Pressure Regulation Research Articles

Strengthening urban deer management with structured decision making

Urban deer management (UDM) decision‐makers face social, ecological, regulatory, and economic pressures when creating an agreeable deer management plan for stakeholders. Historically, decision making techniques (e.g. consensus‐based analyses) have not effectively balanced UDM elements leading to short‐lived management progress. Structured decision making (SDM) is a formal, values‐based approach to identifying an optimal management solution. Although SDM has been applied to other wildlife management decisions, it has not been applied in UDM. We provide the first case‐study of SDM‐based UDM and streamline the process for wildlife managers. We focused on one suburban and one semi‐rural community near Atlanta, Georgia, USA. We established a problem statement to capture what decision‐makers must address in UDM programs and reviewed the primary literature and UDM plans from five states to establish four fundamental objectives. We then utilized a support–effectiveness analysis to identify acceptable UDM alternatives and gathered expert insights to calculate the consequences of alternatives on objectives. Finally, we asked each community's decision‐makers to weigh objectives against each other. Using this framework, education was the most optimal UDM technique to implement in the suburban community, and sharpshooting was the most optimal UDM technique to implement in the semi‐rural community. This paper positions SDM as a transparent, defensible, inclusive, and adaptive approach to UDM. Furthermore, our SDM framework provides managers with the means and justification to create an optimal plan of action for communities in need of UDM.

Angiotensin II as a linking factor in cardiovascular disease enhanced cancer growth

Abstract Introduction Several publications have demonstrated that cardiovascular diseases (CVD) promote tumor growth in mouse models of breast, lung, and colon cancer, suggesting a causal relationship between both diseases. Cancer and CVD share several risk factors and pathophysiological mechanisms, including inflammation, oxidative stress, neurohormonal activation, and immune system dysfunction that combined could explain why patients with CVD are prone to develop cancer. Recent reports also suggest a link between hypertension and lung cancer, and between cardiac hypertrophy and breast cancer. Angiotensin II (ANGII) is a hormone involved in blood pressure regulation, vascular hemostasis and hypertrophy development. Moreover, ANGII is cancerogenic by increasing proliferation of several cancer cell types. Hence, ANGII could be a link in CVD-induced enhancement of cancer growth. Here, we investigated whether ANGII treatment, and subsequent hypertension and cardiac hypertrophy, could promote cancer growth and metastasis. Methods ANGII (2000ng.kg-1.min-1, 4w) was administered to 10w old C57B6/J mice using subcutaneous osmotic minipumps. After 3w, 5*10^5 Lewis lung carcinoma (LLC) cells or 2*10^5 MC38 colon cancer cells were injected onto the right flank of the mice. Tumor growth was monitored over 21d using a digital caliper. Tumor volume was calculated using the following formula: Length × width² × 0.5 On day 22, mice were sacrificed for further post-mortem analysis. Cardiac echography was performed after 3w of ANGII treatment and before sacrifice to assess cardiac function (data not shown). To assess the formation of cardiac fibrosis trichrome staining’s were performed. In addition, the effect of ANGII on LLC metastasis was investigated. Mice were treated with ANGII as described above. LLC cells, 2*10^6, were injected intravenously (i.v.). Mice were sacrificed 21d after cell injection. Metastatic growth was visualized and quantified by organ weighing and H&E staining. Results LLC tumor growth was significantly increased by ANGII treatment. In addition, post-mortem tumor weight was increased (0.62 ± 0.05 g control vs. 1.17 ± 0.24 g ANGII). Furthermore, we found lung weight increased in the ANGII-treated group injected i.v. with LLC cells, indicating an increase in metastatic growth (0.41 ± 0.08 g control vs. 0.57 ± 0.04 g ANGII). Interestingly, MC38 tumor growth decreased in the ANGII treated group as portrayed by the tumor weight (0.42 ± 0.06 g control vs. 0.19 ± 0.05 g ANGII). Figure 1 shows the tumor growth over time and tumor volume, weight post-mortem. Conclusion Our data suggest a role for ANGII in CVD-enhanced cancer growth, but also that this effect is not universal, illustrated by a differential effect of ANGII on distinct cancer types. Although further investigation is required to unravel the role of ANGII, screening cancer patients with CVD comorbidities for ANGII involvement might be warranted.

Causal Associations Between the Gut Microbiota and Hypertension-Related Traits Through Mendelian Randomization: A Cross-Sectional Cohort Study.

Previous studies have suggested a link between the gut microbiome and hypertension-related traits like blood pressure. However, these reports are often limited by weak causal evidence. This study investigates the potential causal association between gut microbiota and hypertension-related traits using Mendelian randomization with summary data from genome-wide association studies. The inverse-variance weighted method revealed that the Clostridium innocuum group (Odds ratio [OR]: 1.0047, 95% confidence interval [CI]: 1.0004-1.0090, p=0.0336), Eubacterium fissicatena group (OR: 1.0047, 95% CI: 1.0005-1.0088, p=0.0266), Lachnospiraceae FCS020 group (OR: 1.0063, 95% CI: 1.0004-1.0122, p=0.0361), and Olsenella (OR: 1.0044, 95% CI: 1.0001-1.0088, p=0.0430) were associated with an increased risk of hypertension. Conversely, Flavonifractor (OR: 0.9901, 95% CI: 0.9821-0.9982, p=0.0166), Parabacteroides (OR: 0.9874, 95% CI: 0.9776-0.9972, p=0.0121), and Senegalimassilia (OR: 0.9907, 95% CI: 0.9842-0.9974, p=0.0063) were associated with a decreased risk of hypertension. External validation with the Guangdong Gut Microbiome Project confirmed a negative correlation between Parabacteroides and hypertension, potentially through metabolic pathways. These findings provide further evidence supporting the hypothesis that microbes and their metabolites play a role in blood pressure regulation.

Lumped Parameter Analysis of Autogenous Propellant Pressurization System for Nuclear Thermal Rocket

This work proposes a new propellant management configuration for an ammonia-fueled nuclear thermal propulsion system. The suggested configuration maximizes the advantage deriving from the autogenous pressurization of ammonia by exploiting the thermal power lost by the nuclear reactor toward the vacuum space due to leaking radiation. In this layout, a tank containing ammonia in saturated conditions is placed near the nuclear reactor and receives an input thermal power proportional to the dose of gamma rays and neutrons absorbed by the tank walls and the ammonia itself. Such a thermal power accelerates the vaporization process of the saturated ammonia, thus increasing the pressure in the tank. A pressure regulator valve exploits this overpressure to pressurize the ammonia propellant contained in a run tank to the level required by the mission by connecting the two ammonia volumes. The pressure achieved inside the run tank pushes the propellant with an adequate mass flow rate inside the nuclear reactor. The developed lumped parameter analysis shows how this propellant management system can provide a constant mass flow to the nuclear reactor without using a turbopump assembly. Moreover, it is shown how the proposed concept allows for a reduction in the radiation shield mass.

Physiological characteristics of blood pressure responses after combined exercise in elderly hypertensive patients: a systematic review and meta-analysis

ObjectiveThe aim of this investigation is to explore the efficacy of combined exercise in elderly patients with hypertension. Moreover, we aim to delve into the underlying mechanisms governing blood pressure regulation, with the objective of promoting the adoption of this exercise regimen among elderly hypertensive individuals.MethodsIn our study, we conducted a thorough search across multiple databases, including PubMed, Web of Science, Cochrane Library, Embase, and Scopus. This extensive search resulted in the preliminary screening of 2,347 articles. Among these, 9 studies were carefully selected for an in-depth analysis. For our meta-analysis, we employed Review Manager 5.3 and Stata 15.0, enabling us to perform detailed subgroup analyses and assess the possibility of publication bias.ResultsIn comparison to the control group (n = 194), individuals enrolled in the combined exercise group (n = 200) exhibited a notable decrease in both resting systolic blood pressure (SBP) [weighted mean difference (WMD) = −11.17 mm Hg, 95% confidence interval (CI) (−17.13, −5.22), Z = 3.68, P < 0.05] and diastolic blood pressure (DBP) [WMD = −5.93 mm Hg, 95% CI (−9.24, −2.61), Z = 3.51, P < 0.05]. Nonetheless, no statistically significant alteration was observed in pulse pressure (PP) [WMD = −9.05 mm Hg, 95% CI (−22.65, 4.55), Z = 1.3, P = 0.192]. Further subgroup analyses elucidated that combined exercise regimens, characterized by aerobic training intensities below 85% of HRmax, durations of up to 12 weeks, weekly frequencies of either ≥3 or <3 sessions, total session times under 60 min, and a sequence of aerobic exercise followed by resistance training (AE-RT), were particularly effective in enhancing SBP and DBP among elderly patients with hypertension. Additionally, regular engagement in combined exercise led to significant improvements in SBP and DBP across individuals aged 60–70, those older than 70 years, and regardless of whether participants were using antihypertensive medications or not.ConclusionCombined exercise serves as an efficacious adjunctive therapy for reducing blood pressure among elderly individuals with hypertension, exerting beneficial influences on multiple physiological mechanisms pertinent to blood pressure regulation. Moreover, the integration of aerobic exercise with resistance training presents a more varied training program, thereby eliciting wider-ranging positive effects on both the physical and mental well-being of elderly patients afflicted with hypertension.

Modulation of blood pressure by dietary potassium and sodium: Sex differences and modeling analysis.

High Na+ intake has been linked to elevations in blood pressure, whereas K+ has the opposite effect. The underlying mechanisms involve complex interactions among renal function, fluid volume, fluid-regulatory hormones, the vasculature, cardiac function, and the autonomic nervous system. These mechanisms are likely moderated by sex, given the known sex differences in blood pressure regulation and the higher prevalence of hypertension in men. The source of these observed sex differences may be traced to organ and tissue levels, given that kidney function, intrarenal renin-angiotensin system components, renal sympathetic nervous activity, and nitric oxide bioavailability all exhibit sex differences. To assess the functional impact of each of these sex differences, we developed sex-specific computational models to simulate whole-body Na+, K+, and fluid homeostasis, and the effects on blood pressure. The models describe the interactions among the renal system, cardiovascular system, gastrointestinal system, renal sympathetic nervous system, and renin-angiotensin-aldosterone system. Model simulations suggest that women's attenuated blood pressure response to hypertensive stimuli, including high Na+ intake, may be largely attributable to the female renal transporter abundance pattern. Additionally, we investigated the causal link between high K+ intake and blood pressure reduction. The models simulate renal response to high K+ intake, including the immediate gastrointestinal feedforward signals to the kidneys to increase K+ excretion, and the longer-term response to decrease proximal fractional Na+ reabsorption and distal K+ reabsorption. With these assumptions, simulations of high K+ intake yielded kaliuresis, natriuresis, and a substantial reduction in blood pressure, even when combined with high Na+ intake.

The FSGS protein actinin-4 (ACTN4) interacts with NKCC2 to regulate Thick Ascending Limb (TAL) NaCl reabsorption.

In the kidney, the thick Ascending Limb (TAL) of the loop of Henle is crucial for NaCl homeostasis and blood pressure regulation. In animal models of salt-sensitive hypertension, NaCl reabsorption via the apical Na+/K+/2Cl cotransporter (NKCC2) is abnormally increased in the TAL. We showed that NaCl reabsorption is controlled by the presence of NKCC2 at the apical surface of TALs. However, the molecular mechanisms that maintain the steady-state levels of NKCC2 at the apical surface are not clearly understood. Here, we report that NKCC2 interacts with the F-actin cross-linking protein actinin-4 (ACTN4). We find that ACTN4 is expressed in TALs by Western blot and immunofluorescence microscopy. ACTN4 immunoprecipitated with NKCC2 and recombinant GST-ACTN4 pulled down NKCC2 from TAL lysates. ACTN4 is involved in endocytosis in other cells. Therefore, we hypothesized that ACTN4 binds apical NKCC2 and regulates its trafficking. To study this, we silenced ACTN4 in vivo via shRNA or CRISPR/Cas9 system to decrease ACTN4 expression in TALs. We observed that silencing ACTN4 in vivo via shRNA or CRISPR/Cas9 system increased the amount NKCC2 at the apical surface of TALs. Bumetanide-induced diuresis and natriuresis were enhanced by 35% after silencing of ACTN4 in vivo (AV-NKCC2-Cas9: 3841±709 vs AAV-gRNA-ACTN4: 5546±622 µmols Na/8h, n=5, p<0.05). We conclude that ACTN4, binds NKCC2 to regulate its surface expression. Selective depletion of ACTN4 in TALs using shRNA or CRISPR/Cas9 enhances surface NKCC2 and TAL NaCl reabsorption, indicating that regulation of the ACTN4-NKCC2 interaction is important for renal NaCl reabsorption and could be related to hypertension.

Enhancing financial reporting and management efficiency through enterprise resource planning (ERP) systems: A theoretical review for large-scale energy operations

Enterprise Resource Planning (ERP) systems have emerged as essential tools in streamlining financial reporting and improving management efficiency across various industries, including large-scale energy operations. This theoretical review explores how ERP systems enhance financial reporting by integrating real-time data, automating financial processes, and fostering transparency. In energy operations, where financial activities are complex and data-intensive, ERP systems centralize financial data, reducing errors, improving compliance, and supporting decision-making through enhanced visibility and accuracy. By automating tasks such as budgeting, forecasting, and financial statement generation, ERP systems enable energy companies to efficiently manage their financial resources, thus optimizing cost control and profitability. Additionally, ERP systems provide significant benefits for management efficiency, particularly in large-scale operations. The integration of financial, operational, and managerial processes within a single platform allows for better resource allocation, improved communication across departments, and faster response times to market fluctuations. These capabilities are crucial in the energy sector, where companies face volatile market conditions, regulatory pressures, and high operational risks. ERP systems enhance managerial decision-making by providing real-time insights into key performance indicators (KPIs), enabling executives to make data-driven decisions that support long-term strategic goals. However, implementing ERP systems in large-scale energy operations presents challenges, including high costs, lengthy implementation periods, and the need for employee training. This review also examines these barriers and suggests strategies for successful ERP adoption, including phased implementation, stakeholder engagement, and customization to industry-specific needs. In conclusion, ERP systems hold the potential to revolutionize financial reporting and management efficiency in large-scale energy operations. By leveraging ERP's real-time data integration and process automation, energy companies can significantly improve their financial management, enhance decision-making, and adapt more quickly to market changes. Keywords: ERP Systems, Financial Reporting, Management Efficiency, Large-Scale Energy Operations, Process Automation, Real-Time Data Integration, Decision-Making, Cost Control, Market Fluctuations, Energy Sector.

OPTIMIZING HVAC EFFICIENCY AND RELIABILITY: A REVIEW OF MANAGEMENT STRATEGIES FOR COMMERCIAL AND INDUSTRIAL BUILDINGS

This study presents a comprehensive review of strategies to optimize HVAC systems in commercial and industrial buildings, focusing on enhancing energy efficiency, system reliability, and environmental sustainability. HVAC systems are major energy consumers, contributing significantly to operational costs in large buildings. With increasing energy costs, regulatory pressures, and the push for sustainability, technological advancements and management strategies have emerged to improve HVAC performance. Following PRISMA guidelines, this review analyzed 58 high-quality peer-reviewed studies published between 2010 and 2023. Key findings show that energy management systems (EMS) can reduce energy consumption by up to 30%, while Building Management Systems (BMS) enhance system reliability through centralized control and predictive maintenance. The adoption of eco-friendly refrigerants and energy-efficient designs, such as heat recovery and variable refrigerant flow (VRF) technologies, further lowers energy usage and environmental impact. Additionally, integrating renewable energy sources like solar and geothermal into HVAC systems can reduce energy consumption by as much as 40%. Green building certifications, such as LEED and BREEAM, drive the adoption of optimized HVAC technologies, delivering both environmental and financial benefits. This review underscores the crucial role of HVAC optimization in reducing energy consumption, lowering carbon footprints, and improving the operational performance of buildings, offering valuable insights for building managers, engineers, and policymakers.

Salt Responsive Gut Microbiota Induces Sex Specific Blood Pressure Changes.

Tryptophan metabolism is important in blood pressure regulation. The tryptophan-indole pathway is exclusively mediated by the gut microbiota. ACE2 (angiotensin-converting enzyme 2) participates in tryptophan absorption, and a lack of ACE2 leads to changes in the gut microbiota. The gut microbiota has been recognized as a regulator of blood pressure. Furthermore, there is ample evidence for sex differences in the gut microbiota. However, it is unclear whether such sex differences impact blood pressure differentially through the tryptophan-indole pathway. To study the sex-specific mechanisms of gut microbiota-mediated tryptophan-indole pathway in hypertension, we generated a novel rat model with Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-targeted deletion of Ace2 in the Dahl salt-sensitive rat. Cecal microbiota transfers from donors of both sexes to female S recipients were performed. Also, Dahl salt-sensitive rats of both sexes were orally gavaged with indole to investigate blood pressure response. The female gut microbiota and its tryptophan-indole pathway exhibited greater buffering capacity when exposed to tryptophan, due to Ace2 deficiency, and salt. In contrast, the male gut microbiota and its tryptophan-indole pathway were more vulnerable. Female rats with male cecal microbiota responded to salt with a higher blood pressure increase. Indole, a tryptophan-derived metabolite produced by gut bacteria, increased blood pressure in male but not in female rats. Moreover, salt altered host-mediated tryptophan metabolism, characterized by reduced serum serotonin of both sexes and higher levels of kynurenine derivatives in the females. We uncovered a novel sex-specific mechanism in the gut microbiota-mediated tryptophan-indole pathway in blood pressure regulation. Salt tipped the tryptophan metabolism between the host and gut microbiota in a sex-dependent manner. Our study provides evidence for a novel concept that gut microbiota and its metabolism play sex-specific roles in the development of salt-sensitive hypertension.

Deciphering Regulatory Role of Melatonin in Foliar Nastic Movements of Portulaca oleracea: Visual Insights from Histology and Anatomy

AbstractPlant nastic movements exhibit unique behavioural patterns that synchronize with external cues. Given that the foliar nastic motions of Portulaca species are solely circadian, it is intriguing to investigate whether and how melatonin governs these movements. Analysis of histological traits concurrent with anatomical traits such as stomatal behaviour provides visual data on the plant species' gnosophysiology, offering clues and validation of the influence of multiple external stimuli on hydraulic forces that in turn alter turgor pressure. The current study aims to elucidate how exogenous melatonin modulates foliar nastic movements in Portulaca oleracea. Our findings indicate that melatonin functions as an intracellular hydraulic flux controller, influencing idioblast and crystal densities, as well as stomatal behaviour. Timepoint studies at specific Zeitgebers reveal that abiotic variables such as light and temperature can influence the endogenous melatonin concentration of P. oleracea. Therefore, this hormone potentially serves as an additional internal regulator of turgor pressure, influenced by both light and temperature. Thus, melatonin plays a crucial role in shaping the characteristic foliar nastic movements observed in P. oleracea, inherently tied to the circadian rhythm. Further investigation into idioblast and crystal torques, along with their angular momentum, is warranted to calculate the hydraulic forces at work in the leaf lamina. Thus the study underscores the multifaceted role of melatonin in navigating nastic movement processes through turgor pressure alterations brought about by intracellular depositions. The study in future could unravel melatonin's pleiotropic actions and the underlying mechanisms of foliar idiosyncratic nastic motions in other plant species as well. Moreover, both histology and anatomy play vital roles in the present study as it has provided visual evidence of the underlying mechanisms of foliar nastic movements in P. oleracea. Graphical Abstract

A systematic review of lithium biology and pharmacology and toxicological evaluation of new organic lithium salts

Objective: to systematize scientific data on biomedical studies investigating trace element lithium over the past 70 years; evaluate toxic properties of lithium ascorbate (LiAsc) as an important promising candidate molecule.Material and methods. An analysis of 49,959 publications on lithium biomedical research retrieved from PubMed/MEDLINE database was carried out using modern data mining methods developed within the framework of topological approach to recognizing (Yu.I. Zhuravlev scientific school). Publications found by experts and not indexed in PubMed/MEDLINE were used in discussing the results of a systematic analysis of publications array retrieved from PubMed/MEDLINE. An experimental study of chronic 180 day-long LiAsc (at doses of 5, 50 and 150 mg/kg) toxicity was performed on 36 “Soviet chinchilla” rabbits by assessing local irritant action. Intoxication clinical picture, body weight dynamics, water and food intake as well as physiological, hematological and biochemical parameters were analyzed.Results. Classification and systematization of all currently available publications on lithium biology and medicine were performed. It was shown that pharmacological applications of lithium salts in mental disorders as well as lithium effects on simple sugars metabolism, lipid metabolism, blood pressure regulation, hematopoiesis, inflammation and tumor growth inhibition, neurotransmitter homeostasis, neurotrophic and neuroprotective molecular mechanisms as well as homeostasis of other electrolytes comprised promising fields of lithium drug research. The prospects for using organic lithium salts, particularly LiAsc, for various therapeutic goals were also discussed. 180-day-long oral administration of LiAsc at doses of 5, 50, 150 mg/kg resulted in no macroscopic signs of local inflammatory reaction while examining its local irritant effect.Conclusion. The lithium-ion effect on neurotransmitters promotes neuroprotection and reduces a risk of addiction. The antihypertensive, antiatherosclerotic, antidiabetic, antitumor and neurotrophic effects related to organic lithium salts may be beneficial in various therapeutic applications.

Human Anterior Segment Perfusion Organ Culture.

The human anterior segment perfusion organ culture is an ex vivo model system for studying the human conventional outflow pathway with reference to pressure regulation. In this model, anterior segments dissected from human donor eyes can be fixed to a modified petri dish and perfused with media along with various study agents at the physiological flow rate of 2.5μL/min. The model mimics the one-way flow of aqueous humor in human eyes and can be used to evaluate the effects of various drugs on eye pressure in real time. Using this model, cells and tissues of the anterior segment can be maintained for up to 28days, enabling histological and molecular evaluations.

The effect of cpap therapy on blood pressure in the mild obstructive sleep apnea population

This retrospective study uniquely focused on the effects of continuous positive airway pressure (CPAP) on blood pressure in patients with mild obstructive sleep apnea (OSA), a condition characterized by intermittent upper airway collapse. OSA is a well-established risk factor for hypertension, with positive airway pressure (PAP) therapy being the most common treatment. While substantial evidence supports PAP therapy in moderate and severe OSA, the impact of CPAP on mild OSA, which accounts for 50%-70% of all cases, remains underexplored. The primary objective of this study was to investigate whether CPAP therapy, particularly the degree of adherence to treatment, has a measurable impact on blood pressure regulation in patients with mild OSA. Specifically, this research aimed to evaluate whether consistent CPAP use could lower systolic and diastolic blood pressure and assess how varying levels of adherence influence these outcomes. Participants were stratified into two groups based on CPAP adherence: Group A (n = 45) included those who used CPAP for four or more hours per night on at least 70% of nights, while Group B (n = 15) consisted of those with less than four hours of CPAP use per night on 70% of nights. Interestingly, greater systolic and diastolic blood pressure reductions were observed in Group B, suggesting that lower CPAP adherence may still contribute to significant cardiovascular improvements. These findings offer new insights into the management of blood pressure in patients with mild OSA and the role of CPAP adherence.

Measuring The Pulse of Sustainable Investment: A Systematic Review &amp; Bibliometric Perspective

In recent times, increasing regulatory pressure and changes in investor preferences have led to an increase in the importance of sustainable investment at both academic and practitioner levels, with the field still occupying the formative stage. Therefore, the objectives of this study are to explore the intellectual underpinnings of and suggest future research avenues in the discipline of sustainable investment, as well as to conduct a systematic review and bibliometric analysis. In total 1,222 articles were selected from the Scopus database for the period 2013-2023. The study follows the SPAR-4-SLR protocol, involving performance analysis and science mapping using VOSviewer and the R-package. Network analysis revealed eight major clusters primarily focusing on firms’ financial performance, stock returns, contributions to climate change, economic growth, sustainable development goals, risk assessment, and corporate social responsibility. Additionally, the study developed a unified taxonomy model based on a causal framework that includes the foremost independent, mediating, moderating, and dependent variables, studied in the field of sustainable investment.

Nitric Oxide: Structure, Pathophysiology and Clinical Significance

Hypertension is the most important modifiable risk factor and, if treated, leads to a reduction in cardiovascular diseases and mortality. A recent perspective emphasizes the central role of nitric oxide bioavailability in the maintenance of healthy vasculature and the regulation of blood pressure. The molecule nitric oxide is very complex with far-reaching implications concerning cardiovascular well-being and pathology. Synthesis of nitric oxide as well as signaling cascades and their regulation thus stands as a critical process in acquiring an understanding regarding its involvement under physiological as well as pathological conditions. With the rapid pace at which NO research is evolving, there are significant gaps in our knowledge that must be filled in if we are ever to take full advantage of its therapeutic potential. Nitric oxide is also considered to be a very important molecule involved in the defense of hypertension through its effects on endothelial function and vascular homeostasis. This review will summarize the current state of knowledge regarding the relationship between NO and hypertension and will attempt to identify those areas where significant lacunae exist and where further research would be appropriate. In addition, focus is directed toward the structure and clinical relevance of NO, describing its functions in endothelial activity, cardiovascular health, and any possible clinical utility.

Combretum micranthum G. Don (Combretaceae): Its physiological effects on hydro-electrolyte metabolism, renal tubular function and blood pressure

BackgroundHydro-electrolyte balance is necessary to maintain body homeostasis and blood pressure values within narrow limits. This is accomplished, in part, by renal responses. We conducted this study to determine the effects of Combretum micranthum on hydro-electrolyte metabolism, renal function and arterial blood pressure. Subjects and methodsWe conducted a pilot study including 40 subjects: 10 control subjects, 10 subjects under Combretum micranthum G. Don (400 mg/day), 10 subjects under furosemide (120 mg/day), and 10 subjects under spironolactone (50 mg/day).Anthropobiometric, cardiovascular parameters and the body composition were collected from each subject. Blood and 24-hour urine samples were collected for biological tests. ResultsAt baseline, clinical and biological parameters were comparable for all groups. Consumers of combretum micranthum had a significant decrease in global body fat percentage (−1.63 %; p = 0.045). In the group of combretum micranthum consumers, the body water mass (BWM) is significantly evolved in the direction of an increase (4.37; p = 0.023) and similar to what was observed in the group of subjects treated with spironolactone (0.67; p = 0.042). Consumption of combretum micranthum showed a marked reduction in hypertension indices (systolic blood pressure, diastolic blood pressure and heart rate) identical to that induced by consumption of furosemide or spironolactone. The consumption of combretum micranthum resulted in a significant reduction in kaliemia (−1.07; p < 0.0001) and without any notable effect on natremia (p = 0.119) and chloremia (p = 0.708). In contrast, furosemide and spironolactone caused a significant decrease in natremia (respectivly, −0.80; p = 0.022 and −0.50; p = 0.009). In the combretum micrathum group, the kaliuresis and the chloruresis were significantly increased (respectively, 373.9; p = 0.005 and 441.3; p = 0.028), interestingly, we found a remarkable decrease in natriuresis (−193.3; p = 0.074). In the group of furosemide consumers, the kaliuresis and the chloruresis were significantly increased (respectively, 380.24; p = 0.013 and 425.5; p = 0.013), but with a tendency to increase natriuresis. In the group of subjects taking spironolactone, the urinary concentrations of the three electrolytes studied (natriuresis, kaliuresis and chloruresis) was increased significantly (respectively, 357.5; p = 0.037 and 222.5; p = 0.005 and 563.4; p = 0.007). ConclusionCombretum micranthum would have constituents involved in the maintenance of hydro-electrolyte homeostasis and in the regulation of blood pressure through the involvement of several mechanisms, especially at the renal level. These actions would be attributable to its polyphenolic components. A broader study is needed to better understand the physiological mechanisms underlying these effects.

Caution for Multidrug Therapy: Significant Baroreflex Afferent Neuroexcitation Coordinated by Multi-Channels/Pumps Under the Threshold Concentration of Yoda1 and Dobutamine Combination

Multi-drug therapies are common in cardiovascular disease intervention; however, io channel/pump coordination has not been tested electrophysiologically. Apparently, inward currents were not elicited by Yoda1/10 nM or Dobutamine/100 nM alone in Ah-type baroreceptor neurons, but were by their combination. To verify this, electroneurography and the whole-cell patch-clamp technique were performed. The results showed that Ah- and C-volley were dramatically increased by the combination at 0.5 V and 5 V, in contrast to A-volley, as consistent with repetitive discharge elicited by step and ramp with markedly reduced current injection/stimulus intensity. Notably, a frequency-dependent action potential (AP) duration was increased with Iberiotoxin-sensitive K+ component. Furthermore, an increased peak in AP measured in phase plots suggested enhanced Na+ influx, cytoplasmic Ca2+ accumulation through reverse mode of Na+/Ca2+ exchanger, and, consequently, functional KCa1.1 up-regulation. Strikingly, the Yoda1- or Dbtm-mediated small/transient Na+/K+-pump currents were robustly increased by their combination, implying a quick ion equilibration that may also be synchronized by hyperpolarization-induced voltage-sag, enabling faster repetitive firing. These novel findings demonstrate multi-channel/pump collaboration together to integrate neurotransmission at the cellular level for baroreflex, providing an afferent explanation in sexual dimorphic blood pressure regulation, and raising the caution regarding the individual drug concentration in multi-drug therapies to optimize efficacy and minimize toxicity.

Transcriptomic profiling of Schlemm’s canal cells reveals a lymphatic-biased identity and three major cell states

Schlemm’s canal (SC) is central in intraocular pressure regulation but requires much characterization. It has distinct inner and outer walls, each composed of Schlemm’s canal endothelial cells (SECs) with different morphologies and functions. Recent transcriptomic studies of the anterior segment added important knowledge, but were limited in power by SEC numbers or did not focus on SC. To gain a more comprehensive understanding of SC biology, we performed bulk RNA sequencing on C57BL/6 J SC, blood vessel, and lymphatic endothelial cells from limbal tissue (~4,500 SECs). We also analyzed mouse limbal tissues by single-cell and single-nucleus RNA sequencing (C57BL/6 J and 129/Sj strains), successfully sequencing 903 individual SECs. Together, these datasets confirm that SC has molecular characteristics of both blood and lymphatic endothelia with a lymphatic phenotype predominating. SECs are enriched in pathways that regulate cell-cell junction formation pointing to the importance of junctions in determining SC fluid permeability. Importantly, and for the first time, our analyses characterize three molecular classes of SECs, molecularly distinguishing inner wall from outer wall SECs and discovering two inner wall cell states that likely result from local environmental differences. Further, and based on ligand and receptor expression patterns, we document key interactions between SECs and cells of the adjacent trabecular meshwork (TM) drainage tissue. Also, we present cell type expression for a collection of human glaucoma genes. These data provide a new molecular foundation that will enable the functional dissection of key homeostatic processes mediated by SECs as well as the development of new glaucoma therapeutics.

Transcriptomic profiling of Schlemm's canal cells reveals a lymphatic-biased identity and three major cell states.

Schlemm's canal (SC) is central in intraocular pressure regulation but requires much characterization. It has distinct inner and outer walls, each composed of Schlemm's canal endothelial cells (SECs) with different morphologies and functions. Recent transcriptomic studies of the anterior segment added important knowledge, but were limited in power by SEC numbers or did not focus on SC. To gain a more comprehensive understanding of SC biology, we performed bulk RNA sequencing on C57BL/6 J SC, blood vessel, and lymphatic endothelial cells from limbal tissue (~4,500 SECs). We also analyzed mouse limbal tissues by single-cell and single-nucleus RNA sequencing (C57BL/6 J and 129/Sj strains), successfully sequencing 903 individual SECs. Together, these datasets confirm that SC has molecular characteristics of both blood and lymphatic endothelia with a lymphatic phenotype predominating. SECs are enriched in pathways that regulate cell-cell junction formation pointing to the importance of junctions in determining SC fluid permeability. Importantly, and for the first time, our analyses characterize three molecular classes of SECs, molecularly distinguishing inner wall from outer wall SECs and discovering two inner wall cell states that likely result from local environmental differences. Further, and based on ligand and receptor expression patterns, we document key interactions between SECs and cells of the adjacent trabecular meshwork (TM) drainage tissue. Also, we present cell type expression for a collection of human glaucoma genes. These data provide a new molecular foundation that will enable the functional dissection of key homeostatic processes mediated by SECs as well as the development of new glaucoma therapeutics.