Mechanisms Of Blood Pressure Regulation Research Articles

Novel Metabolites Associated With Blood Pressure After Dietary Interventions.

The blood pressure (BP) etiologic study is complex due to multifactorial influences, including genetic, environmental, lifestyle, and their intricate interplays. We used a metabolomics approach to capture internal pathways and external exposures and to study BP regulation mechanisms after well-controlled dietary interventions. In the ProBP trail (Protein and Blood Pressure), a double-blinded crossover randomized controlled trial, participants underwent dietary interventions of carbohydrate, soy protein, and milk protein, receiving 40 g daily for 8 weeks, with 3-week washout periods. We measured plasma samples collected at baseline and at the end of each dietary intervention. Multivariate linear models were used to evaluate the association between metabolites and systolic/diastolic BP. Nominally significant metabolites were examined for enriching biological pathways. Significant ProBP findings were evaluated for replication among 1311 participants of the BHS (Bogalusa Heart Study), a population-based study conducted in the same area as ProBP. After Bonferroni correction for 77 independent metabolite clusters (α=6.49×10-4), 18 metabolites were significantly associated with BP at baseline or the end of a dietary intervention, of which 11 were replicated in BHS. Seven emerged as novel discoveries, which are as follows: 1-linoleoyl-GPE (18:2), 1-oleoyl-GPE (18:1), 1-stearoyl-2-linoleoyl-GPC (18:0/18:2), 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), maltose, N-stearoyl-sphinganine (d18:0/18:0), and N6-carbamoylthreonyladenosine. Pathway enrichment analyses suggested dietary protein intervention might reduce BP through pathways related to G protein-coupled receptors, incretin function, selenium micronutrient network, and mitochondrial biogenesis. Seven novel metabolites were identified to be associated with BP at the end of different dietary interventions. The beneficial effects of protein interventions might be mediated through specific metabolic pathways.

Novel Properties of Old Propranolol-Assessment of Antiglycation Activity through In Vitro and In Silico Approaches.

Hypertension has earned the "silent killer" nickname since it may lead to a number of comorbidities, including diabetes and cardiovascular diseases. Oxidative stress and protein glycation play vital roles in the pathogenesis of hypertension. Several studies have shown that they profoundly account for vascular dysfunction, endothelial damage, and disruption of blood pressure regulatory mechanisms. Of particular note are advanced glycation end products (AGEs). AGEs alter vascular tissues' functional and mechanical properties by binding to receptors for advanced glycation end products (RAGE), stimulating inflammation and free radical-mediated pathways. Propranolol, a nonselective beta-adrenergic receptor antagonist, is one of the most commonly used drugs to treat hypertension and cardiovascular diseases. Our study is the first to analyze propranolol's effects on protein glycoxidation through in vitro and in silico approaches. Bovine serum albumin (BSA) was utilized to evaluate glycoxidation inhibition by propranolol. Propranolol (1 mM) and BSA (0.09 mM) were incubated with different glycating (0.5 M glucose, fructose, and galactose for 6 days and 2.5 mM glyoxal and methylglyoxal for 12 h) or oxidizing agents (chloramine T for 1 h). Biomarkers of protein glycation (Amadori products (APs), β-amyloid (βA), and advanced glycation end products (AGEs)), protein glycoxidation (dityrosine (DT), kynurenine (KYN), and N-formylkynurenine (NFK)), protein oxidation (protein carbonyls (PCs), and advanced oxidation protein products (AOPPs)) were measured by means of colorimetric and fluorimetric methods. The scavenging of reactive oxygen species (hydrogen peroxide, hydroxyl radical, and nitric oxide) and the antioxidant capacity (2,2-diphenyl-1-picrylhydrazyl radical and ferrous ion chelating (FIC) assays)) of propranolol were also evaluated. Additionally, in silico docking was performed to showcase propranolol's interaction with BSA, glycosides, and AGE/RAGE pathway proteins. The products of protein glycation (↓APs, ↓βA, ↓AGEs), glycoxidation (↓DT, ↓KYN, ↓NFK), and oxidation (↓PCs, ↓AOPPs) prominently decreased in the BSA samples with both glycating/oxidizing factors and propranolol. The antiglycoxidant properties of propranolol were similar to those of aminoguanidine, a known protein oxidation inhibitor, and captopril, which is an established antioxidant. Propranolol showed a potent antioxidant activity in the FIC and H2O2 scavenging assays, comparable to aminoguanidine and captopril. In silico analysis indicated propranolol's antiglycative properties during its interaction with BSA, glycosidases, and AGE/RAGE pathway proteins. Our results confirm that propranolol may decrease protein oxidation and glycoxidation in vitro. Additional studies on human and animal models are vital for in vivo verification of propranolol's antiglycation activity, as this discovery might hold the key to the prevention of diabetic complications among cardiology-burdened patients.

Impact of an active lifestyle on cardiovascular autonomic modulation and oxidative stress in males with overweight and parental history of hypertension.

Family history of hypertension is associated with early autonomic dysfunction and increased oxidative stress. These alterations have been found to be reinforced by the overweight factor. Conversely, an active lifestyle is effective in improving the mechanisms regulating blood pressure control. Hence, we ought to investigate the effects of an active lifestyle on the hemodynamic, autonomic and oxidative stress parameters in individuals carrying both family history of hypertension and overweight risk factors. Fifty-six normotensive males were divided into four groups: eutrophic offspring of normotensive parents (EN, n = 12), eutrophic and inactive with hypertensive parents (EH, n = 14), overweight and inactive with hypertensive parents (OH, n = 13), and overweight and physically active with hypertensive parents (OAH, n = 17). Cardiovascular autonomic modulation was assessed by heart rate (HRV) and blood pressure (BPV) variability indexes. Oxidative stress included pro/antioxidant markers and nitrite concentration. Inactive offspring of hypertensive parents (EH and OH) showed higher LFSBP (vs EN), an indicator of sympathetic outflow to the vasculature and reduced anti-oxidant activity (vs EN), while higher pro-oxidant markers were found exclusively in OH (vs EN and EH). Conversely, the OAH group showed bradycardia, higher vagally-mediated HFabs index (vs OH and EN), lower sympathovagal balance (vs OH) and preserved LFSBP. Yet, the OAH showed preserved pro/antioxidant markers and nitrite levels. Our findings indicates that overweight offspring of hypertensive parents with an active lifestyle have improved hemodynamic, cardiac autonomic modulation and oxidative stress parameters compared to their inactive peers.

Genetic and Epigenetic Mechanisms Regulating Blood Pressure and Kidney Dysfunction.

The pioneering work of Dr Lewis K. Dahl established a relationship between kidney, salt, and high blood pressure (BP), which led to the major genetic-based experimental model of hypertension. BP, a heritable quantitative trait affected by numerous biological and environmental stimuli, is a major cause of morbidity and mortality worldwide and is considered to be a primary modifiable factor in renal, cardiovascular, and cerebrovascular diseases. Genome-wide association studies have identified monogenic and polygenic variants affecting BP in humans. Single nucleotide polymorphisms identified in genome-wide association studies have quantified the heritability of BP and the effect of genetics on hypertensive phenotype. Changes in the transcriptional program of genes may represent consequential determinants of BP, so understanding the mechanisms of the disease process has become a priority in the field. At the molecular level, the onset of hypertension is associated with reprogramming of gene expression influenced by epigenomics. This review highlights the specific genetic variants, mutations, and epigenetic factors associated with high BP and how these mechanisms affect the regulation of hypertension and kidney dysfunction.

Monogenic Hypertension Linked to the Renin-Angiotensin-Aldosterone System.

Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon's syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options.

Hypertension after the Menopause: What Can We Learn from Experimental Studies?

Hypertension is the most prevalent cardiovascular disease of the adult population and is closely associated with serious cardiovascular events. The burden of hypertension with respect to vascular and other organ damage is greater in women. These sex differences are not fully understood. The unique feature in women is their transition to menopause accompanied by profound hormonal changes that affect the vasculature that are also associated with changes of blood pressure. Results from studies of hormone replacement therapy and its effects on the cardiovascular system are controversial, and the timing of treatment after menopause seems to be important. Therefore, revealing potential sex- and sex hormone-dependent pathophysiological mechanisms of hypertension in experimental studies could provide valuable information for better treatment of hypertension and vascular impairment, especially in postmenopausal women. The experimental rat models subjected to ovariectomy mimicking menopause could be useful tools for studying the mechanisms of blood pressure regulation after menopause and during subsequent therapy.

Transgenerational effects of opioids on cardiovascular outcomes of the rat offspring

Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2020, more than 69,000 Americans died of a drug overdose involving opioids. Starting in 2014, an alarming third wave is on the rise now caused by synthetic opioids, specifically illicit fentanyl (FEN). OUD among pregnant women is an understudied area related to the opioid epidemic, showing a 5-fold increase incidence of neonatal opioid withdrawal syndrome (NOWS). Currently, the only two FDA-approved medications indicated for medication assisted treatment (MAT) during pregnancy are methadone and buprenorphine. While some general guidelines have been established to place pregnant woman on MAT, the misuse of fentanyl has challenged the current pharmacotherapies, urging for the characterization of pre-clinical models.The aim of this study was to investigate the trasngenerational effects of opioids on the cardiovascular system. We subjected female rats to opioids exposure during pregnancy. We investigated: 1) In the newborns, the morphometrics and withdrawal symptoms; 2) In the adult offspring, the locomotor sensitization 3) The short and long-term plasma endogenous opioids peptides status, and 4) the transcriptomics of brain areas involved in the neural interface between motivation and action.We found that female and male neonates from opioids-treated dams are smaller through the lifespan compared to VEH-exposed counterparts (n=6, p<0.05). Also, adult offspring exposed to MOR in utero displayed sympathetic activation and increased cardiometabolic risk factors along with increased locomotor sensitization to MOR (n=4, p<0.05). In addition, we performed RNAseq analysis of the perivascular nucleolus of the hypothalamus in MOR-exposed offspring, showing increased FOSb expression (n=3 per group). ΔFosB, encoded by the fosB gene, is induced in the brain's reward regions by chronic exposure drugs of abuse and mediates sensitized responses to drug exposure.We also found that rat neonates exposed to opiods showed behavioral NOWS-like symptoms. Importantly, we found that the prenatal exposure to opioids induces a long-term dysregulation of the endogenous opioids peptides (EOP) pro-enkephalin and pro-dynorphin.Both endogenous and exogenous opioids can bind to opioid receptors, which are G-protein coupled receptors (GPCRs) that can dimerize and affect the function of other GPCRs with important neurobehavioral functions.This study provides insights regarding how opioids could affect the programming of the mechanisms regulating blood pressure control later in life. This is the full abstract presented at the American Physiology Summit 2023 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.

A candidate locus in the renalase gene and susceptibility to blood pressure responses to the dietary salt.

High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts. A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting. A top signal (rs10887801; beta = 4.57, P = 5.03E - 07) at the renalase gene ( RNLS ) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP ( P ≤ 0.00001) and lower PRA ( P = 0.0076) compared with the nonrisk allele. We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake.

Fluid homeostasis induced by sodium-glucose cotransporter 2 inhibitors: novel insight for better cardio-renal outcomes in chronic kidney disease.

Hypertension in chronic kidney disease (CKD) patients is a risk factor for end-stage renal disease, cardiovascular events, and mortality. Thus, the prevention and appropriate management of hypertension in these patients are essential strategies for better cardio-renal outcomes. In this review, we show novel risk factors for hypertension with CKD, several promising prognostic markers and treatment for cardio-renal outcomes. Of note, the clinical use of sodium-glucose cotransporter 2 (SGLT2) inhibitors has recently expanded to non-diabetic patients with CKD and heart failure as well as diabetic patients. SGLT2 inhibitors have an antihypertensive effect, but are also associated with a low risk of hypotension. This unique mechanism of blood pressure regulation by SGLT2 inhibitors may partially depend on body fluid homeostasis, which is mediated by the autoregulation property between "accelerator" (diuretic action) and "brake" (increase in anti-diuretic hormone vasopressin and fluid intake). Mineralocorticoid receptor (MR) blockers are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR blocker, finerenone, has been launched as a treatment for CKD with type 2 diabetes. These advances in relation to hypertension in CKD may contribute to the reduction of renal and cardiovascular events.

PS-B11-9: LOW COLONIC PH AND PROTON-SENSOR GPR65: A MISSING BRIDGE LINKING DIET, GUT MICROBIOTA AND CARDIOVASCULAR HEALTH

Objective: Dietary fibre regulates blood pressure (BP) through gut microbial production of acidic metabolites called short-chain fatty acids (SCFAs). The acidic environment in the large intestine activates a proton-sensing G-protein coupled receptor, GPR65. We aimed to characterize the luminal pH in the intestine of hypertensive patients and normotensive individuals, and to validate in a murine model that dietary fibre intake is a critical determinant for intestinal pH. Furthermore, we aimed to determine whether pH-sensing by GPR65 mediates the cardiovascular protection conferred by dietary fibre. Design and method: 15 normotensive and 40 hypertensive (16 treated) participants had ambulatory BP profiles recorded using a Mobil-O-Graph device (CardioScan). Their intestinal luminal pH was measured in real-time by a SmartPillTM Motility Testing System (Medtronic). Analyses were performed on SPSS. Intestinal pH of C57BL/6J wild-type (WT) mice was measured after a 7-day dietary intervention of high-fibre (HF) or low-fibre (LF) diets (n = 5/group). Male WT and Gpr65-/- mice fed with HF or LF diets were implanted with minipumps containing angiotensin II (Ang-II, 0.5 mg/kg/day, 28 days, n = 11–12/group). BP was measured by tail-cuff, cardiac function by ultrasound, and fibrosis by Massons trichrome staining. Results: Compared to normotensive individuals, hypertensive participants had higher colonic minimum pH (mean ± SEM: 5.03 ± 0.08 vs 5.22 ± 0.34, the beta coefficient = 2.98, P = 0.024 adjusted for age, sex, BMI), driven by changes in the transverse colon where dietary fibre is fermented. In our murine model, HF fed mice exhibited lower colonic pH compared to LF fed mice (HF vs LF, 6.03 ± 0.42 vs 7.58 ± 0.31, P &lt; 0.001). This was abolished when mice were treated with antibiotics. Under HF diet, Ang-II treated Gpr65-/- mice had significantly higher BP (mean arterial pressure, WT vs Gpr65-/-, 90.7 ± 2.22 vs 101.3 ± 1.82mmHg, P = 0.022), heart to tibia length ratio (0.0096 ± 0.0004 vs 0.0112 ± 0.0018 g/mm, P = 0.036), left ventricle posterior wall in the diastole (0.831 ± 0.016 vs 0.966 ± 0.020 mm, P = 0.010), cardiac fibrosis (1.44 ± 0.15% vs 2.30 ± 0.09%, P = 0.026) and lower ejection fraction (65.65 ± 1.94% vs 54.65 ± 1.60%, P &lt; 0.001) and fractional shortening (22.70 ± 1.52% vs 15.63 ± 0.69%, P &lt; 0.001) than Ang-II treated WT mice. The cardiovascular impact of Gpr65 genotype when Ang-II mice were fed with LF diet was negligible (All P &gt; 0.05). Conclusions: This is the first evidence hypertensive participants have a higher luminal pH in the colon. This likely results from the difference in dietary fibre intake, which in a murine model profoundly determined the colonic pH. Low pH activates GPR65 signalling, which underlies the cardiovascular protection by dietary fibre. Our findings demonstrate a novel mechanism for BP regulation.

Exploring mechanisms of blood pressure regulation in response to device-guided and non-device-guided slow breathing: A mini review.

Hypertension is a widespread disease that, if persistent, increases the risks of coronary heart disease mortality and morbidity. Slow breathing is a recommended blood pressure-lowering strategy though the mechanisms mediating its effects are unknown. This review aims to evaluate autonomic and vascular function as potential mediators driving BP adaptive responses with slow breathing. We searched EBSCO host, Web of Science, Cochrane Central Register of Controlled Trials, and PubMed using key words for optimized search results. Nineteen studies were included in this review (11 device-guided; 8 non-device-guided breathing). Though some studies showed increased vagally mediated components of heart rate variability during slow breathing, results from acute and long-term studies were incongruent. Increases in baroreflex sensitivity (BRS) following a single device-guided slow breathing bout were noted in normotensive and hypertensive adults. Long-term (4weeks to 3months) effects of slow breathing on BRS were absent. Device-guided breathing resulted in immediate reductions in muscle sympathetic nerve activity (MSNA) in normo- and hyper-tensive adults though results from long-term studies yielded inconsistent findings. Non-device-guided slow breathing posed acute and chronic effects on vascular function with reductions in arterial stiffness in adults with type I diabetes and increases in microvascular endothelial function in adults with irritable bowel syndrome. Non-device guided breathing also reduced pro-inflammatory cytokines in healthy and hypertensive adults in acute and chronic studies. No adverse effects or non-adherence to treatment were noted in these trials. Device-guided slow breathing is a feasible and effective modality in improving BRS, HRV, and arterial stiffness though its long-term effects are obscure. Though less evidence exists supporting the efficacy of non-device-guided slow breathing, acute and chronic studies demonstrate improvements in vascular function and inflammatory cytokines. More studies are needed to further explore the long-term effects of slow breathing in general and non-device-guided breathing in particular.

JS-HR-2: HYPERTENSION MANAGEMENT IN CKD: UPDATE FOR BETTER CARDIO-RENAL OUTCOMES

Hypertension in CKD patients is a risk factor for end-stage renal disease, cardiovascular events, and mortality. Thus, the prevention and appropriate management of hypertension in these patients are essential strategies for better cardio-renal outcomes. Recently, novel risk factors for hypertension have been reported. Circulating fibroblast growth factor 21, an endocrine hormone mainly secreted by the liver, is associated with elevated blood pressure (BP) and/or aortic stiffness with renal dysfunction. Furthermore, several promising prognostic markers for cardio-renal outcomes have been suggested. A higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in CKD patients. Higher albumin-to-creatinine ratios significantly increased the risk of first stroke or first ischemic stroke. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and mineralocorticoid receptor (MR) blockers are promising treatment options for better cardio-renal outcomes. The clinical use of SGLT2is has recently expanded to non-diabetic patients with CKD and heart failure as well as diabetic patients. SGLT2is have an antihypertensive effect, and the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a minor reduction or slight increase is observed in patients with lower baseline BP. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis, but are also associated with a low rate of hypovolemia, which is evident by the compensatory upregulation of renin and vasopressin levels. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP and better cardio-renal outcomes. MR blockers are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been launched as a treatment for CKD with type 2 diabetes. In the FIDELIO-DKD study, finerenone significantly reduced the risk of kidney and cardiovascular events in CKD and type 2 diabetes.

A New Perspective on the Renin-Angiotensin System

Cardiovascular disease (CVD) is the leading cause of death in the world. Hypertension is a serious medical problem not only in adults but also in children and adolescents. The renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms regulating blood pressure and the balance of water and electrolytes. According to the latest reports, RAAS acts not only on endocrine but also on paracrine, autocrine, and intracrine. Moreover, RAAS has a component associated with hypotension and cardioprotective effects. These components are called alternative pathways of RAAS. The most important peptide of the alternative pathway is Ang 1-7, which is related to the Mas receptor. Mas receptors have widely known antihypertension properties, including vasodilatation, the release of nitric oxide, and increased production of anti-inflammatory cytokines. Another interesting peptide is angiotensin A, which combines the properties of the classical and alternative pathways. No less important components of RAAS are the proteolytic enzymes angiotensin convertase enzyme type 1 and 2. They are responsible for the functioning of the RAAS system and are a hypertension therapeutic target. Also involved are tissue-specific enzymes that form a local renin-angiotensin system. Currently, a combination of drugs is used in hypertension treatment. These drugs have many undesirable side effects that cannot always be avoided. For this reason, new treatments are being sought, and the greatest hope comes from the ACE2/ang 1-7/MasR axis.

TILT TEST TOLERANCE AFTER TWO-WEEKS BED REST IN OLDER ADULTS IS NOT PROTECTED BY DAILY AEROBIC AND RESISTANCE EXERCISE

Abstract Bed rest is associated with increased risk of orthostatic intolerance on return to upright posture and, at least in young adults, regular exercise during bed rest is proposed as protective. 22 older adults (55-65 years, half women) participated in a randomized trial with 14-days of continuous 6-degree head-down bed rest. Half completed 60 min/day of aerobic and high-intensity interval cycling plus resistance exercises (Ex) while the other half were control (Con). A passive 80-degree head-up tilt (HUT) to a maximum of 15-min assessed orthostatic tolerance while cardio- and cerebrovascular responses were monitored to a pre-syncopal level of systolic blood pressure &amp;lt; 90 mmHg. In pre-bed rest baseline, all but 3 women (Ex) completed 15-min HUT. After 14-days bed rest, only 3 men (1 Ex) and 1 woman (Ex) completed 15-min with no differences in tolerance between men and women or Ex and Con. Vasovagal syncope presented in 5 participants (2 M-Con, 1 M-Ex, 1 F-Con, 1 F-Ex), most other non-finishers had progressive reduction in stroke volume without adequate vasoconstriction. Reductions in cerebral blood velocity measured during HUT by Doppler ultrasound revealed strong linear relationships to both end-tidal PCO2 and mean arterial pressure across all participants. These data indicate that neither older men nor older women were protected from orthostatic intolerance by 60-min per day exercise including high-intensity interval training. These data contrast with previous findings in younger adults in controlled trials of bed rest pointing to the need for greater understanding of mechanisms regulating blood pressure and brain blood flow.

Molecular Mechanism of Blood Pressure Regulation through the Atrial Natriuretic Peptide.

Simple SummaryAtrial natriuretic peptide (ANP) is a cardiac peptide hormone that was identified by Kangawa and Matsuo in 1984. In Japan, ANP has been used as an intravenous drug for the treatment of acute heart failure since 1995. Because ANP has a hypotensive effect, it is important to avoid excessive lowering of blood pressure when ANP is used. Recently, a compound that inhibits neutral endopeptidase, the enzyme that degrades ANP, has been developed (angiotensin receptor-neprilysin inhibitor (ARNI)). ARNI has been approved worldwide for the treatment of chronic heart failure and has been authorized in Japan as an antihypertensive drug. However, it is not understood exactly how ANP exerts its hypotensive effect. In this review, we discuss the molecular mechanism of the blood pressure-regulating effects of ANP, focusing on our recent findings.Natriuretic peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), have cardioprotective effects and regulate blood pressure in mammals. ANP and BNP are hormones secreted from the heart into the bloodstream in response to increased preload and afterload. Both hormones act through natriuretic peptide receptor 1 (NPR1). In contrast, CNP acts through natriuretic peptide receptor 2 (NPR2) and was found to be produced by the vascular endothelium, chondrocytes, and cardiac fibroblasts. Based on its relatively low plasma concentration compared with ANP and BNP, CNP is thought to function as both an autocrine and a paracrine factor in the vasculature, bone, and heart. The cytoplasmic domains of both NPR1 and NPR2 display a guanylate cyclase activity that catalyzes the formation of cyclic GMP. NPR3 lacks this guanylate cyclase activity and is reportedly coupled to Gi-dependent signaling. Recently, we reported that the continuous infusion of the peptide osteocrin, an endogenous ligand of NPR3 secreted by bone and muscle cells, lowered blood pressure in wild-type mice, suggesting that endogenous natriuretic peptides play major roles in the regulation of blood pressure. Neprilysin is a neutral endopeptidase that degrades several vasoactive peptides, including natriuretic peptides. The increased worldwide clinical use of the angiotensin receptor-neprilysin inhibitor for the treatment of chronic heart failure has brought renewed attention to the physiological effects of natriuretic peptides. In this review, we provide an overview of the discovery of ANP and its translational research. We also highlight our recent findings on the blood pressure regulatory effects of ANP, focusing on its molecular mechanisms.

Abstract P034: Increased Toll-Like Receptor 4 In Perirenal Adipose Tissue Is Associated With Elevated Systolic Blood Pressure In Obese Mice

Obesity is a major risk factor for the development of vascular dysfunction and hypertension. According to the Framingham Heart Study, obesity accounts for 70% of cases of primary hypertension. Emerging evidence suggests that perirenal adipose tissue (PRAT) is linked to cardiovascular complications in obesity. Whether PRAT is linked with blood pressure regulation in obesity remains unknown. We hypothesize that, in obesity, PRAT expands and activates local Toll-like receptor 4 (TLR4), a key factor of the immune system, in association with increased systolic blood pressure (SBP). Eight-week-old male and female C57BL6 mice were randomized into two experimental groups. The control group (n=10) received a standard chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose]) and the obese group (n=10) received a Western Diet (WD) (40% fat, 43% carbohydrates [34% sucrose]) for 38 weeks. Central obesity was confirmed by increased body weight (Females: 34.88 ± 2.71 g vs. 22.86 ± 0.68 g controls, p&lt;0.001; Males: 45.39 ± 1.98 g vs. 29.21 ± 0.79 g controls, p&lt;0.0001), BMI (Females: 0.37 ± 0.01 kg/m2 vs. 0.27 ± 0.01 kg/m2 controls, p&lt;0.0001; Males: 0.45 ± 0.02 kg/m2 vs. 0.32 ± 0.01 kg/m2 controls, p&lt;0.001), and waist circumference (Females: 8.95 ± 0.44 cm vs. 7.65 ± 0.17 cm controls, p&lt;0.05; Males: 10.79 ± 0.25 cm vs. 8.70 ± 0.16 cm controls, p&lt;0.0001). Significant increase in PRAT weight was detected in the WD groups (Females: 11.78 ± 1.79 mg/g vs. 3.19 ± 0.31 mg/g controls, p&lt;0.05; Males: 17.42 ± 2.34 mg/g vs. 2.92 ± 0.43 mg/g controls, p&lt;0.001). By using radiotelemetry system, we found that SBP was significantly increased in the WD male group in the light cycle (125.12 ± 2.11 mmHg vs. 115.19 ± 2.19 mmHg controls, p&lt;0.05) and dark cycle (132.42 ± 1.72 mmHg vs. 123.13 ± 1.67 mmHg controls, p&lt;0.05). Strikingly, TLR4 expression in PRAT from male obese mice was significantly increased (2.1 fold of increase, p&lt;0.05). In conclusion, our results show that obese male mice exhibit expanded PRAT with increased TLR4 expression in association with elevated SBP, suggesting a local inflammation in PRAT potentially contributing to disturbance of renal mechanisms of blood pressure regulation.

Blood pressure regulation and mechanism of hypertension development in dogs and cats: A review

The review article aims at discussing the mechanisms of blood pressure regulation and hypertension development in dogs and cats. This will enhance the knowledge of clinicians and researchers on the pathophysiology of hypertension and mechanisms of normal blood pressure regulation in small animals. Hypertension is a risk factor for other cardiovascular diseases in man and animals, however, most small animal clinicians do not routinely check the blood pressure until the animals are presented with complications. Hypertension in animals can be essential or secondary but the secondary type is predominant. Blood pressure is regulated by vasoactive agents and hormones such as nitric oxide, bradykinin, endothelin-1, angiotensin II and aldosterone. The blood vessels and the kidney also play major roles in blood pressure regulation. Alterations in the regulation frameworks result in hypertension and cardiovascular diseases as elucidated in this review article. It is therefore essential that the body maintain good anatomic, physiologic and biochemical functions to maintain blood pressure. In conclusion, adequate knowledge of the mechanism by which blood pressure is regulated and the pathophysiology of hypertension will enhance research and potentiate the management of cardiovascular diseases and associated disorders in small animals.

Effect of Parkinson's Disease on Cardio-postural Coupling During Orthostatic Challenge.

Cardiac baroreflex and leg muscles activation are two important mechanisms for blood pressure regulation, failure of which could result in syncope and falls. Parkinson’s disease is known to be associated with cardiac baroreflex impairment and skeletal muscle dysfunction contributing to falls. However, the mechanical effect of leg muscles contractions on blood pressure (muscle-pump) and the baroreflex-like responses of leg muscles to blood pressure changes is yet to be comprehensively investigated. In this study, we examined the involvement of the cardiac baroreflex and this hypothesized reflex muscle-pump function (cardio-postural coupling) to maintain blood pressure in Parkinson’s patients and healthy controls during an orthostatic challenge induced via a head-up tilt test. We also studied the mechanical effect of the heart and leg muscles contractions on blood pressure. We recorded electrocardiogram, blood pressure and electromyogram from 21 patients with Parkinson’s disease and 18 age-matched healthy controls during supine, head-up tilt at 70°, and standing positions with eyes open. The interaction and bidirectional causalities between the cardiovascular and musculoskeletal signals were studied using wavelet transform coherence and convergent cross mapping techniques, respectively. Parkinson’s patients displayed an impaired cardiac baroreflex and a reduced mechanical effect of the heart on blood pressure during supine, tilt and standing positions. However, the effectiveness of the cardiac baroreflex decreased in both Parkinson’s patients and healthy controls during standing as compared to supine. In addition, Parkinson’s patients demonstrated cardio-postural coupling impairment along with a mechanical muscle pump dysfunction which both could lead to dizziness and falls. Moreover, the cardiac baroreflex had a limited effect on blood pressure during standing while lower limb muscles continued to contract and maintain blood pressure via the muscle-pump mechanism. The study findings highlighted altered bidirectional coupling between heart rate and blood pressure, as well as between muscle activity and blood pressure in Parkinson’s disease. The outcomes of this study could assist in the development of appropriate physical exercise programs to reduce falls in Parkinson’s disease by monitoring the cardiac baroreflex and cardio-postural coupling effect on maintaining blood pressure.

Role of Chrononutrition in the Antihypertensive Effects of Natural Bioactive Compounds.

Hypertension (HTN) is one of the main cardiovascular risk factors and is considered a major public health problem. Numerous approaches have been developed to lower blood pressure (BP) in hypertensive patients, most of them involving pharmacological treatments. Within this context, natural bioactive compounds have emerged as a promising alternative to drugs in HTN prevention. This work reviews not only the mechanisms of BP regulation by these antihypertensive compounds, but also their efficacy depending on consumption time. Although a plethora of studies has investigated food-derived compounds, such as phenolic compounds or peptides and their impact on BP, only a few addressed the relevance of time consumption. However, it is known that BP and its main regulatory mechanisms show a 24-h oscillation. Moreover, evidence shows that phenolic compounds can interact with clock genes, which regulate the biological rhythm followed by many physiological processes. Therefore, further research might be carried out to completely elucidate the interactions along the time–nutrition–hypertension axis within the framework of chrononutrition.

Вплив програми фізичної терапії на поліпшення функціонального стану серцево-судинної системи у жінок середнього віку, хворих на артеріальну гіпертензію

The purpose of the study was to prove the effectiveness of the developed program of physical therapy for women with hypertension based on the indicators of the functional state of the cardiovascular system. Materials and methods. The paper presents an analysis and generalization of modern scientific and methodological literature of domestic and foreign authors according to the Internet and the PubMed resource. A large group of medical and biological methods was used: 6-minute walk test, tonometry, registration of electrocardiogram, electroencephalogram and heart rate variability. Results and discussion. Based on the analysis of literature sources, it was found that in the problem of physical therapy of people with hypertension there are a number of unresolved issues regarding their use for effective recovery and increase adaptability. The program of physical therapy for women with hypertension was developed based on data on the etiology and pathogenesis of the disease, as well as data from previous examinations. That is why the therapies were selected according to their effect on the mechanisms of blood pressure regulation. After physical therapy according to our proposed program, the 6-minute test in women of the main group probably (p &lt;0.05) increased and amounted to 512.52±14.30 meters, which is 105.05 meters more. In women of the comparison group, this figure increased by 50.5 meters. Statistically significant (p &lt;0.05) decreased systolic and diastolic pressure to 128.2±8.9 mm Hg and 82.3±4.1, respectively. In the women of the comparison group, these reductions were not statistically significant. The ratio of sympathetic to parasympathetic activity in terms of heart rate variability changed in women of the main group from 1.7±0.11 to 0.53±0.03 (p &lt;0.05), due to a decrease in sympathetic and increased parasympathetic activity, which also manifested in a reduction in the QT interval of the electrocardiogram. In women of the comparison group, the ratio of sympathetic to parasympathetic activity changed from 1.7±0.18 to 1.04±0.06 (p &lt;0.05). After physical therapy in 100% of cases in women of the main group the power and in 85% the frequency of α-electrocardiogram rhythm decreased, which indicated a decrease in excitability and increased energy intensity of central processes. In women of the comparison group, these figures were 74% and 60%, respectively. Conclusion. The data obtained indicate the feasibility of selected means and methods of physical therapy for middle-aged women with hypertension