Control Of Systemic Blood Pressure Research Articles

К ВОПРОСУ ОБ ОЦЕНКЕ ОРТОСТАТИЧЕСКОЙ УСТОЙЧИВОСТИ ОРГАНИЗМА ЧЕЛОВЕКА

Ratio of blood pressure (BP) and heart rate (HR) has been used as a quantitative indicator of the human orthostatic tolerance. The indicator was conventionally designated as an efficiency coefficient (EC) of the mechanisms involved in systemic BP control during the passive orthostatic test (POT). The coefficient is measured in conventional units and calculated by formula EC (conv.unit) = BP (mm Hg) / HR (beats/min). Informativity of this indicator was verified by means of a retrospective analysis of 118 POTs performed by 30 essentially healthy male subjects (aged 19 to 40 yrs) before and after bed rest of varying duration. Prior to POT, EC in supine position made up 1.88 ± 0.04 conv. units. The EC decrease to 1.3 – 0.95 conv. units during POT evidenced clearly the extent of changes in the cardiovascular functioning and POT endurance. After bed rest, all subjects demonstrated an increased cardiovascular strain and reduced POT endurance; however, EC values were reliably higher for the subjects who had shown a higher POT endurance before bed rest. Based on analysis of individual reactions, the EC reduction to 1 conv.unit corresponded to the first pre-collapse signs and called for immediate POT termination. These results of the investigation make us believe that EC is an informative objective criterion for orthostatic tolerance evaluation that can be proposed for aerospace medicine applications.

The Fate of Angiotensin II in Placental Tissue and Blood.

The existence of a non-canonical pathway of renin-angiotensin system in the blood pressure control system has been highlighted over the past three decades. The enzymes involved in this pathway include a series of angiotensinases such as neprilysin (NEP), aminopeptidase A (APA), carboxypeptidase, and angiotensin converting enzyme 2. The physiological roles of these peptidases have been reconsidered in this study, based on the publications of other research groups and the results from our previous study, regarding the liberation of constituent amino acids from angiotensin II by placenta tissue and blood serum, respectively.

Retraction statement: Role of the immune system in vascular function and blood pressure control induced by faecal microbiota transplantation in rats.

Toral, M, Robles-Vera, I, de la Visitación, N, et al. Role of the immune system in vascular function and blood pressure control induced by faecal microbiota transplantation in rats. Acta Physiol. 2019; 227:e13285. https://doi.org/10.1111/apha.13285. The above article, published online on April 20, 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Pontus B. Persson, the Scandinavian Physiological Society, and John Wiley and Sons Ltd. The retraction has been agreed due to the similarity of a figure and inconsistencies regarding underlying data between this article and the following article published in Front Physiol, "Critical Role of the Interaction Gut Microbiota-Sympathetic Nervous System in the Regulation of Blood Pressure" by Toral M, Robles-Vera I, de la Visitación N, et al., 2019; 10:231. doi: 10.3389/fphys.2019.00231.

"The Chemical Engineer’s Perspective on the Role of the Central Nervous System (CNS) in Blood Pressure Control "

"The Chemical Engineer’s Perspective on the Role of the Central Nervous System (CNS) in Blood Pressure Control "

Left Atrial Structural and Functional Response in Kidney Transplant Recipients Treated With Mesenchymal Stromal Cell Therapy and Early Tacrolimus Withdrawal

Autologous bone marrow-derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation. Kidney transplant recipients randomized to MSC therapy-infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)-or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable. Fifty-four participants (MSC therapy=27; tacrolimus therapy=27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P=.021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P=.012 and P=.027, respectively). The combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax.

Relationship between blood pressure and intraocular pressure in the JPHC-NEXT eye study

Although a positive link between hypertension and intraocular pressure (IOP) has been suggested, the individual effects of systolic and diastolic blood pressure (SBP and DBP, respectively) on IOP remain unclear, particularly among Japanese populations. Here, we conducted a large-scale, cross-sectional study to determine individual and combined effects of SBP/DBP and hypertension on IOP. In total, 6783 Japanese people aged over 40 years underwent systemic and ophthalmological examinations, including measurements of blood pressure and IOP, conducted using non-contact tonometers. After adjusting for a priori known confounding factors, SBP and DBP levels were found to be positively correlated with IOP levels. The multivariable-adjusted odds ratio when comparing the hypertensive and normotensive groups for the prevalence of ocular hypertension was 1.88 (95% confidence interval, 1.14–3.08). When analysing the combined effects of SBP and DBP on ocular hypertension, SBP elevation had a greater effect on ocular hypertension than DBP increase. In conclusion, SBP and DBP levels and the prevalence of systemic hypertension were found to be positively associated with IOP levels and the prevalence of ocular hypertension in an ophthalmologically healthy Japanese population. Our findings suggest that systemic blood pressure control may be key for controlling IOP.

Antagonistic Atrial Natriuretic Peptide with the Renin-Angiotensin-Aldosterone System and Effects on Systemic Blood Pressure Regulation

The atrial natriuretic peptide (ANP) presents, from the point of view of systemic blood pressure regulation, a relevant antagonistic association when compared to the renin-angiotensin-aldosterone system (RAAS). Through a careful review, the aim of the study was to evidence the process and the link between systems and hormones, from prohormone secretion, conversion, interaction with receptors, ANP action, correlating its antagonistic effects to RAAS, and the association between the mechanisms of action and SBP. The method adopted was a systematic review through electronic scientific articles in the database of the Virtual Health Library, PubMed and Cochrane. The process of searching and selecting the articles followed the rule of systematic review – PRISMA. The study demonstrates that the effects of ANP release due to cardiac atrial expansion are effectively counterregulators to the effects of RAAS malfunction, acting in a way to preserve the back, cardiac and vascular issues from blood pressure control. This mechanism acts via hydroelectrolytic regulation, especially through processes of resorption and excretion of sodium and water by the removal tubules, where the RAAS acts to increase blood volume and ANP acting to potentiate diuretic mechanisms. It is concluded that the degrading effects of the malfunction of RAAS, to some extent, be counter-regulated by the effects of ANP release, acting in the control of systemic blood pressure, alone or concomitantly with pharmacological treatment.

Abstract P112: Evidence Of Renin Expression And Function In The Brainstem

The role of the brain renin-angiotensin system (RAS) in blood pressure (BP) and autonomic control isrecognized. However, the lack of the precise source of renin in the brain is one of the main barrierstowards a complete understanding of how the brain RAS operates. Here, we hypothesized that renin isexpressed in brain regions involved in sympathetic control such as the rostroventral lateral medulla(RVLM). We employed RNAscope, a highly sensitive and specific in situ hybridization technology.Surprisingly, the renin positive signals were absent in the RVLM, but we identified renin transcripts inthe nucleus ambiguus (NA), a site in the vicinity of the RVLM that contains cardiac vagal motoneurons.There was no signal in this region with the negative control scrambled probe. The signal strength wasgreater than that observed in other regions of the brain classically associated with the brain RAS. Wealso observed that the NA contains other necessary RAS components to produce angiotensin.Interestingly, renin was colocalized with cells expressing choline acetyltransferase (ChAT), suggesting itspossible role in cholinergic neurotransmission. Therefore, we generated mice lacking renin specifically incholinergic neurons (Ren-a ChAT-null ). Because we previously identified an alternative brain-specific reninisoform (ren-b) that elicits cardioprotective roles, we also generated mice lacking ren-b in cholinergicneurons (Ren-b ChAT-null ). At baseline, Ren-a ChAT-null exhibited a trend towards decreased BP, while Ren-b ChAT-null exhibited higher BP, although these differences were not statistically significant. Importantly,Ren-a ChAT-null exhibited an attenuated tachycardiac and pressor responses to atropine (p<0.005 andp<0.05, respectively; n=4-7), indicating a lower parasympathetic tone in these mice. Conversely, Ren-b ChAT-null exhibited an augmented pressor response to atropine (p<0.005; n=7) suggesting an elevatedparasympathetic tone. These data suggest that the activation of the brain RAS in the NA might play arole in cholinergic neurotransmission, and it defines the NA as a potential source of endogenous renin inthe brainstem. Studies to understand the differential contribution of Ren-a and Ren-b in the NA to BPare in progress.

Low Blood Pressure is Independent of Plasma Renin in the Bmal1 Knockout Rat

Blood pressure (BP) is a crucial physiological parameter that exhibits a circadian rhythm in healthy individuals. Loss of this rhythm is associated with morbidity and mortality. To determine the contribution of the molecular clock to BP regulation, we developed a rat strain with whole body loss of Bmal1 gene expression,a core component of the transcription/translation feedback loop known as the molecular clock. We previously reported that Bmal1‐/‐ rats of both sexes have rhythmic BP, but lower than Bmal1+/+ controls. Given the importance of the renin‐angiotensin system in BP control, we hypothesized that loss of Bmal1 may reduce plasma renin activity in the Bmal1‐/‐ rat. For this experiment, male rats were housed in a 12:12h light/dark cycle with constant humidity and temperature. Water and food (0.49% NaCl) were available ad libitum. BP was measured by a telemetry transmitter implanted in the abdominal aorta of 10‐week‐old rats. After a 10‐day surgical recovery period, BP was recorded for 2 minutes every 10 minutes at 1000 samples/second. Mean BP, assessed by cosinor analysis, was lower in male Bmal1‐/‐ (MBP MESOR: 109±2 mmHg, n=9) animals compared to littermate Bmal1+/+ controls (MBP MESOR: 117±3 mmHg, n=8, p<0.05, ANOVA). In a separate cohort of animals, plasma was collected from male Bmal1‐/‐ rats and littermate Bmal1+/+ controls across the circadian day every four hours in groups of 2‐6 at each time point starting at zeitgeber time (ZT) 0 (07:00) and ending at ZT 20. Plasma renin activity (PRA) and total prorenin/renin were measured by ELISA (name the kits used). PRA was similar between male Bmal1‐/‐ and Bmal1+/+ rats during the light (Bmal1+/+: 1.4±0.5 vs Bmal1‐/‐: 2.5±0.6 ng/mL, p=0.21, Student’s t‐test) and dark (Bmal1+/+:2.4±0.7 vs Bmal1‐/‐: 2.4±0.5 ng/mL, p=0.97, Student’s t‐test) periods. Plasma total prorenin/renin was similar between Bmal1‐/‐ and Bmal1+/+ rats during the light (Bmal1+/+: 8.8±1.7 vs Bmal1‐/‐: 6.9±0.7 ng/mL, p=0.36, Student’s t‐test) and dark (Bmal1+/+: 2.7±1.3 vs Bmal1‐/‐: 5.2±1.7 ng/mL, p=0.27, Student’s t‐test) periods. These data suggest that loss of Bmal1 does not directly affect systemic plasma renin activity or total prorenin/renin concentrations in the rat. Furthermore, the lowered blood pressure observed in rats lacking Bmal1 does not appear to be a result of systemic changes in circulating renin activity or concentration.

Kidney‐Specific BMAL1 Knockout is Protective in High Salt Diet‐Induced Renal Inflammation

The circadian clock factor BMAL1, particularly within the kidney, has been shown to influence systemic blood pressure (BP) control. A diet high in salt is linked to immune cell infiltration in the kidney and development of hypertension. Previously, we generated renal distal segment BMAL1 knockout mice (KS‐BMAL1 KO) using Ksp‐cadherin Cre. Male KS‐BMAL1 KO exhibit lower BP than control floxed BMAL1 Cre negative mice (CNTL). In this study, we tested the effect of a low potassium, high salt (0KHS; 4% NaCl) diet in order to determine if KS‐BMAL1 KO are protected from salt‐sensitive hypertension. The goal of this study was to test the hypothesis that male KS‐BMAL1 KO display reduced BP and a lower renal inflammatory phenotype than CNTL in response to a 0KHS diet. BP was measured via telemeter implants (N=7‐8). Panels of inflammatory and injury markers were measured using Millipore multiplex immunoassay kits in renal cortical and medullary tissue from KS‐BMAL1 KO and CNTL on a normal diet and following 10 days of 0KHS diet (N=6‐7). Additionally, whole kidney tissue from mice treated with 0KHS for 10 days was digested and flow cytometric analysis was performed (N=5‐6). KS‐BMAL KO did not exhibit the increase in BP as seen in control mice following 0KHS (CNTL: 125±2 to 132±1; KO: 123±2 to 122±2 mmHg; Interaction P<0.05). CNTL had a greater increase in cortical Kidney Injury Molecule‐1 levels following 0KHS than KS‐BMAL1 KO (CNTL: 31±5 to 975±103; KO: 20±6 to 651±61 pg/mg; Interaction P=0.02). Additionally, CNTL displayed a greater increase in cortical interleukin (IL) 6 following 0KHS than CNTL (CNTL: 0.5±0.04 to 9±1; KO: 0.4±0.07 to 5±0.9 pg/mg; Interaction P=0.04). Medullary IL6 levels were more than 15 times greater following 0KHS but no genotype effect was seen. Although cortical interferon gamma (IFNγ) levels increased more than 8‐fold following 0KHS, there were no differences between genotypes. However, CNTL had a greater increase in cortical IL17 following 0KHS than CNTL (CNTL: 0.8±0.03 to 2.5±0.2; KO: 0.8±0.04 to 1.9±0.1 pg/mg; Interaction P=0.01). CNTL also had greater medullary IL17. Furthermore, CNTL had nearly 2 times greater CD45+ total leukocytes and neutrophils than KS‐BMAL1 KO following 0KHS. BMAL1 in renal distal segments contributes to BP regulation. Additionally, KS‐BMAL1 KO exhibit a reduced proinflammatory phenotype following 0KHS compared to CNTL. These data suggest that BMAL1 may play a role in the renal inflammatory response to 0KHS. Whether BMAL1 protects against inflammation because of or in addition to the lower BP phenotype remains to be determined.

Telehealth Blood Pressure Monitoring Models In Hypertensive Patients: A Scoping Review

The main global cause of death in the world is non-communicable diseases (NCDs). One of NCD is hypertension. Increased hypertension during the Covid-19 pandemic is associated with risk factors for lifestyle changes, social restrictions, lack of physical activity, and stress. Therefore, a remote blood pressure control system is needed to monitor the patient’s health status. The purpose of writing this literature review is to provide an overview of health care practices with remote monitoring of blood pressure of hypertension patients based on online management with telemonitoring. the method used is scoping review with the inclusion criteria of articles were published from 2017 – 2021, used the research designs of Randomized Control Trial and Study Experimental, and were published in English and Indonesian. Articles selections were using PRISMA Flow Diagram 2009 and selection for eligibility were using. The Joanna Briggs Institute Critical Appraisal. Four articles were included in the study and 1037 articles were excluded from the study. It was found that telehealth blood pressure monitoring carried out in hypertensive patients was home and online blood pressure management, TASMINH (Telemonitoring and Self-Management in the Control of Hypertension), and scale-up blood pressure. Telemonitoring was found to be significant in reducing and monitoring patients with home care-based hypertension Self-Monitoring Blood Pressure (SMBP) at home using a digital sphygmomanometer accompanied by direct monitoring of doctors and nurses via the internet can be a solution for monitoring blood pressure during a pandemic.

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study.

Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

Smooth muscle Rac1 contributes to pulmonary hypertension.

Background and PurposePulmonary hypertension (PH) is a multifactorial chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signalling in PA plays a major role in PH. We recently described the involvement of the Rho protein Rac1 in the control of systemic blood pressure through its involvement in NO‐mediated relaxation of arterial smooth muscle cell (SMC). The aim of this study was to analyse the role of SMC Rac1 in PH.Experimental ApproachPH is induced by exposure of control and SMC Rac1‐deficient (SM‐Rac1‐KO) mice to chronic hypoxia (10% O2, 4 weeks). PH is assessed by the measurement of RV systolic pressure and hypertrophy. PA reactivity is analysed by isometric tension measurements. PA remodelling is quantified by immunofluorescence in lung sections and ROS are detected using the dihydroethidium probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence.Key ResultsRac1 activation in PA of hypoxic mice and patients with idiopathic PH. Hypoxia‐induced rise in RV systolic pressure, RV hypertrophy and loss of endothelium‐dependent relaxation were significantly decreased in SM‐Rac1‐KO mice compared to control mice. SMC Rac1 deletion also limited hypoxia‐induced PA remodelling and ROS production in pulmonary artery smooth muscle cells (PASMCs).Conclusion and ImplicationsOur results provide evidence for a protective effect of SM Rac1 deletion against hypoxic PH. Rac1 activity in PASMCs plays a causal role in PH by favouring ROS‐dependent PA remodelling and endothelial dysfunction induced by chronic hypoxia.

Skin Sodium and Blood Pressure Regulation.

Hypertension is a major public health concern due to its high prevalence and increased risk of cardiovascular disease and mortality. Complex traits resulting from both genetic and environmental factors affect the development of hypertension. Among environmental factors, a high salt diet is an important cause for hypertension. Humans show a heterogeneous blood pressure (BP) response to sodium intake. Although the precise mechanisms for the association between salt sensitivity and hypertension have not been fully elucidated, renal sodium handling has been considered to play a pivotal role. However, this conventional view has recently been challenged in that a third compartment, namely, skin may have a role in the regulation of sodium homeostasis. Skin is comprised of a significant portion of interstitium, which is a major extracellular fluid compartment, and its complex capillary network regulates body temperature and skin perfusion. Growing evidence indicates that local regulatory action of cutaneous blood flow as well as salt and water metabolism is associated with systemic BP control. Previous experimental studies have shown that dietary salt loading resulted in nonosmotic sodium accumulation via glycosaminoglycans and lymphatics embedded in the skin that were mediated by several endogenous factors and attenuated an increase in BP. Studies in humans have also suggested that the skin serves as a buffer system for sodium storage and that skin sodium contributes to salt sensitivity and hypertension. Thus, skin sodium storage provides the possibility of being an additional buffering system in response to salt loading and concomitant BP changes in humans.

The bioequivalence of fixed-dose combination tablets of bisoprolol and ramipril and its drug-drug interaction potential.

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed‐dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open‐label, bioequivalence (BE) studies and one drug‐drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two‐way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (Cmax) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of Cmax for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well‐tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co‐administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

The Effect of COVID-19 on Blood Pressure Control in Hypertension Patients– A Literature Review

COVID-19 is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). First identifiedin Wuhan, China, in December 2019, and declared an International Public Health Emergency in January2020, the WHO declared a pandemic in March 2020. Hypertension, a disease that has long been a problemfor most people in Indonesia and around the world . COVID-19 can affect blood pressure control for peoplewith hypertension due to obstruction of the RAAS system. This research was conducted to find out whateffect COVID-19 has on blood pressure control in people with hypertension. In the condition of COVID-19patients with comorbid hypertension, SARS-CoV-2 which attacks ACE2 can eliminate the role of ACE2 inthe RAAS system. Inhibition of ACE2 can also cause buildup of angiotensin II which has a vasoconstrictiveeffect. This results in the absence of homeostasis in the blood pressure control system and makes bloodpressure conditions that continue to be at high pressure.

Smooth muscle Rac1 contributes to pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a multifactorial and chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration NO/cGMP signaling in PA play a major role in PAH. We described the involvement of Rac1 in the control of systemic blood pressure through its involvement in NO-mediated relaxation of arterial smooth muscle cell (SMC). The aim of this study was to decipher the role of SMC Rac1 in PAH. Rac1 activation, Rac-GTP, is determined by immunofluorescence in lungs biopsies from control and PAH patients. PAH is induced by exposure of wild-type (WT) and SMC Rac1-deficient mice (SM-Rac1-KO mice) to chronic hypoxia (10% O 2 , 4 weeks). PAH is assessed by the measurement of RV systolic pressure and hypertrophy. The proliferation of pulmonary arterial SMC (PASMC) in hypoxic condition is measured by EdU staining. Oxidative stress is assessed by immunofluorescence using the DHE probe and by electron spin resonance (ESR). In biopsies from PAH patients, we detected an increase (3-fold) of Rac-GTP in PA compared to control ( n = 4–6). To decipher the role of Rac activation in PAH, WT and SM-Rac1-KO mice were exposed to hypoxia to induce PAH. The elevation of systolic pressure in RV and RV hypertrophy were decreased by 32.5% and 60% ( n = 5–7) in SM-Rac1-KO mice. Deletion of Rac1 in SMC reduced the hypoxia-induced remodeling. In vitro, we observed that hypoxia-induced PASMC proliferation is decreased by 50% by the Rac1 inhibitor, EHT1864. We demonstrated that Rac1 inhibition or deletion in SMC prevent ROS production in PASMC and limit PASMC proliferation and vascular remodeling. Our results suggest that Rac1 activity in PASMC plays a causal role in PAH by favoring ROS dependent PA remodelling induced by chronic hypoxia. Therefore, Rac1 deletion or inhibition protect against hypoxic PAH.

New-Onset Diabetes after Kidney Transplantation.

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient’s diet, amount of exercise, and renal function.

Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets.

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. The standard treatments for diabetic patients are glucose and blood pressure control, lipid lowering, and renin-angiotensin system blockade; however, these therapeutic approaches can provide only partial renoprotection if started late in the course of the disease. One major limitation in developing efficient therapies for DN is the complex pathobiology of the diabetic kidney, which undergoes a set of profound structural, metabolic and functional changes. Despite these difficulties, experimental models of diabetes have revealed promising therapeutic targets by identifying pathways that modulate key functions of podocytes and glomerular endothelial cells. In this review we will describe recent advances in the field, analyze key molecular pathways that contribute to the pathogenesis of the disease, and discuss how they could be modulated to prevent or reverse DN.

The sympathetic muscle metaboreflex is not different in the third trimester in normotensive pregnant women.

Isometric handgrip (IHG) is used to assess sympathetic nervous system responses to exercise and may be useful at predicting hypertension in both pregnant and nonpregnant populations. We previously observed altered sympathetic nervous system control of blood pressure in late pregnancy. Therefore, we measured muscle sympathetic nerve activity (MSNA) and blood pressure during muscle metaboreflex activation (IHG) in normotensive pregnant women in the third trimester compared with in healthy nonpregnant women. Further, 19 pregnant (32 ± 3 wk gestation) and 14 nonpregnant women were matched for age, non/prepregnant body mass index (BMI), and parity. MSNA (microneurography), heart rate (ECG), and arterial blood pressure (Finometer) were continuously recorded during 10 min of rest, and then during 2 min of IHG at 30% of maximal voluntary contraction, and 2 min of postexercise circulatory occlusion (PECO). Baseline sympathetic nerve activity (SNA) was elevated in pregnant (41 ± 11 bursts/min) compared with nonpregnant women (27 ± 9 bursts/min; P = 0.005); however, the sympathetic baroreflex gain and neurovascular transduction were not different between groups (P = 0.62 and P = 0.32, respectively). During IHG and PECO, there were no significant differences in the pressor responses (ΔMAP) between groups, (P = 0.25, main effect of group) nor was the sympathetic response different between groups (interaction effect: P = 0.16, 0.25, and 0.27 for burst frequency, burst incidence, and total SNA, respectively). These data suggest that pregnant women who have maintained sympathetic baroreflex and neurovascular transduction also have similar sympathetic and pressor responses during exercise.NEW & NOTEWORTHY We compared sympathetic nervous system activation by muscle metaboreflex between pregnant women in the third trimester and nonpregnant women. We show that the sympathetic nerve activity and associated pressor responses to isometric handgrip and post-exercise circulatory occlusion are not different between third-trimester pregnant and nonpregnant women. These data suggest that unlike other reflexes (e.g., cold pressor test or head-up tilt), metaboreflex control is maintained in pregnant women.