Role In Blood Pressure Regulation Research Articles

Increased daytime and awakening salivary free aldosterone in essential hypertensive men.

While aldosterone plays an important role in blood pressure regulation, its role in essential hypertension (EHT) remains unclear. Here, we systematically investigated the secretion of biologically-active free aldosterone in saliva in response to awakening (AldAR) and during the day (AldDay) in EHT compared to normotensive controls (NT). In 30 men with EHT and 30 age-matched NT, AldAR saliva samples were collected immediately after awakening and 15, 30, 45, and 60 min thereafter and AldDay samples were collected from 08:30-22:00 h on two consecutive days. Over the course of the day, men with EHT had higher repeated AldDay levels compared to NT (p = .002) with higher concentrations in the morning hours (p's ≤ .047), a steeper decline over the course of the day (p's ≤ .018), and similar concentrations in the evening (p's ≥ .21). Regarding AldAR, we observed higher concentrations in EHT at awakening (p = .017) and borderline higher concentrations at 15 min (p = .086). No differences were found 30-60 min after awakening (p's ≥ .34). Analyses with repeated and aggregated AldAR levels resulted in borderline significantly higher free aldosterone in EHT (p's ≤ .077). Complementary analyses confirmed linear associations between higher blood pressure and higher AldAR and AldDay levels. Our data point to elevated salivary free aldosterone secretion in EHT over the course of the day, particularly in the morning hours. As the free aldosterone fraction is considered biologically active, our data may point to a biological mechanism underlying EHT.

Urinary hyaluronidase activity is closely related to vasopressinergic system following an oral water load in men: a potential role in blood pressure regulation and early stages of hypertension development.

Blood pressure (BP) regulation is a complex process involving several factors, among which water-sodium balance holds a prominent place. Arginin-vasopressin (AVP), a key player in water metabolism, has been evoked in hypertension development since the 1980s, but, to date, the matter is still controversial. Hyaluronic acid metabolism has been reported to be involved in renal water management, and AVP appears to increase hyaluronidase activity resulting in decreased high-molecular-weight hyaluronan content in the renal interstitium, facilitating water reabsorption in collecting ducts. Hence, our aim was to evaluate urinary hyaluronidase activity in response to an oral water load in hypertensive patients (HT, n=21) compared to normotensive subjects with (NT+, n=36) and without (NT-, n=29) a family history of hypertension, and to study its association with BP and AVP system activation, expressed by serum copeptin levels and urine Aquaporin 2 (AQP2)/creatinine ratio. Eighty-six Caucasian men were studied. Water load test consisted in oral administration of 15-20 ml of water/kg body weight over 40-45 min. BP, heart rate, serum copeptin, urine hyaluronidase activity and AQP2 were monitored for 4 hours. In response to water drinking, BP raised in all groups with a peak at 20-40 min. Baseline levels of serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio were similar among groups and all decreased after water load, reaching their nadir at 120min and then gradually recovering to baseline values. Significantly, a blunted reduction in serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio was observed in NT+ compared to NT- subjects. A strong positive correlation was also found between urinary hyaluronidase activity and AQP2/creatinine ratio, and, although limited to the NT- group, both parameters were positively associated with systolic BP. Our results demonstrate for the first time the existence in men of a close association between urinary hyaluronidase activity and vasopressinergic system and suggest that NT+ subjects have a reduced ability to respond to water loading possibly contributing to the blood volume expansion involved in early-stage hypertension. Considering these data, AVP could play a central role in BP regulation by affecting water metabolism through both hyaluronidase activity and AQP2 channel expression.

Angiotensinergic effect of β-Caryophyllene on Lipopolysaccharide- induced systemic inflammation

Renin-Angiotensin System (RAS) is a peptidergic system, canonically known for its role in blood pressure regulation. Furthermore, a non-canonical RAS regulates pathophysiological phenomena, such as inflammation since it consists of two main axes: the pro-inflammatory renin/(pro)renin receptor ((P)RR) axis, and the anti-inflammatory angiotensin-converting enzyme 2 (ACE2)/Angiotensin-(1–7) (Ang-(1–7))/Mas Receptor (MasR) axis. Few phytochemicals have shown to exert angiotensinergic and anti-inflammatory effects through some of these axes; nevertheless, anti-inflammatory drugs, such as phytocannabinoids have not been studied regarding this subject. Among phytocannabinoids, β-Caryophyllene stands out as a dietary phytocannabinoid with antiphlogistic activity that possess a unique sesquiterpenoid structure. Although its cannabinergic effect has been studied, its angiotensinergic effect reminds underexplored. This study aims to explore the angiotensinergic effect of β-Caryophyllene on inflammation and stress at a systemic level. After intranasal Lipopolysaccharide (LPS) installation and oral treatment with β-Caryophyllene, the concentration and activity of key RAS elements in the serum, such as Renin, ACE2 and Ang-(1–7), along with the stress hormone corticosterone and pro/anti-inflammatory cytokines, were measured in mice serum. The results show that β-Caryophyllene treatment modified RAS levels by increasing Renin and Ang-(1–7), alongside the reduction of pro-inflammatory cytokines and corticosterone levels. These results indicate that β-Caryophyllene exhibits angiotensinergic activity in favor of anti-inflammation.

Chronic circadian stress raises mean arterial pressure in male, but not female, Bmal1-knockout rats

Shiftwork and other forms of circadian disruption are associated with an increased risk of cardiovascular and kidney disease, however, the mechanisms driving these associations have yet to be elucidated. It has been suggested that dyssynchrony between the endogenous molecular clock and the external environment during shiftwork may be connected with the development of cardiorenal pathologies and the dysregulation of blood pressure (BP). Brain and muscle arntl-like protein 1, or Bmal1, is a core component of the molecular clock. Loss of Bmal1 in both male and female rats results in lower BP compared to wild-type (WT) littermate controls. We hypothesized that Bmal1 is necessary for the acclimation to circadian stress induced by chronic circadian stress (CCS). Telemeters were surgically implanted in the abdominal aorta of 12-14 week old rats. After a 2 week recovery, animals were placed in a light-controlled room on a 12:12hr light/dark cycle. After 1 week acclimation, lights were phase-advanced 6hrs every week for 4 weeks. Telemetry data was collected for 2 minutes every 10 minutes each hour at 1000 samples/second and analyzed using cosinor analysis. The MESOR of mean arterial pressure (MAP) was similar pre- and post- CCS in male WT rats (n=8, 107±1 vs. 109±1 mmHg; 2-way ANOVA, p>0.05) and in female WT rats (n=9, 110±1 vs. 112±2 mmHg; p>0.05). Male Bmal1-KO rats (n=9) had higher MAP MESOR after CCS (103±1 vs 108±1mmHg; p<0.05), but female Bmal1-KO rats (n=6) had no change in MAP MESOR after CCS (100±2. vs 100±2 mmHg, p>0.05). MAP amplitude was similar between WT and KO males before- (6.5±0.7 vs. 5.2±0.8 mmHg) and after-CCS (5.1±0.4 vs. 5.3±0.4 mmHg, p>0.05). WT and KO females had similar MAP amplitude before- (7.2±0.6 vs 5.5±0.9 mmHg) and after-CCS (5.7±1.1 vs. 5.6±0.6, p>0.05). In summary, loss of Bmal1 combined with circadian stress resulted in higher BP in a sex- dependent manner. Despite having lower blood pressures pre-CCS, male Bmal1-KO rats had higher MAP after CCS while female Bmal1-KO rats were protected from increased BP. This suggests that Bmal1, a crucial component of the molecular clock, has a sex-specific role in BP regulation and the response to stress. This work is supported by NIH TL1DK139566-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

In-depth in silico and in vitro screening of selected edible plants for identification of selective C-domain ACE-1 inhibitor and its synergistic effect with captopril

Angiotensin converting enzyme (ACE) is a crucial enzyme in renin angiotensin aldosterone system (RAAS), having a pivotal role in blood pressure regulation. Despite its widespread medical applications in hypertension, heart diseases, diabetic nephropathy, and many others, inhibitors of the ACE enzyme suffer from different side effects that limit their use. Plants and natural products are the primary sources of renewable natural compounds that could act as potential leads for different ailments. The following study represents the identification of ACE inhibitors from carefully selected edible plants through adopting combined in silico techniques with biological testing. Molecular docking studies were performed on 1526 phytoconstituents present in 19 edible plants. Biochemical testing of extracts from the top ten hit plants revealed that Moringa oleifera is a potent ACE-1 inhibitor with an IC50 value of 104.4 μg/mL. On top of that, its isolated compound 4-O-caffeoylquinic acid had IC50 value of 62.92 μM. In silico combination analysis showed synergistic effects of moringa extract and 4-O-caffeoylquinic acid combined with captopril, especially at 90% effect level. This, in turn, is likely to reduce side effects and toxicity. Furthermore, selective domain docking showed strong affinity of 4-O-caffeoylquinic acid to the C-domain of ACE enzyme. Since the inflammatory responses and elevated reactive oxygen species in vasculature increase hypertension, the antioxidant effect of the compound was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and it possessed an acceptable effect with IC50 value of 73.82 μM. These findings advocate the antihypertensive potential of moringa leaves extract. Besides, we introduce 4-O-caffeoylquinic acid as a candidate lead for the design of safe, bidirectional ACE-1 inhibitor with strong antioxidant effect.

Impaired vestibular function associated with orthostatic hypotension in patients with multiple system atrophy.

Orthostatic hypotension (OH) is one of the most common symptoms in patients with multiple system atrophy (MSA). Vestibular system plays an important role in blood pressure regulation during orthostatic challenges through vestibular-sympathetic reflex. The current study aimed to investigate the relationship between vestibular function and OH in patients with MSA. Participants with MSA, including 20 with OH (mean age, 57.55 ± 8.44years; 7 females) and 15 without OH (mean age, 59.00 ± 8.12years; 2 females) and 18 healthy controls (mean age, 59.03 ± 6.44years; 8 females) were enrolled. Cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) tests were conducted to evaluate vestibular function. Patients with MSA presented with significantly higher rate of absent cVEMPs (57.1% vs 11.1%, p = 0.001) and oVEMPs (25.7% vs 0, p = 0.021) than controls. MSA patients with OH showed more absent cVEMPs (75.0% vs 11.1%, Bonferroni corrected p < 0.001) and oVEMPs (40.0% vs 0, Bonferroni corrected p = 0.003) than controls. Patients with OH also showed higher rate of absent cVEMPs than those without OH (33.3%, Bonferroni corrected p = 0.014). Our results demonstrated that impairment of vestibular function was associated with MSA, particularly in those with OH. Absent VEMPs may be a potential marker for MSA severity. Our findings suggest that impaired vestibular function is involved in OH development and may serve as an intervention target.

Unraveling the crosstalk between renin-angiotensin system receptors.

The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.

Predicting sex differences in the effects of diuretics in renal epithelial transport during angiotensin II-induced hypertension.

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.

Detection and identification of factors in the atrium responsible for blood pressure regulation in patients with hypertension

Resection of the left atrial appendage reportedly improves blood pressure in patients with hypertension. This study aimed to validate the transcriptional profiles of atrial genes responsible for blood pressure regulation in patients with hypertension as well as to identify the molecular mechanisms in rat biological systems. RNA sequencing data of left atrial appendages from patients with (n = 6) and without (n = 6) hypertension were subjected to unsupervised principal component analysis (PCA). Reduction of blood pressure was reflected by third and ninth principal components PC3 and PC9, and that eighteen transcripts, including endothelin-1, were revealed by PCA-based pathway analysis. Resection of the left atrial appendage in hypertensive rats improved their blood pressure accompanied by a decrease in serum endothelin-1 concentration. Expression of the endothelin-1 gene in the atrium and atrial appendectomy could play roles in blood pressure regulation in humans and rats.

Lymphocyte-Specific Protein 1 Regulates Expression and Stability of Endothelial Nitric Oxide Synthase.

Nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), plays a critical role in blood pressure regulation. Genome-wide association studies have identified genetic susceptibility loci for hypertension in human lymphocyte-specific protein 1 (LSP1) gene. LSP1 is recognized as modulator of leukocyte extravasation, and endothelial permeability, however, the role of LSP1 in regulation of NO signaling within endothelial cells (ECs) remains unknown. The present study investigated the role of LSP1 in the regulation of eNOS expression and activity utilizing human macrovascular ECs in vitro and LSP1 knockout (KO) mice. In ECs, specific CRISPR-Cas9 genomic editing deleted LSP1 and caused downregulation of eNOS expression. LSP1 gain-of-function through adenovirus-mediated gene transfer was associated with enhanced expression of eNOS. Co-immunoprecipitation and confocal fluorescence microscopy revealed that eNOS and LSP1 formed a protein complex under basal conditions in ECs. Furthermore, LSP1 deficiency in mice promoted significant upregulation and instability of eNOS. Utilizing a mass-spectrometry-based bottom-up proteomics approach, we identified novel truncated forms of eNOS in immunoprecipitates from LSP1 KO aortae. Our experimental data suggest an important role of endothelial LSP1 in regulation of eNOS expression and activity within human ECs and murine vascular tissues.

Blood Pressure Regulation in Persons with a Transfemoral Amputation: Effects of Wearing a Prosthesis

ABSTRACT INTRODUCTION The purpose of this study was to investigate the effect of wearing a transfemoral prosthesis (FP) on blood pressure regulation in response to postural change. METHODS We enrolled seven persons with a transfemoral amputation who underwent a head-up tilt test while wearing an FP (PROS test) and without wearing an FP (control [CON] test). Systolic blood pressure (SBP), heart rate variability, and muscle blood flow using near-infrared spectroscopy were measured continuously. RESULTS In the CON (no FP) test, SBP decreased from supine to standing positions in all participants (P = 0.001). In contrast, in the PROS (wearing an FP) test, SBP increased (P = 0.001) during the postural change. CONCLUSIONS The findings suggest that a transfemoral prosthesis increases peripheral vascular resistance in the lower limbs and stimulates the baroreflex, helping to stabilize the circulatory dynamics upon postural change. CLINICAL RELEVANCE Because circulatory dynamics may be hampered in persons with a transfemoral amputation, wearing a prosthesis not only assists in ambulation but can also play a significant role in blood pressure regulation during activities of daily living.

Taurocholic acid ameliorates hypertension through the activation of TGR5 in the hypothalamic paraventricular nucleus.

Diets rich in taurine can increase the production of taurine-conjugated bile acids, which are known to exert antihypertensive effects. Despite their benefits to the heart, kidney and arteries, their role in the central nervous system during the antihypertensive process remains unclear. Since hypothalamic paraventricular nucleus (PVN) plays a key role in blood pressure regulation, we aimed to investigate the function of bile acids in the PVN. The concentration of bile acids in the PVN of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKY) fed with normal chow was measured using LC-MS/MS, which identified taurocholic acid (TCA) as the most down-regulated bile acid. To fully understand the mechanism of TCA's functions in the PVN, bi-lateral PVN micro-infusion of TCA was carried out. TCA treatment in the PVN led to a significant reduction in the blood pressure of SHRs, with decreased plasma levels of norepinephrine and improved morphology of cardiomyocytes. It also decreased the number of c-fos+ neurons, reduced the inflammatory response, and suppressed oxidative stress in the PVN of the SHRs. Most importantly, the TGR5 receptors in neurons and microglia were activated. PVN infusion of SBI-115, a TGR5 specific antagonist, was able to counteract with TCA in the blood pressure regulation of SHRs. In conclusion, TCA supplementation in the PVN of SHRs can activate TGR5 in neurons and microglia, reduce the inflammatory response and oxidative stress, suppress activated neurons, and attenuate hypertension.

The Effect of Skeletal Muscle-Pump on Blood Pressure and Postural Control in Parkinson's Disease.

Activation of the calf (gastrocnemius and soleus) and tibialis anterior muscles play an important role in blood pressure regulation (via muscle-pump mechanism) and postural control. Parkinson's disease is associated with calf (and tibialis anterior muscles weakness and stiffness, which contribute to postural instability and associated falls. In this work, we studied the role of the medial and lateral gastrocnemius, tibialis anterior, and soleus muscle contractions in maintaining blood pressure and postural stability in Parkinson's patients and healthy controls during standing. In addition, we investigated whether the activation of the calf and tibialis anterior muscles is baroreflex dependent or postural-mediated. We recorded electrocardiogram, blood pressure, center of pressure as a measure of postural sway, and muscle activity from the medial and lateral gastrocnemius, tibialis anterior, and soleus muscles from twenty-six Parkinson's patients and eighteen sex and age-matched healthy controls during standing and with eyes open. The interaction and bidirectional causalities between the cardiovascular, musculoskeletal, and postural variables were studied using wavelet transform coherence and convergent cross-mapping techniques, respectively. Parkinson's patients experienced a higher postural sway and demonstrated mechanical muscle-pump dysfunction of all individual leg muscles, all of which contribute to postural instability. Moreover, our results showed that coupling between the cardiovascular, musculoskeletal, and postural variables is affected by Parkinson's disease while the contribution of the calf and tibialis anterior muscles is greater for blood pressure regulation than postural sway. The outcomes of this study could assist in the development of appropriate physical exercise programs that target lower limb muscles to improve the muscle-pump function and reduce postural instability in Parkinson's disease.

Association between Daytime Sleepiness, Fatigue and Autonomic Responses during Head-Up Tilt Test in Multiple Sclerosis Patients.

We aimed to assess dynamic changes in hemodynamic and autonomic function in response to the head-up tilt test (HUTT) in patients with multiple sclerosis (MS) compared to healthy controls (HCs) and evaluate its relationship with the patients' reported daytime sleepiness and fatigue symptoms. A total of 58 MS patients and 30 HCs were included in the analysis. Fatigue and sleepiness were evaluated using the Chalder Fatigue Scale (CFQ) and the Epworth Sleepiness Scale (ESS), respectively. Hemodynamic response, baroreflex sensitivity, heart rate variability, and systolic and diastolic blood pressure (BP) variability (SBPV, DBPV) parameters were calculated at rest, and in response to the HUTT. The MS patients displayed attenuated BP responses coupled with a more pronounced decrease in cardiac index as well as a reduced increase in the low frequency (LFnu) of DBPV (p = 0.021) and the sympathovagal ratio (p = 0.031) in the latter-phase orthostatic challenge compared to HCs. In MS patients, the ESS score showed no correlation with CFQ or clinical disease outcomes, but exhibited a moderate correlation with LFnu of BPVrest. Fatigue and disease variants predicted blood pressure response to HUTT. These findings underscore the importance of subjective daytime sleepiness and fatigue symptoms and their role in blood pressure regulation in MS patients.

Genetically engineered Lactobacillus paracasei rescues colonic angiotensin converting enzyme 2 (ACE2) and attenuates hypertension in female Ace2 knock out rats

Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2-/- and Ace2-/y). Our findings reveal a sex-specific reduction in blood pressure in female (Ace2-/-) but not male (Ace2-/y) rats following colonization with the Lacto-hACE2. This beneficial effect of lowering blood pressure was aligned with a specific reduction in colonic angiotensin II, but not renal angiotensin II, suggesting the importance of colonic Ace2 in the regulation of blood pressure. We conclude that this approach of targeting the colon with engineered bacteria for delivery of ACE2 represents a promising new paradigm in the development of antihypertensive therapeutics.

Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.

Blood pressure (BP) follows a circadian pattern that rises during the active phase of the day (morning surge) and decreases during the inactive (night dipping) phase of the day. The morning surge coincides with increased circulating glucocorticoids and aldosterone, ligands for glucocorticoid receptors and mineralocorticoid receptors, respectively. Serum- and glucocorticoid-induced kinase 1 (SGK1), a clock-controlled and glucocorticoid receptor- and mineralocorticoid receptor-induced gene, plays a role in BP regulation in human and animal models. However, the role of SGK1 in BP circadian regulation has not yet been demonstrated. Using telemetry, we analyzed BP in the inducible renal tubule-specific Sgk1Pax8/LC1 model under basal K+ diet (1% K+) and high-K+ diet (HKD; 5% K+). Our data revealed that, under basal conditions, renal SGK1 plays a minor role in BP regulation; however, after 1 wk of HKD, Sgk1Pax8/LC1 mice exhibited significant defects in diastolic BP (DBP), including a blunted surge, a decreased amplitude, and reduced day/night differences. After prolonged HKD (7 wk), Sgk1Pax8/LC1 mice had lower BP than control mice and exhibited reduced DBP amplitude, together with decreased DBP day/night differences and midline estimating statistic of rhythm (MESOR). Interestingly, renal SGK1 deletion increased pulse pressure, likely secondary to an increase in circulating aldosterone. Taken together, our data suggest that 1) the kidney plays a significant role in setting the BP circadian rhythm; 2) renal tubule SGK1 mediates the BP surge and, thus, the day/night BP difference; 3) long-term renal SGK1 deletion results in lower BP in mutant compared with control mice; and 4) renal SGK1 indirectly regulates pulse pressure due to compensatory alterations in aldosterone levels.NEW & NOTEWORTHY Dysregulation of blood pressure (BP) circadian rhythm is associated with metabolic, cardiovascular, and kidney diseases. Our study provides experimental evidence demonstrating, for the first time, that renal tubule serum- and glucocorticoid-induced kinase 1 (SGK1) plays an essential role in inducing the BP surge. Inhibitors and activators of SGK1 signaling are parts of several therapeutic strategies. Our findings highlight the importance of the drug intake timing to be in phase with SGK1 function to avoid dysregulation of BP circadian rhythm.

Abstract 063: Pregnancy Protects Aged G Protein-coupled Estrogen Receptor 1 Knock-out Mice Against Hypertension

Hypertension, a major cause of premature death worldwide, is more prevalent in postmenopausal women compared to premenopausal women. Data implicate a protective effect of G protein-coupled estrogen receptor 1 (GPER1) in cardiovascular diseases. A recent study showed that previous pregnancy lowers blood pressure in hyperandrogenemic rats. We hypothesized that pregnancy protects against hypertension elicited in aged female mice lacking GPER1. 16-20 month-old GPER1 wild-type (WT) and knock-out (KO) mice with or without a history of former pregnancies were implanted with telemeters for blood pressure recording and placed in metabolic cages for 24h urine collection. Plasma, adrenal glands and kidneys were collected. GPER1 deletion increased mean arterial pressure in virgin mice (125±3 vs. 109±2 mmHg; n=3,7; p=0.0005), and previous pregnancies (PP) eliminated this genotypic effect (106±1 mmHg; n=6; p≤0.0001). Aldosterone plays a critical role in blood pressure regulation, we measured its urinary excretion and revealed lower levels in PP KO mice compared to virgin KO mice (4.8±0.8 vs. 13.0±3.0 pg/day; n=6; p=0.0099). PP KO mice elicited greater levels of circulating estradiol levels compared to virgin KO mice (42.8±5.2 vs. 29.5±3.4 pg/mL; n=8,6; p=0.0451). To explore the role of adrenal estrogen receptors (ER) in regulating aldosterone production, we assessed the adrenal expression of ER and CYP112B, the gene coding for aldosterone synthase. No difference was observed in ERα, however ERβ expression was higher in PP KO mice compared to virgin KO mice (2.4±0.3 vs. 1.1±0.1 fold change; n=6,5; p=0.0359). GPER1 deletion increased CYP112B expression in virgin mice (2.0±0.4 vs. 1.0±0.2 fold change; n=7,5; p=0.0265), and this was eliminated with PP (0.9±0.2 fold change; n=5; p=0.0260). Aldosterone regulates renal epithelial sodium channel (ENaC), so we assessed its subunits’ expression. Renal ENaCα and ENaCβ increases with the deletion of GPER1 in the virgin group, and this effect was lost with PP. ENaCγ withheld the same trend, but it did not reach significance. Overal, our data suggest that GPER1 and former pregnancy protect from hypertension in aged females at least partially via regulating aldosterone and ENaC signaling.

Abstract 036: The Single-cell Gene Expression Landscape Of The Hypothalamus During The Development Of Hypertension In Three Major Models

The hypothalamus plays a key role in blood pressure regulation through coordinating and integrating signals in the central nervous system. However, it’s remains underexplored how the cell signaling network in the hypothalamus changes during the progression of hypertension, the key regulators involved, and whether shared or distinct pathophysiological mechanisms underlie the development of hypertension triggered by various genetic susceptibility or environmental factors. To address these questions, we applied the single-nucleus RNA sequencing technology to analyze hypothalamus samples from three well-established models of hypertension with distinct pathogenesis - mice treated with Ang II, the Dahl salt-sensitive rat, and the spontaneous hypertensive rat - along with their respective controls. Data were obtained from 238,445 nuclei from 24 samples under 12 experimental conditions. By characterizing the cellular composition under different disease conditions, we discovered an elevated glia-to-neuron ratio in Ang II-induced hypertension, with increases of 3.1-fold in astrocytes, 4.0-fold in microglia, and 3.4-fold in oligodendrocytes. Moreover, astrocytes underwent a transition from the resting state to a reactive mode associated with neuroinflammation and stronger neuron adhesion. Additionally, multiple neuronal signal communication pathways were overactivated in response to Ang II, including neurexin-neuroligin signaling, nitric oxide-guanylate cyclase pathway, and glutamate and its receptors. In the salt-sensitive hypertension, a 2.3-fold expansion of pro-inflammatory microglia via Cd74 activation was observed after a short-term high-sodium diet, which leveled off thereafter. With a prolonged high-salt intake, there was a 1.7-fold increase in the proportion of Plagl1+ GABA-ergic neurons. In 26 weeks old spontaneously hypertensive rats, a distinctive 1.4-fold increase in the proportion of Slit3+ Glu-ergic neurons was observed, setting them apart from WKY rats. These findings provide new insights into how the hypothalamus may be involved in the development of hypertension under different disease conditions.

Association between CYP4A11 and EPHX2 genetic polymorphisms and chronic kidney disease progression in hypertensive patients

BackgroundThere is evidence indicating that some metabolites of arachidonic acid produced by cytochromes P450 (CYP) and epoxide hydroxylase (EPHX2), such as hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) or dihydroxyeicosatrienoic acids (DHETEs), play an important role in blood pressure regulation and they could contribute to the development of hypertension (HT) and kidney damage. Therefore, the main aim of the study was to evaluate whether the genetic polymorphisms of CYP2C8, CYP2C9, CYP2J2, CYP4F2, CYP4F11 and EPHX2, responsible for the formation of HETEs, EETs and DHETEs, are related to the progression of impaired renal function in a group of patients with hypertension. Methods151 HT patients from a hospital nephrology service were included in the study. Additionally, a group of 87 normotensive subjects were involved in the study as control group. For HT patients, a general biochemistry analysis, estimated glomerular filtration rate and genotyping for different CYPs and EPHX2 variant alleles were performed. ResultsCYP4A11 rs3890011, rs9332982 and EPHX2 rs41507953 polymorphisms, according to the dominant model, presented a high risk of impaired kidney function, with odds ratios (OR) of 2.07 (1.00–4.32; P=0.049), 3.02 (1.11–8.23; P=0.030) and 3.59 (1.37–9.41; P=0.009), respectively, and the EPHX2 rs1042032 polymorphism a greater risk according to the recessive model (OR=6.23; 95% CI=1.50–25.95; P=0.007). However, no significant differences in allele frequencies between HT patients and in normotensive subjects for any of the SNP analyzed. In addition, the patients with diagnosis of dyslipidemia (n=90) presented higher frequencies of EPHX2 K55R (rs41507953) and *35A>G (rs1042032) variants than patients without dyslipidemia, 4% vs. 14% (P=0.005) and 16 vs. 27% (P=0.02), respectively. ConclusionsIn this study has been found higher odds of impaired renal function progression associated with rs3890011 and rs9332982 (CYP4A11) and rs41507953 and rs1042032 (EPHX2) polymorphisms, which may serve as biomarkers for improve clinical interventions aimed at avoiding or delaying, in chronic kidney disease patients, progress to end-stage kidney disease needing dialysis or kidney transplant.

Calcium handling coupled to the endothelin ETA and ETB receptor-mediated vasoconstriction in resistance arteries: Differential regulation by PI3K, PKC and RhoK

Abnormal endothelin-1 (ET-1) activity is involved in the pathogenesis of vascular diseases such as essential and pulmonary arterial hypertension, coronary artery disease, and cerebrovascular disease, blockade of ET receptors having shown efficacy in clinical assays and experimental models of hypertension. Augmented Ca2+ influx and changes in Ca2+ sensitization associated with arterial vasoconstriction underlie increased systemic vascular resistance in hypertension. Since peripheral resistance arteries play a key role in blood pressure regulation, we aimed to determine here the specific Ca2+ signaling mechanisms linked to the ET receptor-mediated vasoconstriction in resistance arteries and their selective regulation by protein kinase C (PKC), Rho kinase (RhoK), the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK). ET-1-induced contraction was mediated by the endothelin ETA receptor with a minor contribution of vascular smooth muscle (VSM) endothelin ETB receptors. ET receptor activation elicited Ca2+ mobilization from intracellular stores, extracellular Ca2+ influx and Ca2+ sensitization associated with contraction in resistance arteries. Vasoconstriction induced by ET-1 was largely dependent on activation of canonical transient receptor potential channel 3 (TRPC3) and extracellular Ca2+ influx through nifedipine-sensitive voltage-dependent Ca2+ channels. PI3K inhibition reduced intracellular Ca2+ mobilization and Ca2+ entry without altering vasoconstriction elicited by ET-1, while PKC has dual opposite actions by enhancing Ca2+ influx associated with contraction, and by inhibiting Ca2+ release from intracellular stores. RhoK was a major determinant of the enhanced sensitivity of the contractile filaments underlying ET-1 vasoconstriction, with also a modulatory positive action on Ca2+ influx and intracellular Ca2+ release. Augmented RhoK and PKC activities are involved in vascular dysfunction in hypertension and vascular complications of insulin-resistant states, and these kinases are thus potential pharmacological targets in vascular diseases in which the ET pathway is impaired.