Pathophysiology Of Hypertension Research Articles

Pulmonary hypertension associated with diazoxide: the SUR1 paradox.

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.

Coexistence of hypertension with diabetes mellitus and its pharmacotherapy

Diabetes mellitus and hypertension are common comorbidities, as hypertension is reported to be twice as frequent in diabetic patients as people who are non- diabetics. In diabetic condition, the risk and progression of cardiac disease, peripheral vascular disease, stroke, retinopathy, and nephropathy is greatly increased in the presence of hypertension. Persistent increase in blood pressure termed hypertension, can be either primary hypertension (essential hypertension) or secondary hypertension in nature. Primary or essential hypertension is characterized by elevated blood pressure caused by inherited factors which are characteristic of essential hypertension whereas identifiable causes such as chronic kidney diseases, endocrine disorders, constriction of the kidney arteries, or the use of drugs are among the etiology of secondary hypertension. Diabetes causes hyperinsulinemia which increases the risk of hypertension. This condition increases the amount of sodium that the body absorbs. It also promotes the stimulation of the sympathetic nervous system. Treatment of both conditions is crucial as they are considered risk factors for coronary artery disease, cerebrovascular disease, renal failure and congestive heart failure. In any age group, a considerable increase in systolic blood pressure causes a significant increase in cardiovascular disease. To achieve sufficient blood pressure control, most people with hypertension and diabetes require more than one medication. This review is aimed to discuss hypertension and diabetes mellitus comorbidities and their treatment.

Determinants of serum cytokines in a population sample of healthy subjects from Iran

IntroductionCytokines are synthesized and released by immune system cells and mediate critical immune responses. Aging is associated with increased serum levels of some pro-inflammatory cytokines . A positive correlation between the concentration of several cytokines and blood pressure has been reported; higher cytokine concentrations may be related to the underlying causes of hypertension through the effects of inflammatory responses or as an independent etiology for hypertension .To assess the relationship between the serum levels of inflammatory cytokines and growth factors, with biochemical and anthropometric characteristics in healthy Iranian subjects.Material and methodsAnthropometric measurements and blood sampling were performed in 103 healthy Iranian participants. Fasting blood glucose (FBG), hs-CRP and lipid profile were measured in these participants. 12 serum cytokines/growth factors (MCP-1, TNF-α, EGF, IFN-γ, VEGF, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8 and IL-10 were measured.ResultsFBG was positively associated with serum IL-2, IL-4 and IL-1α (P = 0.044, < 0.001 and = 0.017, respectively). Serum EGF and IL-4 were positively associated with age (P < 0.001). IL-8 was inversely associated with SBP (P = 0.002) and gender (P = 0.028). There was a positive association between VEGF and HDL (P = 0.007). The serum levels of IFN-γ and TNF-α were positively associated with serum TG (P = 0.018 and 0.006, respectively).ConclusionsThere are associations between various pro-and anti-inflammatory cytokines in serum and several anthropometric measurements.

A randomized controlled trial comparing the efficacy of nifedipine and enalapril in the postpartum period

Postpartum hypertension is a common medical complication of pregnancy and is associated with increased healthcare use, including unplanned interactions with the medical system and readmission, which can add significant stress to both a newly postpartum patient and the medical care delivery system. We currently do not know what the best antihypertensive treatment for postpartum hypertension is and tend to use antihypertensives commonly used during pregnancy. However, the mechanism of action of angiotensin-converting enzyme inhibitors may be well suited for the pathophysiology of hypertension in the postpartum period and may help to provide better control of hypertension and, in turn, decrease healthcare use. This study aimed to determine if enalapril is superior to nifedipine in preventing prolonged hospitalizations, unplanned medical visits, and/or readmission among women with postpartum hypertension. We performed an open-label, randomized controlled trial(ClinicalTrials.gov registered: NCT04236258)in which patients≥18 years with chronic hypertension, gestational hypertension, or preeclampsia were recruited to receive either 10 mg enalapril daily or 30 mg extended-release nifedipine daily as an initial antihypertensive agent in the period from delivery to 6 weeks postpartum. Recruitment occurred at a tertiary academic hospital from January 2020 to February 2021. Exclusion criteria included being on an antihypertensive when pregnancy started or requiring≥2 daily antihypertensives during pregnancy. The antihypertensive regimen was managed by the participants' obstetrical provider after the initial randomization. The primary outcome was a composite of prolonged hospitalization, unplanned clinic visits, triage visits, and/or readmission. A total of 40 patients in each arm were needed to detect a decrease in the primary outcome rate from 70% to 40% (α=0.05; power 0.80). Analyses were performed based on the intention-to-treat principal, and each arm was oversampled because of the risk for participant dropout. A total of 47 patients were randomized to each arm. Aside from the mode of delivery and twin gestation, the maternal demographics were similar between the 2 groups. The primary outcome occurred in 31 of 47 patients (66%) randomized to the nifedipine group and in 30 of 47 (64%) randomized to the enalapril group (P=.83). There was no significant difference in the primary outcome after controlling for mode of delivery and twin gestation. More patients in the enalapril arm had a second antihypertensive added during their primary hospitalization (16 vs 6) and more patients in the nifedipine arm were still on their antihypertensive at 2 weeks postpartum (42 vs 36). There were no adverse events in either group. Enalapril was not superior to nifedipine when used as an initial antihypertensive in the immediate postpartum period in terms of decreasing healthcare use.

Unraveling the relationship between the renin-angiotensin system and endometrial cancer: a comprehensive review.

Endometrial cancer (EC), the most common adenocarcinoma, represents 90% of uterine cancer in women with an increased incidence of occurrence attributed to age, obesity, hypertension, and hypoestrogenism. Being the most common gynecological malignancy in women, it shows a relation with the activation of different components of the renin-angiotensin system (RAS), which is predominantly involved in maintaining blood pressure, salt, water, and aldosterone secretion, thereby playing a significant role in the etiology of hypertension. The components of the RAS, i.e., ACE-I, ACE-II, AT1R, AT2R, and Pro(renin) receptor, are widely expressed in both glandular and stromal cells of the endometrium, with varying levels throughout the different phases of the menstrual cycle. This causes the endometrial RAS to implicate angiogenesis, neovascularization, and cell proliferation. Thus, dysfunctioning of the endometrial RAS could predispose the growth and spread of EC. Interestingly, the increased expression of AngII, AGTR1, and AGTR2 showed advancement in the stages and progression of EC via the prorenin/ATP6AP2 and AngII/AGTR1 pathway. Therefore, this review corresponds to unraveling the relationship between the progression and development of endometrial cancer with the dysfunction in the expression of various components associated with RAS in maintaining blood pressure.

FRI161 An in Vitro Triple Screen Model for Human Mineralocorticoid Receptor Activity

Abstract Disclosure: H. Liu: None. S.M. Konzen: None. A. Coy: None. J. Rege: None. C.E. Gomez-Sanchez: None. W.E. Rainey: None. A.F. Turcu: None. Background: The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron. MR is expressed in a variety of other tissues, including gastrointestinal tract, exocrine glands, central nervous system, heart, and adipose tissue. Aldosterone, the prototypical mineralocorticoid, regulates electrolyte and fluid balance. Cortisol binds to MR with equal affinity to aldosterone. In humans, cortisol concentrations far exceed those of aldosterone, but many MR-expressing tissues inactivate cortisol to cortisone via 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Dysregulated MR activation contributes to direct cardiovascular tissue insults. Besides aldosterone and cortisol, a variety of MR agonists and/or HSD11B2 inhibitors are putative players in the pathophysiology of low-renin hypertension (LRH), and cardiovascular and metabolic pathology. Objective: To develop an in vitro human MR (hMR) model, to facilitate screening for MR agonists, antagonists, and HSD11B2 inhibitors. Methods: The CV1 monkey kidney cells were transduced with lentivirus to stably express hMR and an MR-responsive gaussian luciferase gene. Clonal populations of MR-expressing cells (CV1-MRluc) were further transduced to express HSD11B2 (CV1-MRluc-HSD11B2). CV1-MRluc and CV1-MRluc-HSD11B2 cells were treated with aldosterone, cortisol, 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18OHB), 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), progesterone, or 17-hydroxyprogesterone (17OHP). Cells were also treated with serum from patients with LRH (N=3) or primary hypertension (PH, N=3). Luminescence was measured in conditioned medium using coelenterazine. Results: In CV1-MRLuc cells, aldosterone and DOC displayed similar potency (EC50: 0.45nM and 0.30nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6nM and 56.0nM, respectively) but similar maximal hMR activation (25- and 27-fold increase, respectively); cortisol and corticosterone exhibited higher maximal responses (73- and 52-fold, respectively); 18OHF showed no MR activation. Progesterone and 17OHP inhibited aldosterone-mediated MR activation. In the MRluc-HSD11B2 model, the EC50 of cortisol for MR activation increased from 20nM (CV1-MRLuc) to 850nM, while the EC50 for aldosterone remained unchanged. Serum from patients with both LRH and PH led to variable degrees of luminescence in the CV1-MRLuc cells, but not in the CV1-MRluc-HSD11B2 cells, suggesting a cortisol-mediated MR activation in these patients, possibly via glycyrrhetinic acid-like factors. Conclusions: Together, these two cell models will facilitate the discovery of novel MR-modulators, informing MR-mediated pathophysiology mechanisms and drug development efforts. Presentation Date: Friday, June 16, 2023

The Modulation Effect of a Fermented Bee Pollen Postbiotic on Cardiovascular Microbiota and Therapeutic Perspectives.

Hypertension is a frequent comorbidity in patients with heart failure; therefore, blood pressure management for these patients is widely recommended in medical guidelines. Bee pollen and postbiotics that contain inactivated probiotic cells and their metabolites have emerged as promising bioactive compounds sources, and their potential role in mitigating cardiovascular (CV) risks is currently being unveiled. Therefore, this preliminary study aimed to investigate the impact of a lactic-fermented bee pollen postbiotic (FBPP) on the CV microbiota via in vitro tests. A new isolated Lactobacillus spp. strain from the digestive tract of bees was used to ferment pollen, obtaining liquid and dried atomized caps postbiotics. The modulating effects on a CV microbiota that corresponds to the pathophysiology of hypertension were investigated using microbiological methods and qPCR and correlated with the metabolic profile. Both liquid and dried FBPPs increased the number of the beneficial Lactobacillus spp. and Bifidobacterium spp. bacteria by up to 2 log/mL, while the opportunistic pathogen E. coli, which contributes to CV pathogenesis, decreased by 3 log/mL. The short-chain fatty acid (SCFA) profile revealed a significant increase in lactic (6.386 ± 0.106 g/L) and acetic (4.284 ± 0.017 g/L) acids, both with known antihypertensive effects, and the presence of isovaleric acid, which promotes a healthy gut microbiota. Understanding the impact of the FBPP on gut microbiota could lead to innovative strategies for promoting heart health and preventing cardiovascular diseases.

Role of monocytes/macrophages in renin-angiotensin system-induced hypertension and end organ damage.

The renin-angiotensin system (RAS) is a central modulator of cardiovascular physiology. Pathophysiology of hypertension is commonly accompanied by hyper-activation of RAS. Angiotensin II receptor blockers (ARBs) and Angiotensin-converting enzyme (ACE) inhibitors are the gold standard treatment for hypertension. Recently, several studies highlighted the crucial role of immune system in hypertension. Angiotensin-II-induced hypertension is associated with low grade inflammation characterized by innate and adaptive immune system dysfunction. Throughout the progression of hypertension, monocyte/macrophage cells appear to have a crucial role in vascular inflammation and interaction with the arterial wall. Since myelomonocytic cells potentially play a key role in angiotensin-II-induced hypertension and organ damage, pharmacological targeting of RAS components in monocyte/macrophages may possibly present an innovative strategy for treatment of hypertension and related pathology.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. This was a single-centre, retrospective study with a median follow-up of 365days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5±13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1±20.4%; mean pulmonary arterial pressure, ≥25mmHg; and pulmonary arterial wedge pressure (PAWP), >15mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26±2.22mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11±2.29mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P=0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Diagnostic imaging in determining the signs of possible bleeding from gastric varicose veins (literature review)

Annotation. Gastric varicose veins are one of the common causes of gastrointestinal bleeding in patients with portal hypertension. Bleeding of this localization has a greater percentage of death and difficulty in achieving hemostasis than bleeding from esophageal varices. This paper discusses the etiology and main aspects of the pathophysiology of portal hypertension, the mechanisms of bleeding, which play an important role in the prevention of complications prevention. The venous outflow from the stomach, variants of porto-systemic collateral anastomoses and types of varicose veins of the stomach itself are presented in sufficient detail. The advantages and disadvantages of diagnostic imaging in the assessment of gastric varicose veins and the possible prediction of the risk of bleeding are demonstrated.Aim: to analyze the data of foreign and domestic literature on varicose veins of the stomach, to identify criteria that determine the risks of bleeding according to the methods of diagnostic imaging.Results. Analysis of foreign and domestic literature showed that the problem of diagnosing gastric varicose veins is extremely relevant and requires special consideration of all its various aspects. There are many diagnostic methods with certain advantages and disadvantages. But, in our opinion, the possibilities of non-invasive methods, especially computed tomography, in the diagnosis of varicose veins of the stomach and the prognosis of bleeding from them are underestimated and require further study.

Portal Hypertension in Children at the Department of Pediatric Gastroenterology & Nutrition, BSMMU, Dhaka, Bangladesh

Background: Portal hypertension is the hemodynamic abnormality frequently associated with serious liver disease, although it is recognized in a variety of extrahepatic diseases also. Portal hypertension is an important cause of morbidity and mortality in Bangladeshi children. Development of esophageal varices and bleeding is one of the major complications of CLD. The mortality from each episode of variceal bleeding is 30-50% depending on the clinical status of the patient. All conditions that interfere with blood flow at any level within the portal system can lead to portal hypertension. For better management of this disorder, it is important to determine the underlying cause. Objective: To assess the portal hypertension in children at the Department of Pediatric Gastroenterology & Nutrition, BSMMU, Dhaka, Bangladesh. Methods: This cross-sectional descriptive study was conducted at the Department of Pediatric Gastroenterology & Nutrition, BSMMU during the period Jan 2018 to July 2019. 50 patients who were diagnosed as portal hypertension were determined by Upper GI Endoscopy. Doppler USG was also done for supporting the diagnosis of Portal HTN as well as to differentiate between extrahepatic Portal HTN and CLD with portal HTN. Demographic data and other related information regarding etiology and complications were recorded in a standard datasheet. Results: Results: A total of 50 cases were included in this study. Their age range was 1.5-16 years. It was observed that 21 (42.0%) patients belonged to age group 6-10 years. The mean age was 9.22±9.85 years with ranged from 2.5 to 16 years. It was observed that almost two third 31 (62.0%) patients were male and 19 (38.0%) were female. Among 50 patients 29 were diagnosed as extrahepatic portal hypertension and 21 were diagnosed as CLD with portal HTN. Shows the etiology of portal hypertension of studied patients. Extrahepatic portal hypertension was the most common etiology (58.0%). Among CLD patients Wilson disease was the most common (13; 26.0%). Two (4.0%) patients were cryptogenic CLD and two (4.0%) were Budd Chiari Syndrome. One patient was Biliary cirrhosis and one patient had Auto immune hepatitis. Conclusion: We concluded that Extrahepatic Portal HTN is the most common cause of portal hypertension in children in this center. Among the intrahepatic causes of portal HTN Wilson disease was the

Plasma untargeted metabolomics with proteinase K discloses phospholipid signature associated with pulmonary arterial hypertension

Pulmonary arterial hypertension is a rare but life-threatening and clinically heterogeneous disease. The diagnostic schedule of this disorder is complex, and no specific indicator of the arterial etiology has been explored. In this study, untargeted plasma metabolomics was applied to evaluate the metabolic fingerprints of pulmonary arterial hypertension patients. Plasma samples were prepared using a new approach, which applies proteinase K during the sample preparation procedure to increase the metabolite coverage. The metabolic fingerprints were determined via LC–MS and subsequently analyzed with the use of both uni- and multivariate statistics. A total of 21 metabolites were discovered to be significantly altered in pulmonary arterial hypertensive patients. The metabolites were mainly related to the phospholipid metabolic pathways. In this study, decreases were found in the phosphatidylcholines (PCs) [PC(32:0), PC(40:7), PC(42:7)], phosphatidylethanolamine PE(18:0/18:2), lysophosphatidylethanolamines (LPEs) [LPE(22:6), LPE(18:2), LPE(18:0), LPE(20:4), LPE(20:1), LPE(20:0)], lysophosphatidylcholine LPC(20:4) and lysophosphatidylserine LPS(19:0), as well as increase of sphingomyelin SM(36:2), in the plasma samples of pulmonary arterial hypertensive patients in comparison to the control group. Besides their function as components of the biological membranes, these metabolites are also involved in the intracellular signaling pathways that are related to cell proliferation and apoptosis. The results obtained during this study confirm the potential of (untargeted) metabolomics to identify the molecular characteristics of the pathophysiology of pulmonary arterial hypertension. The clinical relevance of this study constitutes the selection of a metabolic panel that can potentially detect and properly diagnose the disease.

Pathophysiology of primary hypertension in children and adolescents.

The progress in research on the physiology of the cardiovascular system made in the last 100years allowed for the development of the pathogenesis not only of secondary forms of hypertension but also of primary hypertension. The main determinants of blood pressure are described by the relationship between stroke volume, heart rate, peripheral resistance, and arterial stiffness. The theories developed by Guyton and Folkow describe the importance of the volume factor and total peripheral resistance. However, none of them fully presents the pathogenesis of essential hypertension. The multifactorial model of primary hypertension pathogenesis developed by Irving Page in the 1940s, called Page's mosaic, covers most of the pathophysiological phenomena observed in essential hypertension. The most important pathophysiological phenomena included in Page's mosaic form a network of interconnected "nodes". New discoveries both from experimental and clinical studies made in recent decades have allowed the original Page mosaic to be modified and the addition of new pathophysiological nodes. Most of the clinical studies confirming the validity of the multifactorial pathogenesis of primary hypertension concern adults. However, hypertension develops in childhood and is even perinatally programmed. Therefore, the next nodes in Page's mosaic should be age and perinatal factors. This article presents data from pediatric clinical trials describing the most important pathophysiological processes associated with the development of essential hypertension in children and adolescents.

End-Organ Damage in Hypertension: An Insight on a Differentiated Outpatient Consultation.

The objective of this study was to determine the prevalence of end-organ damage in hypertensive patients attending an outpatient consultation. Patients were selected from an outpatient consultation at a tertiary hospital care center. All patients who consulted between July 2022 and March 2023 were included. Data on demographic characteristics, blood pressure records, hypertension etiology, medication use, and the presence of target organ damage were collected. A total of 73 patients were included in the study, with 34 patients being male (46.6%) and 39 patients being female (53.4%). The mean age of the patients was 49.8 years. Among the cases of hypertension, 14 (19.2%) were classified as secondary arterial hypertension (AH). The most common cause of secondary AH was obstructive sleep apnea (OSA) (42.9%). Approximately 23.2% of patients had documented end-organ damage potentially related to hypertension, with kidney disease being the most frequent (n = 10, 13.7%). The most commonly prescribed pharmacological classes were angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists (n = 46, 63%). Despite numerous studies and trials on arterial hypertension, it remains a significant contributor to morbidity and mortality, necessitating the continued awareness of its long-term implications.

Alkaloids as Vasodilator Agents: a Review.

The pathophysiology of hypertension is often associated with endothelial dysfunction and the impairment of endothelium-dependent vasodilation mechanisms, as well as alterations in vascular smooth muscle (VSM) tone. Natural products, particularly alkaloids, have received increased attention in the search for new vasodilator agents. This review aims to summarize the noteworthy results from ex-vivo and in-vitro studies that explored the vasodilatory effects of some selected alkaloids (Berberine, Sinomenine, (S)-Reticuline, Neferine, Nuciferine, Villocarine A, 8-Oxo-9-Dihydromakonakine, Harmaline, Harman, and Capsaicin) and the underlying mechanisms implicated. The results obtained from the literature revealed that these selected alkaloids exhibited vasodilation in various vascular models, including mesenteric, carotid, and coronary arteries, thoracic aorta, and cultured HUCECs and VSMCs. Furthermore, most of these alkaloids induced vasodilation through endothelium-dependent and endothelium-independent mechanisms, which were primarily mediated by activating eNOS/NO/sGC/cGMP pathway, opening various potassium (K+ ) channels, or modulating calcium (Ca2+) channels. Additionally, several alkaloids exerted vasodilatory effects through multiple mechanism pathways. Moreover, different alkaloids demonstrated the ability to protect endothelial function by reducing oxidative stress, endoplasmic reticulum and inflammation. In conclusion, this class of secondary metabolites holds interesting therapeutic potential in the prevention and treatment of cardiovascular diseases (CVD), particularly hypertension.

Metabolic profile of blood serum in experimental arterial hypertension.

The etiology of essential hypertension is intricate, since it employs simultaneously various body systems related to the regulation of blood pressure in one way or another: the sympathetic nervous system, renin-angiotensin-aldosterone and hypothalamic-pituitary-adrenal systems, renal and endothelial mechanisms. The pathogenesis of hypertension is influenced by a variety of both genetic and environmental factors, which determines the heterogeneity of the disease in human population. Hence, there is a need to perform research on experimental models - inbred animal strains, one of them being ISIAH rat strain, which is designed to simulate inherited stress-induced arterial hypertension as close as possible to primary (or essential) hypertension in humans. To determine specific markers of diseases, various omics technologies are applied, including metabolomics, which makes it possible to evaluate the content of low-molecular compounds - amino acids, lipids, carbohydrates, nucleic acids fragments - in biological samples available for clinical analysis (blood and urine). We analyzed the metabolic profile of the blood serum of male ISIAH rats with a genetic stress-dependent form of arterial hypertension in comparison with the normotensive WAG rats. Using the method of nuclear magnetic resonance spectroscopy (NMR spectroscopy), 56 metabolites in blood serum samples were identified, 18 of which were shown to have significant interstrain differences in serum concentrations. Statistical analysis of the data obtained showed that the hypertensive status of ISIAH rats is characterized by increased concentrations of leucine, isoleucine, valine, myo-inositol, isobutyrate, glutamate, glutamine, ornithine and creatine phosphate, and reduced concentrations of 2-hydroxyisobutyrate, betaine, tyrosine and tryptophan. Such a ratio of the metabolite concentrations is associated with changes in the regulation of glucose metabolism (metabolic markers - leucine, isoleucine, valine, myo-inositol), of nitric oxide synthesis (ornithine) and catecholamine pathway (tyrosine), and with inflammatory processes (metabolic markers - betaine, tryptophan), all of these changes being typical for hypertensive status. Thus, metabolic profiling of the stress-dependent form of arterial hypertension seems to be an important result for a personalized approach to the prevention and treatment of hypertensive disease.

Associations of CKIP-1 and LOX-1 polymorphisms with the risk of type 2 diabetes mellitus with hypertension among Chinese adults.

Type 2 diabetes mellitus (T2DM) and hypertension are common high-incidence diseases, closely related, and have common pathogenic basis such as oxidative stress. Casein kinase 2 interacting protein-1 (CKIP-1) and low-density lipoprotein receptor (LOX-1) are considered to be important factors affect the level of oxidative stress in the body. The main purpose of this study was to explore the relationship between CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 (rs1050283 G > A, rs11053646 C > G) polymorphisms and the risk of hypertension and diabetes, and try to find new candidate genes for diabetes and diabetes with hypertension etiology in Chinese population. 574 T2DM patients and 597 controlsfrequently matched by age and sex were selected for genotyping of CKIP-1 (rs6693817 A > T, rs2306235 C > G) and LOX-1 gene (rs1050283 G > A, rs11053646 C > G). Logistic regression was used to analyze the correlation between different genotypes and the risk of T2DM and T2DM with hypertension, and the results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). We found that the risk of T2DM in the AA + AT genotype of rs6693817 was higher than that in the TT genotype in Chinese population (OR = 1.318, 95%CI: 1.011-1.717, P = 0.041), and the difference was still significant after adjustment (OR = 1.370, 95%CI: 1.043-1.799, Padjusted = 0.024), the difference of heterozygotes (AT vs TT: OR = 1.374, 95%CI: 1.026-1.840, Padjusted = 0.033) was statistically significant. But after Bonferroni correction, the significance of the above sites disappeared. And rs6693817 was associated with the risk of T2DM combined with hypertension before and after adjustment in dominant model (OR = 1.424, 95% CI: 1.038-1.954, P = 0.028; OR = 1.460, 95% CI: 1.057-2.015, Padjusted = 0.021, respectively) and in heterozygote model (OR = 1.499, 95% CI: 1.069-2.102, P = 0.019; OR = 1.562, 95% CI: 1.106-2.207, Padjusted = 0.011, respectively). However, only the statistical significance of the heterozygous model remained after Bonferroni correction. rs2306235, rs1050283 and rs11053646 were not significantly correlated with T2DM and T2DM combined with hypertension risk (P > 0.05). The results suggest that CKIP-1 rs6693817 is related to the susceptibility of Chinese people to T2DM with hypertension, providing a new genetic target for the treatment of diabetes with hypertension with in the future.

Parental History of Hypertension: A Risk for Autonomic Dysfunction and Metabolic and Vascular Derangement in Normotensive Male Offspring.

Children of hypertensive parents have an increased propensity of developing hypertension, at an age very much prior to their parents. Understanding the pathophysiology of hypertension in such young individuals, especially baroreflex sensitivity (BRS), is necessary. Reduced heart rate variability (HRV), insulin resistance (IR), dyslipidemia, and decreased vasodilatory adipokines, namely, apelin and relaxin, in normotensives may predispose to the onset of hypertension. Thus, this study compared autonomic functions, vascular markers, and metabolic profiles between normotensive male offspring with and without parental hypertension. This analytical cross-sectional study comprised 40 male normotensive offspring of hypertensive parents, aged 18-35 years, recruited as the study group and 40 age- and body mass index (BMI)-matched normotensive male offspring with non-hypertensive parents enrolled as controls. Cardiovascular autonomic functions, including BRS, HRV, diastolic blood pressure response to isometric handgrip test (ΔDBPIHG), Valsalva ratio, and metabolic and vascular markers, were assessed. The study group exhibited reduced BRS, HRV, and Valsalva ratio and higher ΔDBPIHG compared to controls, indicating impaired autonomic functions. The study group had higher IR and triglyceride levels and reduced apelin and relaxin levels. BRS showed significant correlations with HRV, Valsalva ratio, ΔDBPIHG, and metabolic and vascular markers. Normotensive male offspring of hypertensive parents exhibit impaired autonomic functions, as evidenced by reduced BRS, HRV, and Valsalva ratio. Additionally, they have higher IR, dyslipidemia, and decreased levels of vasodilatory adipokines, indicating an increased risk for future hypertension development. These findings signify that early identification of hypertensive potential in this high-risk population is warranted, which would enable taking necessary preventive measures.

Regulatory Effects of GPR158 Overexpression in Trabecular Meshwork Cells of the Eye’s Aqueous Outflow Pathways

Elevated intraocular pressure (IOP), the major risk factor for glaucoma, is caused by decreased outflow through the trabecular meshwork (TM). The pathophysiology of ocular hypertension has been linked to stress pathways, including fibrosis, calcification and the unfolded protein response (UPR). In a pharmacogenomic screen, we previously identified the novel G-protein-coupled receptor (GPCR), GPR158, showed that expression is upregulated in TM cells by glucocorticoid stress hormones, and showed that overexpression protects against oxidative stress. We also found that loss of Gpr158 in knockout mice negates IOP reduction due to treatment with the catecholamine stress hormone, epinephrine. An increase in GPR158 would be expected to alter the activity of GPR158-regulated pathways. Here, we profiled gene expression changes due to GPR158 overexpression by microarray, then conducted pathway analysis. We identified five upstream stress regulators relevant to ocular hypertension: dexamethasone and TGFB1 (fibrosis), XBP1 and ATF4 (UPR), and TP53 (cell cycle arrest). Key genes in the first three pathways were downregulated by GPR158 overexpression, but not enough to inhibit dexamethasone-induced fibrosis or calcification in TM cells, and loss of Gpr158 in knockout mice only minimally protected against dexamethasone-induced ocular hypertension. Depending on dose, GPR158 overexpression down- or upregulated the TP53 pathway, suggesting the mechanism for previously observed effects on cell proliferation. A sixth upstream regulator we identified was a GPCR: the beta-adrenergic receptor ADRB1. Adrenergic receptors serve as targets for IOP-lowering drugs, including epinephrine. These data provide new information about pathways regulated by GPR158.

Abstract P321: <RKER-012, A Novel Activin Receptor Type Ilb (actrllb) Ligand Trap, Inhibited Mediators Of Dysregulated Vascular Remodeling In Pulmonary Arterial Endothelial And Smooth Muscle Cells>

Rationale: Imbalance in TGF-β signaling molecules SMAD2/3 and SMAD1/5/9 is a key driver of vascular dysfunction and pulmonary arterial hypertension (PAH) pathophysiology. KER-012, a novel ActRIIB ligand trap, designed to bind activin (Act) A and ActB to inhibit SMAD2/3: thereby permitting bone morphogenic protein (BMP) ligand signaling via SMAD1/5/9 to potentially rebalance TGF-β signaling and restore vascular homeostasis in PAH and associated disorders. Methods: Using hypoxia (1% O2) to mimic the pulmonary cell environment of PAH, we evaluated the effect of KER-012 or RKER -012 (a research form of KER-012) on TGF-β signaling in human pulmonary arterial endothelial cells (HPAECs) and smooth muscle cells (HPASMCs), two key cell types involved in the vascular remodeling in PAH. Gene expression of hypoxia/normoxia cultured cells was assessed by qPCR, phosphorylation of SMAD2 (pSMAD2) by alphaLISA, and ActA protein levels by ELISA. Results: HPAECs and HPASMCs both responded to TGF-β ligands implicated in PAH. ActA and Growth Differentiation Factor (GDF)11 increased SMAD2 phosphorylation and BMP9 increased SMAD1 phosphorylation (pSMAD1), confirming activation of the respective signaling pathways. KER-012 inhibited ActA and GDF11 induced pSMAD2, but not BMP9 induced pSMAD1. In hypoxic HPAECs, ActA gene expression increased >3-fold and BMPR2 expression decreased >2-fold relative to normoxia. ActA protein levels from hypoxic HPAEC supernatant also increased 10-fold, which was associated with an observed increase in pSMAD2 activation. While RKER-012 did not affect ActA gene expression, it did reduce ActA protein levels in supernatant to normoxic levels. This reduction in ActA may represent the fraction not bound to RKER-012, and potentially demonstrates a reduction in ActA availability for SMAD2/3 activation. Conclusions: ActA inhibition by RKER-012 restored homeostatic SMAD2 signaling in HPAECs and HPASMCs in an in vitr o PAH hypoxia model. RKER012 has also shown not to effect BMP signaling in these cells. These studies suggest that RKER-012 can potentially correct imbalanced SMAD signaling in PAH, partially via binding and inhibition of ActA protein.