menopause implicate over activity of the sympathetic nervous system contributes to hypertension. Microglia are believed to be the resident immune cells of the brain. In previous studies, activated glia have been shown to contribute to increased neuronal tone and excitability in the PVN and RVLM and increased sympathetic activity, potentially through the release of pro‐inflammatory cytokines. The role of microglia in hypertension is not clear. The overall objective of these studies is to investigate if estrogen can regulate the activity of microglia. We sought to evaluate how estrogen regulates its cognate receptors using an immortalized microglia 10‐day old female mouse cell line (EOC2). Utilizing immunohistochemical and western blot techniques, our data demonstrate that the microglia cell line expressed estrogen receptor beta (ERβ) and G‐Protein coupled Estrogen Receptor (GPER). Exposing the cells to 10nM of estrogen for 15 minutes demonstrated that estrogen activates the microglia and initiates ERβ translocation from the membrane to the cytosol. We found a dose (1, 10 and 100 nM) and time (5, 15, 30 and 60 minute) dependent change in the protein level of GPER and ERβ. These results demonstrate that estrogen exposure can activate microglial cells and increase expression of estrogen receptors. Future studies will examine if the activation of microglia by estrogen alters the release of cytokines and thus may modulate neuronal function. These findings will contribute to the pivotal role estrogen plays in central blood pressure regulation and will undoubtedly shed light on possible mechanisms of menopause‐induced hypertension.Support or Funding InformationS Clayton DMU IOERM Barnes DMU IOERThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aerobic exercise training normalizes central blood pressure regulation after oral glucose loading in overweight/obese men

ABSTRACTCentral systolic blood pressure (cSBP) decreases after a meal or glucose challenge, but this response is impaired in obesity-related disorders. We investigated whether aerobic exercise training improves cSBP regulation during an oral glucose tolerance test (OGTT) in overweight/obese men. Thirteen overweight/obese men and six normal-weight men (as an alternative comparison instead of a no-exercise group) completed a 12-week aerobic exercise training program. Before and after the program, cSBP (i.e., radial second systolic pressure) was measured using an applanation tonometry at fasting and both 60 min and 120 min after 75 g glucose loading. Before and during the program, physical activity (PA) time was recorded using a tri-axial accelerometer. Pre-training, cSBP was significantly decreased with glucose loading in normal-weight men, while cSBP did not change in overweight/obese men. Post-training, a significant decrease in cSBP was observed in both groups following glucose loading. In addition, the increase in vigorous PA time during the exercise program was significantly correlated to the increase in area above the curve for cSBP during OGTT (demonstrating an improvement in the cSBP response to glucose loading) after the exercise program. These findings may provide novel insights into the role of PA in reducing the cardiovascular risk in obesity.

Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system.

Despite advances in antihypertensive therapeutics, at least 15-20% of hypertensive patients have resistant hypertension through mechanisms that remain poorly understood. In this study, we provide a new mechanism for the regulation of blood pressure (BP) in the central nervous system (CNS) by the (pro)renin receptor (PRR), a recently identified component of the renin-angiotensin system that mediates ANG II formation in the CNS. Although PRR also mediates ANG II-independent signaling, the importance of these pathways in BP regulation is unknown. Here, we developed a unique transgenic mouse model overexpressing human PRR (hPRR) specifically in neurons (Syn-hPRR). Intracerebroventricular infusion of human prorenin caused increased BP in Syn-hPRR mice. This BP response was attenuated by a NADPH oxidase (NOX) inhibitor but not by antihypertensive agents that target the renin-angiotensin system. Using a brain-targeted genetic knockdown approach, we found that NOX4 was the key isoform responsible for the prorenin-induced elevation of BP in Syn-hPRR mice. Moreover, inhibition of ERK significantly attenuated the increase in NOX activity and BP induced by human prorenin. Collectively, our findings indicate that an ANG II-independent, PRR-mediated signaling pathway regulates BP in the CNS by a PRR-ERK-NOX4 mechanism. NEW & NOTEWORTHY This study characterizes a new transgenic mouse model with overexpression of the human (pro)renin receptor in neurons and demonstrated a novel angiotensin II-independent mechanism mediated by human prorenin and the (pro)renin receptor in the central regulation of blood pressure.

The prorenin receptor in the cardiovascular system and beyond.

Since the prorenin receptor (PRR) was first reported, its physiological role in many cellular processes has been under intense scrutiny. The PRR is currently recognized as a multifunctional receptor with major roles as an accessory protein of the vacuolar-type H+-ATPase and as an intermediary in the Wnt signaling pathway. As a member of the renin-angiotensin system (RAS), the PRR has demonstrated to be of relevance in cardiovascular diseases (CVD) because it can activate prorenin and enhance the enzymatic activity of renin, thus promoting angiotensin II formation. Indeed, there is an association between PRR gene polymorphisms and CVD. Independent of angiotensin II, the activation of the PRR further stimulates intracellular signals linked to fibrosis. Studies using tissues and cells from a variety of organs and systems have supported its roles in multiple functions, although some remain controversial. In the brain, the PRR appears to be involved in the central regulation of blood pressure via activation of RAS- and non-RAS-dependent mechanisms. In the heart, the PRR promotes atrial structural and electrical remodeling. Nonetheless, animals overexpressing the PRR do not exhibit cardiac injury. In the kidney, the PRR is involved in the development of ureteric bud branching, urine concentration, and regulation of blood pressure. There is great interest in the PRR contributions to T cell homeostasis and to the development of visceral and brown fat. In this mini-review, we discuss the evidence for the pathophysiological roles of the PRR with emphasis in CVD.

Hypotensive Response to Angiotensin II Type 2 Receptor Stimulation in the Rostral Ventrolateral Medulla Requires Functional GABA-A Receptors.

Objectives: Angiotensin II, glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN) modulating the central regulation of blood pressure and sympathetic tone. Our aim was to assess the effects of local angiotensin II type 2 receptor stimulation within the RVLM and the PVN on neurotransmitter concentrations and mean arterial pressure (MAP).Methods: In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for local infusion of the angiotensin II type 2 receptor agonist Compound 21 in the RVLM and the PVN of conscious normotensive Wistar rats. The MAP response to local Compound 21 was monitored with a pressure transducer under anaesthesia. Angiotensin II type 2 receptor selectivity was assessed using the angiotensin II type 2 receptor antagonist PD123319; the GABA-A receptor antagonist bicuculline was used to assess the involvement of GABA-A receptors.Results: Infusion of Compound 21 (0.05 μg/μl/h) in the RVLM significantly increased GABA levels and lowered blood pressure. These effects were abolished by co-infusion with PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Co-infusion of bicuculline abolished the Compound 21 evoked decrease in MAP. Infusion of Compound 21 within the PVN did not change extracellular neurotransmitter levels nor MAP.Conclusion: Selective stimulation of angiotensin II type 2 receptor within the RVLM by local Compound 21 infusion reduces blood pressure and increases local GABA levels in normotensive rats. This hypotensive response requires functional GABA-A receptors, suggesting that GABAergic neurons are involved in the sympatho-inhibitory action underlying this hypotensive response.

Abstract 321: Central Blood Pressure Regulation in Relation to Hypertension and Adiposity in Youth

Introduction: The relationship between different central BP measurements with hypertension status in youth is not well documented. We hypothesized that measures of central BP would be positively associated with hypertension status in youth independent of adiposity. Methods: We recruited 149 males and 160 females for this cross-sectional analysis (mean±SD: age = 12.8±2.7; BMI percentile (%) = 78.5±27.8). Body fat % was measured by dual energy X-ray absorptiometry (DXA) and brachial BP was measured using an automated cuff to calculate systolic BP (SBP) and diastolic BP (DBP). Determined by systolic percentile, there were 238 normotensive (&lt;90 th ), 29 pre-hypertensive (&lt;90 th - &lt;95 th ), and 42 hypertensive (&lt;95 th ) individuals enrolled. Central BP was determined using the SphygmoCor MM3 system to calculate carotid-aorta SBP (caSBP) carotid-aorta DBP (caDBP) radial-aorta SBP (raSBP) and radial-aorta DBP (raDBP). Central BP measures were compared across hypertension status groups using ANCOVA, with post-hoc Tukey HSD, adjusted for age, sex, and race. Pearson correlations (unadjusted) and multiple linear regression models, examining the relationship between central BP measures with brachial BP adjusted for age, sex, race, and height, were conducted with further adjustment for body fat % (shown as β±SE). Results: raSBP, caSBP, raDBP, and caDBP were significantly different between the normotensive and hypertensive groups (all p&lt;0.001). No statistically significant differences were found between normotensive and pre-hypertensive or between pre-hypertensive and hypertensive groups. raSBP and caSBP were correlated to SBP (r=0.59, r=0.62, respectively, p&lt;0.001). raDBP and caDBP were correlated to DBP (r=0.58, r=0.6, respectively, p&lt;0.001). In regression analysis, SBP was positively associated with both raSBP and caSBP (β=0.3±0.06, p&lt;0.001) and (β=0.28±0.08, p&lt;0.001), respectively. DBP was positively associated with raDBP and caDBP (β=0.31±0.06, p&lt;0.001) and (β=0.31 ±0.06, p&lt;0.001), respectively. All associations remained significant after adjustment for body fat %. Conclusion: These data suggest that central BP, regardless of measurement site, is highly associated with brachial BP and hypertension status in youth independent of adiposity.

HYPOTENSIVE RESPONSE TO ANGIOTENSIN II TYPE 2 RECEPTOR STIMULATION IN THE ROSTRAL VENTROLATERAL MEDULLA: INTERACTION WITH GLUTAMATE AND GAMMA-AMINOBUTYRIC ACID

Event Abstract Back to Event HYPOTENSIVE RESPONSE TO ANGIOTENSIN II TYPE 2 RECEPTOR STIMULATION IN THE ROSTRAL VENTROLATERAL MEDULLA: INTERACTION WITH GLUTAMATE AND GAMMA-AMINOBUTYRIC ACID Laura LEGAT1*, Sofie Brouwers2, Ilse Smolders1 and Alain Dupont1, 2, 3 1 Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Belgium 2 UZ Brussel, Department of Pharmacology and Cardiovascular Center, Belgium 3 UZ Brussel, Department of Clinical Pharmacology and Clinical Pharmacy (KFAR), Belgium Objectives Angiotensin II, glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla and the paraventricular nucleus modulating the central regulation of blood pressure and sympathetic tone. Our aim was to assess the effects of local angiotensin II type 2 receptor stimulation within the rostral ventrolateral medulla and the paraventricular nucleus on neurotransmitter concentrations and mean arterial pressure. Methods In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for local infusion of the angiotensin II type 2 receptor agonist Compound 21 in the rostral ventrolateral medulla and the paraventricular nucleus of conscious normotensive Wistar rats. The mean arterial pressure response to local Compound 21 was monitored with a pressure transducer under anaesthesia. Angiotensin II type 2 receptor selectivity was assessed using the angiotensin II type 2 receptor antagonist PD123319; the GABA(A) receptor antagonist bicuculline was used to assess the involvement of GABA(A) receptors. Results Infusion of C21 (0.05µg/µl/h) in the rostral ventrolateral medulla significantly increased GABA levels and lowered blood pressure. These effects were abolished by co-infusion with PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Co-infusion of bicuculline abolished the Compound 21 evoked decrease in mean arterial pressure. Infusion of Compound 21 within the paraventricular nucleus did not change extracellular neurotransmitter levels nor mean arterial pressure. Conclusion Selective stimulation of angiotensin II type 2 receptor within the rostral ventrolateral medulla by local Compound 21 infusion reduces blood pressure and increases local GABA levels in normotensive rats. This hypotensive response requires functional GABA(A) receptors, suggesting that GABAergic neurons are involved in the sympatho-inhibitory action underlying this hypotensive response. Keywords: Renin-angiotensin-system, angiotensin II type 2 receptors, compound 21, mean arterial pressure, rostral ventrolateral medualla, gamma-Aminobutyric Acid Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Oral Presentation Topic: Sensory and Motor Systems Citation: LEGAT L, Brouwers S, Smolders I and Dupont A (2019). HYPOTENSIVE RESPONSE TO ANGIOTENSIN II TYPE 2 RECEPTOR STIMULATION IN THE ROSTRAL VENTROLATERAL MEDULLA: INTERACTION WITH GLUTAMATE AND GAMMA-AMINOBUTYRIC ACID. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00063 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Mrs. Laura LEGAT, Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (FASC), Jette, 1090, Belgium, laura_legat@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Laura LEGAT Sofie Brouwers Ilse Smolders Alain Dupont Google Laura LEGAT Sofie Brouwers Ilse Smolders Alain Dupont Google Scholar Laura LEGAT Sofie Brouwers Ilse Smolders Alain Dupont PubMed Laura LEGAT Sofie Brouwers Ilse Smolders Alain Dupont Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

PP.35.02] EFFECT OF ANGIOTENSIN RECEPTOR STIMULATION IN THE ROSTRAL VENTROLATERAL MEDULLA ON BLOOD PRESSURE IN NORMOTENSIVE RATS

Objective: There is increasing evidence that glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla (RVLM) modulating the central regulation of blood pressure and sympathetic tone. Angiotensin II (Ang II) is the most important effector in the renin-angiotensin-aldosterone system (RAAS) mediating its actions through the angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R). The AT2R is part of the protective arm of the RAAS and mediates opposing effects counterbalancing the AT1R mediated actions. The selective and specific AT2R agonist Compound 21 (C21) is a useful research tool to investigate the AT2R mediated effects. Design and method: In the present study we assess through local stimulation and blockade of AT1R and AT2R the possible role of the brain RAAS at the level of the RVLM on the regulation of blood pressure. In vivo microdialysis, for measurement of extracellular glutamate and GABA levels, was carried out in the RVLM of conscious normotensive Wistar rats while locally infusing C21, Ang II, and PD123319. Glutamate and GABA levels were quantified by HPLC. Subsequently, the effect of central administration of C21, Ang II, and PD123319 on mean arterial pressure was assessed with a pressure transducer for continuous monitoring. Results: Infusion of Ang II into the RVLM significantly increased glutamate levels (P < 0.05) and significantly decreased GABA levels (P < 0.01). Infusion of the AT2R agonist C21 (0.05 μg/μl/h) tended to decrease glutamate and increase GABA levels, while absolutely no change was seen when co-infusing C21 together with the AT2 receptor antagonist PD123319. C21 infusion (0.05 μg/μl/h) significantly lowered blood pressure (P < 0.01). These responses were abolished by co-administration of C21 and PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Conclusions: These data demonstrate that acute specific stimulation of AT2R in the RVLM by local C21 infusion reduces blood pressure in normotensive rats, and suggests that decreases in local glutamate and increases in GABA levels may be involved in the sympatho-inhibitory action underlying this hypotensive response.

Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of “checks and balances”. It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the “crossroad” in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the “deleterious” Ang A as well as from the “protective” angiotensin 1–7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications.