Regulation Of Systemic Blood Pressure Research Articles

A Role of T-Lymphocyte β-Arrestins in Hypertension

The adaptive immune system and T-cells play a central role in the development of essential hypertension. The renin-angiotensin system regulates blood pressure (BP) through multiple mechanisms including effects on the immune system. Among several G-protein coupled receptors (GPCR) that regulate T-cell function, it has been hypothesized that specific T-cell populations use the angiotensin receptor (AT1R) to modulate immune responses in hypertension. Selective ablation of AT1R in T-cells paradoxically increases hypertensive end-organ damage (EOD). While AT1R typically induces the classical G protein signaling, recent studies have uncovered an alternative protective signaling-cascade at this receptor via β-Arrestin ( ARRB) proteins. Thus, we hypothesized that ARRB in T-lymphocytes mediates an anti-hypertensive and anti-inflammatory role in response to angiotensin II (ANG II) thereby decreasing EOD in hypertension. Transgenic mice with T-lymphocyte-specific knock outs of the Arrb1 gene were developed using a CD4-Cre x Arrb1-Flox system. Hypertensive conditions were modeled with a 3-pronged approach designed to induce kidney damage consisting of unilateral nephrectomy (UNX), maintenance on a 4% salt diet, and a continuous infusion of ANG II (1,000 ng/kg/min). Age and sex-matched Cre negative x Arrb1-Flox littermates were used as controls. BP was measured at baseline before and after UNX, and for the following three weeks using radiotelemetry. Inflammation was assessed using quantitative PCR (q-PCR). Preliminary data suggest that loss of T-cell specific Arrb1 is protective against ANG II-induced hypertension. At baseline CD4Arrb1-null and CD4Arrb1-WT mice had similar systolic BP (123.0±2.9 mmHg and 119.6±2.3 mmHg, respectively, n=5-7). However, CD4Arrb1-null mice exhibited an attenuated response to ANG II infusion after three weeks (162.5±11.8 mmHg vs 187.0±5.9 mmHg n=3-5; p = 0.03). After 15 days of ANG II, mice were placed in metabolic cages and urine was collected. In a 24-hour period, CD4Arrb1-null mice excreted significantly more sodium (1.98±0.07 mg/24hrs vs 1.66±0.03 mg/24hrs, n=3-4; p = 0.01). Tissue collected from the renal cortex following three weeks of ANG II infusion was analyzed for inflammatory cytokines using q-PCR. Gene expression was normalized to 18s expression in CD4Arrb1-WT mice under sham experimental conditions. Expression of tumor necrosis factor α (TNF-α) transcripts was attenuated in CD4Arrb1-null mice when compared to CD4Arrb1-WT (1.62±0.24-fold increase vs 0.67±0.07-fold decrease, respectively, n=3-4; p=0.006). Contrary to our hypothesis, these preliminary data suggest that T-cell Arrb1 does not protect against hypertensive or inflammatory responses to ANG II. However, these studies highlight the role of β-arrestin-1 proteins endogenous to T-lymphocytes in the modulation of the hypertensive response to ANG II. Supported by grants from the AHA and NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A modeling analysis of whole body potassium regulation on a high-potassium diet: proximal tubule and tubuloglomerular feedback effects.

Potassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, and hormone secretion and action. Indeed, maintaining K+ balance is critical for normal cell function, as too high or too low K+ levels can have serious and potentially deadly health consequences. K+ homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K+ intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na+-K+-ATPase uptake, and hormone and electrolyte impacts on renal K+ handling. We recently developed a mathematical model of whole body K+ regulation to unravel the individual impacts of these regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high-K+ diet. We conducted model simulations and sensitivity analyses to investigate how these renal alterations impact whole body K+ regulation. Model predictions quantify the sensitivity of K+ regulation to various levels of proximal tubule K+ reabsorption adaptation and tubuloglomerular feedback. Our results suggest that the reduced proximal tubule K+ reabsorption under a high-K+ diet could achieve K+ balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K+ excretion.NEW & NOTEWORTHY Potassium homeostasis is maintained in the body by a complex system of regulatory mechanisms. This system, when healthy, maintains a small extracellular potassium concentration, despite large fluctuations of dietary potassium. The complexities of the system make this problem well suited for investigation with mathematical modeling. In this study, we extend our mathematical model to consider recent experimental results on renal potassium handling on a high potassium diet and investigate the impacts from a whole body perspective.

Investigating the association between nitrate dosing and nitrite generation by the human oral microbiota in continuous culture.

The generation of nitrite by the oral microbiota is believed to contribute to healthy cardiovascular function, with oral nitrate reduction to nitrite associated with systemic blood pressure regulation. There is the potential to manipulate the composition or activities of the oral microbiota to a higher nitrate-reducing state through nitrate supplementation. The current study examined microbial community composition and enzymatic responses to nitrate supplementation in sessile oral microbiota grown in continuous culture. Nitrate reductase (NaR) activity and nitrite concentrations were not significantly different to tongue-derived inocula in model biofilms. These were generally dominated by Streptococcus spp., initially, and a single nitrate supplementation resulted in the increased relative abundance of the nitrate-reducing genera Veillonella, Neisseria, and Proteus spp. Nitrite concentrations increased concomitantly and continued to increase throughout oral microbiota development. Continuous nitrate supplementation, over a 7-day period, was similarly associated with an elevated abundance of nitrate-reducing taxa and increased nitrite concentration in the perfusate. In experiments in which the models were established in continuous low or high nitrate environments, there was an initial elevation in nitrate reductase, and nitrite concentrations reached a relatively constant concentration over time similar to the acute nitrate challenge with a similar expansion of Veillonella and Neisseria. In summary, we have investigated nitrate metabolism in continuous culture oral biofilms, showing that nitrate addition increases nitrate reductase activity and nitrite concentrations in oral microbiota with the expansion of putatively NaR-producing taxa.IMPORTANCEClinical evidence suggests that blood pressure regulation can be promoted by nitrite generated through the reduction of supplemental dietary nitrate by the oral microbiota. We have utilized oral microbiota models to investigate the mechanisms responsible, demonstrating that nitrate addition increases nitrate reductase activity and nitrite concentrations in oral microbiota with the expansion of nitrate-reducing taxa.

Effects of the intensity, duration and muscle mass factors of isometric exercise on acute local muscle hemodynamic responses and systematic blood pressure regulation.

Isometric exercise is a non-pharmacologic intervention to improve muscle hemodynamic responses and blood pressure in humans. However, the effects of intensity, duration, and muscle mass factors of isometric exercise on local muscle hemodynamic responses and systemic blood pressure regulation have not been studied. The purpose of this study was to assess whether various modes of isometric exercise could induce various levels of muscle hemodynamic responses that are related to the blood pressure changes. Near-infrared spectroscopy was used to assess muscle hemodynamic responses after 4 isometric exercise protocols in 20 healthy adults. One-way analysis of variance (ANOVA) with repeated measures was used to assess the effect of factors of isometric exercise on oxyhemoglobin, deoxy-hemoglobin, blood volume, and oxygenation. For oxygenation, the lowest mean was recorded for the unilateral isometric handgrip exercise at 30% of MVC for 2min (-0.317 ± 0.379μM) while the highest mean was observed for the isometric wall squat (1.496 ± 0.498μM, P < 0.05). Additionally, both the bilateral isometric handgrip exercise at 30% MVC for 1min (1.340 ± 0.711μM, P < 0.05) and the unilateral isometric handgrip exercise at 20% MVC for 3min (0.798 ± 0.324μM, P < 0.05) are significantly higher than 30% of MVC for 2min. Blood pressure showed an inverse trend with oxygenation changes of the forearm muscle. The study indicates that the duration and muscle mass of isometric exercise are more effective on oxygenation responses and systematic blood pressure regulation, and suggests that the local muscle oxygenation factor following isometric contractions may mediate systematic blood pressure regulation.

Exercise intervention during pregnancy induces DNA methylation alterations in maternal blood and cord blood.

Exercise intervention during pregnancy induces DNA methylation alterations in maternal blood and cord blood.

THE ROLE OF CYTOKINES IN THE DEVELOPMENT OF ARTERIAL HYPERTENSION

Arterial hypertension (AH) is a common chronic disease characterized by a persistent increase in blood pressure. In addition to the main mechanisms of hypertension development, including activation of the sympathetic nervous system, disruption of the renin-angiotensin-aldosterone cascade, endothelial dysfunction, increased vascular reactivity, and vascular remodeling, it is assumed that inflammation is also involved in the formation of the disease. The review considers the involvement of cytokines in the pathogenesis of AH, as well as their interaction with blood pressure regulatory systems.

PS-C20-5: WARM IV INFUSION IN HYPERTENSIVE URGENCY

Background: Hypertensive Urgency is defined as marked elevation in systemic blood pressure without any evidence of end organ damage. At present, the condition is managed with intravenous (IV) antihypertensives, of which most common is Sodium Nitroprusside. Aim: In this abstract we explore the possibility of slow IV infusion of warm (37–38oC) Normal Saline along with IV antihypertensives for a better and faster management of Hypertensive Urgency. Content: The slow IV will gradually increase the core body temperature of the patient while preventing fluid overload. Homeostatic regulation of Systemic Blood Pressure is maintained by an intricate network of correlated mechanisms, most of which are temperature dependent. The raised body temperature will be useful to control the Blood Pressure through the following mechanisms - Cardiac Output: reduces as core body temperature increases. Baroreflex: decreased post-synaptic adrenergic vasoconstrictor responses. Chemoreceptors: vascular responsiveness to adrenergic receptor stimulation reduces at higher temperatures. RAAS: Kosunen et al recorded reduced Systolic and Diastolic Blood Pressures at raised body temperatures despite increased levels of Angiotensin II &amp; Aldosterone. Endothelin: Serum concentration of Endothelin-I reduces at higher temperatures. Sweat: Thermal stimulation of sweat gland will help excretion of both salt and water, thus maintaining the sodium balance. VEGF: VEGF-A, a potent vasodilator, is increased during elevated body temperature. However, apart from Blood Pressure, a change in core body temperature causes change in many other parameters as well, which must be considered during this discussion. Coagulation profile - Valeri et al noted no change in in-vivo coagulation states till 100oF Effect on other visceral organs - Internal visceral organs like Liver, Kidneys and Brain were not affected till 100oF Infection Control - Core body temperature close to 100oF has also been found to have a protective role against invasive fungal infections in the ICU Discussion: Though the effects of various antihypertensive drugs to raised body temperatures need to be tested, the above points prove that introducing a protocol of warm IV saline Infusion in patients of Hypertensive Urgency may be extremely beneficial, and also prevent clinical inertia.

S-22-3: UNCOVERING NEW GENES, TISSUES AND THERAPEUTIC TARGETS FOR BLOOD PRESSURE THROUGH LARGE-SCALE TRANSCRIPTOME-WIDE ASSOCIATION STUDIES

Objective: Transcriptome-wide association study (TWAS) leverages information from reference panels of human tissues to predict the genetically determined component of expression in much larger datasets for thousands of genes and explore their association with a phenotype/disease of interest in thousands of individuals. Using TWAS, we sought to 1) define contributors to blood pressure (BP) regulation across a panel of 49 human cell-types/tissues 2) detect new kidney genes associated with BP in human kidney samples and 3) identify new pharmacological opportunities for hypertension through TWAS-informed drug repurposing. Design and method: We performed TWAS using PrediXcan across 49 human tissues/cell-types from The Genotype-Tissue Expression project and ranked the overall relevance of tissue of BP according to three independent metrics defining the strength of uncovered tissue-trait associations. We then trained predictors of gene expression from 478 samples from the Human Kidney Tissue Resource by applying a new predictive model which utilises epigenetic and three-dimensional genomic information to prioritise essential genetic variants. The subsequent BP kidney TWAS was conducted in up to ∼750k individuals from UK Biobank and International Consortium for Blood Pressure. Finally, we combined the input from BP kidney TWAS with Connectivity Map to identify drugs capable of inducing or reversing the identified gene expression signatures. Results: We found that fibroblasts, kidney cortex, lymphocytes, brain, thyroid, adrenal glands, aorta and spleen showed the overall strongest associations with BP across 49 human tissues/cell-types. Through TWAS of systolic blood pressure/diastolic blood pressure/pulse pressure we identified 997 kidney genes associated with at least one BP trait. Of these, 562 (56%) have not been reported before. Our computational druggability analysis re-affirmed the potential of several known BP inducers (glucocorticoid receptor agonists, calcineurin inhibitors) to increase BP and uncovered adenylate cyclase system activators to reverse the BP-related changes in the transcriptome. We also found purinergic receptor as a potential gene target for drug repurposing in hypertension. Finally, we found that use of topoisomerase inhibitors, cyclin-dependent kinase inhibitors, inosine monophosphate dehydrogenase inhibitors, and histone deacetylase inhibitors may be associated with hypotension. Conclusion: Our data provided evidence for the role of the kidney as an organ of the key relevance to hypertension and highlighted the importance of immune system in BP regulation. We also identified 997 kidney genes robustly associated with BP. Through TWAS-informed drug repurposing analysis, we uncovered novel targets for drug development in hypertension and highlighted BP drop as a potential side effect of several existing therapeutics.

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.

Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 μM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 μM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 μM apamin, IKCa 10 μM TRAM-34, and BKCa by 10 μM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 μM glibenclamide), or SERCA pump (by 0.1 μM thapsigargin). Inhibition of SGLTs (by 1 μM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.

Chaos: A Complex Noise on Blood Pressure Orchestration

The equilibrium by constancy or just shifts in other intrinsic and extrinsic variables are known as allostatic changes in systemic blood pressure regulation. This short-review intends to introduce the Chaos.

Hypertensive choroidopathy with bilateral multiple ink blot fluorescein leakage similar to acute central serous chorioretinopathy in a patient using synthetic cannabinoids (Bonzai)

We report a case of using synthetic cannabinoids (Bonzai) with hypertensive choroidopathy with bilateral multiple inkblot fluorescein leakage similar to acute central serous chorioretinopathy (CSC). The systemic blood pressure of the patient was 210/140 mm Hg. In fundus fluorescein angiography (FFA), there were multiple inkblot hyperfluorescent areas and an enlarging spot of fluorescein in the early phases and increased in the late phases similar to acute CSC in both eyes. All of the multiple focal hyperfluorescence areas in the FFA had disappeared, and hypofluorescent areas remained in their places at second month with systemic blood pressure regulation.

Etiopathophysiological role of the renin-angiotensin-aldosterone system in age-related muscular weakening: RAAS-independent beneficial role of ACE2 in muscle weakness.

Aging is accompanied by major changes in body composition that can negatively affect functional status in older adults, including a progressive decrease in muscle mass, strength, and quality. The prevalence of sarcopenia has varied considerably, depending on the definition used and the population surveyed-a 2014 meta-analysis across several countries found estimates ranging from 1% to 29% for people aged 60 years or older, who live independently. The potentially relevant studies were retrieved from the ScienceDirect/Medline/PubMed/Public library of science/Mendeley/Springer link and Google Scholar. Multiple keywords were used for the literature search both alone and in combination. Some of the important keywords used for literature search were as follows: "Epidemiology of muscle weakness/muscle disorders," "Pathogenesis of RAAS in muscle weakness," "Role of Angiotensin 1-7/ACE-2/Mas R axis in muscle weakness," and "Correction pathophysiology of muscle weakness via ACE2." The renin-angiotensin system (RAAS), a major blood pressure regulatory system, is a candidate mediator that may promote aging-associated muscle weakness. Previously, studies explored the proof concept for RAAS inhibition as a therapeutic target. Furthermore, in RAAS, angiotensin II, and angiotensin-converting enzyme 2 (ACE2) have been reported to induce endoplasmic reticulum (ER) stress via glucose-regulated protein 78/eukaryotic translation initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/CHOP axis in the liver. In addition, other mitochondria and ER physical interactions contribute to skeletal muscle dysfunction. However, very few studies have investigated the relationship between RAAS and ER stress-associated pathophysiological events and ACE2-mediated biological consequences in muscle weakness. Thus, the study has been designed to investigate the RAAS-independent beneficial role of ACE2 in muscle weakness.

Cardiovascular serotonergic system: Evolution, receptors, transporter, and function.

The serotonergic system, serotonin (5HT), serotonin transporter (SERT), and serotonin receptors (5HT-x), is an evolutionarily ancient system that has clear physiological advantages to all life forms from bacteria to humans. This review focuses on the role of platelet/plasma serotonin and the cardiovascular system with minor references to its significant neurotransmitter function. Platelets transport and store virtually all plasma serotonin in dense granules. Stored serotonin is released from activated platelets and can bind to serotonin receptors on platelets and cellular components of the vascular wall to augment aggregation and induce vasoconstriction or vasodilation. The vascular endothelium is critical to the maintenance of cardiovascular homeostasis. While there are numerous ligands, neurological components, and baroreceptors that effect vascular tone it is proposed that serotonin and nitric oxide (an endothelium relaxing factor) are major players in the regulation of systemic blood pressure. Signals not fully defined, to date, that direct serotonin binding to one of the 15 identified 5HT receptors versus the transporter, and the role platelet/plasma serotonin plays in regulating hypertension within the cardiovascular system remain important issues to better understand many diseases and to develop new drugs. Also, expanded research of these pathways in lower life-forms may serve as important model systems to further our understanding of the evolution and mechanisms of action of serotonin.

Potential therapeutic efficacy via avB3-integrin dependent interaction of developmental endothelial locus-1 (Del-1) after established angiotensin-II dependent hypertension

Abstract Introduction Cardiovascular diseases (CVDs) contribute to about 31% of global death. Hypertension is a major risk factor and also increases the risk of CVDs. An important regulator of systemic blood pressure in the body, the Renin Angiotensin Aldosterone system becomes overactivated during hypertension releasing a critical product, angiotensin-II (ANG-II), a known vasoconstrictor, activating the immune system leading to inflammation and as such mediating the effects of hypertension and subsequent end-organ damage due to the critical role of the innate and adaptive cells in producing pro-inflammatory cytokines such interleukin-17. Del-1, an extracellular matrix protein expressed mostly by endothelial cells is a known potent inhibitor of leukocyte recruitment. Aim We tested the hypothesis that, Del-1 via αvβ3-integrin dependent interaction protects against ANG-II induced cardiovascular remodeling after established hypertension. Methods Wild type (WT) mice were infused with 2 mg/kg/day of ANG-II for 14 days. Soluble Del-1 (Del-1-Fc) and a point mutant unable to bind to αvβ3-integrin (Del-1-RGE-Fc) was injected (50 μg/per injection) daily after 6 days of ANG-II infusion. SBP was measured using tail-cuff. Endothelial function was assessed using Mulvany myograph and quantification of inflammatory cells and IL-17 by flow cytometry. Histological staining for fibrosis, myocardial/medial hypertrophy and elastin degradation was used to evaluate both aortic and cardiac remodeling. Results After 6 days, mice infused with ANG-II showed significantly higher SBP of 140 mmHg as compared to control mice (110 mmHg). However, further progression of SBP after 6 days was blunted in infused mice treated with soluble Del-1 (ANGII+Del-1-Fc) as compared to similar increase in SBP in both infused mice treated with the point mutant (ANGII+Del-1-RGE-Fc) and non-treated infused mice (ANGII+Fc) leading to a difference of ∼20 mmHg. This effect was due to, the well protected endothelium dependent relaxation and reduced wall tension of the aorta in ANGII+Del-1-Fc mice. Further infiltration of CD45+ leukocytes, CD45+/IL-17A+ and TCRβ+T cells was significantly reduced in the aorta and heart of ANGII+Del-1-Fc mice as compared to both ANGII+Del-1-RGE-Fc and ANGII+Fc mice. However, the aorta and heart of ANGII+Del-1-Fc mice showed increased levels of anti-inflammatory regulatory T-cells (CD25+FOXP3+Treg). Also, aortic medial thickness, adventitial collagen and elastin degradation was decreased significantly in ANGII+Del-1-Fc mice. Additionally, in comparison to both ANGII+Del-1-RGE-Fc and ANGII+Fc mice, the hearts of ANGII+Del-1-Fc mice had significantly less interstitial and pericoronary collagen, smaller cardiomyocyte area and subsequently higher lumen-to-wall ratio. Conclusion Our study reveals the cardiovascular protective effects of Del-1 mediated via its association with αvβ3-integrin after established hypertension which could serve as potential therapeutic target. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): German Research Foundation (DFG)National Institutes of Health (NIH)

Purification and characterization of angiotensin-converting enzyme (ACE) from sheep lung.

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) in the renin-angiotensin system regulates blood pressure by catalyzing angiotensin I to the vasoconstrictor angiotensin II. In this study, the ACE was purified and characterized from sheep lung. The kinetic properties of the ACE were designated. The inhibition effect of captopril, a specific ACE inhibitor, was determined. ACE was purified from sheep lung using the affinity chromatography method in one step. NHS-activated Sepharose 4 Fast Flow as column filler and lisinopril as a ligand in this method used. The molecular weight and purity of ACE were designated using the SDS-PAGE method. Optimum temperature and optimum pH were found for purified ACE. KM and Vmax values from Lineweaver–Burk charts determined. The inhibition type, IC50, and Ki values of captopril on purified ACE were identified. ACE was 6405-fold purified from sheep lung by affinity chromatography in one step and specific activity was 16871 EU/mg protein. The purity and molecular weight of ACE were found with SDS-PAGE and observed two bands at around 60 kDa and 70 kDa on the gel. Optimum temperature and optimum pH were designated for purified ACE. Optimum temperature and pH were found as 40 °C and pH 7.4, respectively. Vmax and KM values were calculated to be 35.59 (µmol/min).mL−1 and 0.18 mM, respectively. IC50 value of captopril was found as 0.51 nM. The inhibition type of captopril was determined as non-competitive from the Lineweaver–Burk graph and the Ki value was 0.39 nM. As a result, it was observed in this study that the ACE enzyme can be successfully purified from sheep lungs in one step. Also, it was determined that captopril, which is a specific ACE inhibitor, has a significant inhibitory effect with a very low IC50 value of 0.51 nM.

The Impact of Fractional-Order Control on Blood Pressure Regulation

This paper presents a fractional-order framework for control of blood pressure regulation system. A new perspective is explored to control the blood pressure in lieu of the conventional control framework. A multi-variable scenario is adopted to control two outputs: mean arterial blood pressure (MABP) and cardiac output (CO) simultaneously. Three fractional-order controllers are designed and tuned optimally for the multi-input multi-output (MIMO) blood pressure regulation system. To test the effectiveness of the designed fractional controllers, control investigations are carried out based on controller performance indices and sensitivity performance indices. Stability analysis and sensitivity analysis are carried out in order to assure stable as well as robust feedback design. Sensitivity analysis of the paper reveals the controller's ability to handle model uncertainties of the blood pressure regulation system. Numerical simulation results of the paper unfold the best suitable fractional-order controller for the enhanced closed-loop performance of the blood pressure regulation system.

Decreased cardiac pacemaking and attenuated β-adrenergic response in TRIC-A knockout mice.

Changes in intracellular calcium levels in the sinus node modulate cardiac pacemaking (the calcium clock). Trimeric intracellular cation (TRIC) channels are counterion channels on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors, which play a major role in calcium-induced calcium release (CICR) and the calcium clock. TRIC channels are expected to affect the calcium clock in the sinus node. However, their physiological importance in cardiac rhythm formation remains unclear. We evaluated the importance of TRIC channels on cardiac pacemaking using TRIC-A-null (TRIC-A-/-) as well as TRIC-B+/-mice. Although systolic blood pressure (SBP) was not significantly different between wild-type (WT), TRIC-B+/-, and TRIC-A-/-mice, heart rate (HR) was significantly lower in TRIC-A-/-mice than other lines. Interestingly, HR and SBP showed a positive correlation in WT and TRIC-B+/-mice, while no such correlation was observed in TRIC-A-/-mice, suggesting modification of the blood pressure regulatory system in these mice. Isoproterenol (0.3 mg/kg) increased the HR in WT mice (98.8 ± 15.1 bpm), whereas a decreased response in HR was observed in TRIC-A-/-mice (23.8 ± 5.8 bpm), suggesting decreased sympathetic responses in TRIC-A-/-mice. Electrocardiography revealed unstable R-R intervals in TRIC-A-/-mice. Furthermore, TRIC-A-/-mice sometimes showed sinus pauses, suggesting a significant role of TRIC-A channels in cardiac pacemaking. In isolated atrium contraction or action potential recording, TRIC-A-/-mice showed decreased response to a β-adrenergic sympathetic nerve agonist (isoproterenol, 100 nM), indicating decreased sympathetic responses. In summary, TRIC-A-/-mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to β-adrenergic stimulation, indicating the involvement of TRIC-A channels in cardiac rhythm formation and decreased sympathetic responses.

The apelin/APJ system in the regulation of vascular tone: friend or foe?

The apelin (APJ) receptor was originally cloned as a gene encoding a putative G protein-coupled receptor related to angiotensin receptor type I. To date, two endogenous peptide ligands for APJ have been identified: apelin and elabela/Toddler. The apelin/APJ system regulates blood pressure and vascular tone. The endothelial and smooth muscle apelin/APJ systems exert opposite actions in the regulation of vascular tone. Binding of apelin to endothelial APJ promotes the release of vasodilators, such as nitric oxide and prostacyclin, leading to vasodilation. Alternatively, binding of apelin to smooth muscle APJ induces vasoconstriction, although the molecular mechanisms of the apelin-induced vasoconstriction are poorly understood. Recently, a critical role for interaction of APJ with α1-adrenergic receptor in the apelin-induced vasoconstriction was reported. The action of apelin on vascular tone may depend upon blood vessel type or pathological condition. Although the apelin/APJ system could serve as a potential therapeutic target for hypertension and cardiovascular disease, the role of this system in various cell types appears to be complicated.

Effects of sevoflurane anaesthesia on radioligand binding to monoamine oxidase-B in vivo

BackgroundThe molecular actions underlying the clinical effects of inhaled anaesthetics such as sevoflurane and isoflurane are not fully understood. Unexpected observations in positron emission tomography (PET) studies with [11C]AZD9272, a metabotropic glutamate receptor 5 (mGluR5) radioligand with possible affinity for monoamine oxidase-B (MAO-B), suggest that its binding is sensitive to anaesthesia with sevoflurane. The objective of the present study was to assess the effects of sevoflurane anaesthesia on the binding of [11C]AZD9272 and of [11C]L-deprenyl-D2, a radioligand selective for MAO-B in non-human primates (NHPs). MethodsAltogether, 12 PET measurements were conducted with a high-resolution research tomograph using the ligands [11C]AZD9272 or [11C]L-deprenyl-D2 in six cynomolgus monkeys anaesthetised with sevoflurane or ketamine/xylazine. ResultsThe specific binding of [11C]AZD9272 and [11C]L-deprenyl-D2 was markedly reduced during anaesthesia with sevoflurane compared with ketamine/xylazine. The reduction was 80–90% (n=3) for [11C]AZD9272 and 77–80% (n=3) for [11C]L-deprenyl-D2. ConclusionsSevoflurane anaesthesia inhibited radioligand binding to MAO-B in the primate brain. The observation of lower MAO-B binding at clinically relevant concentrations of sevoflurane warrants further exploration of the potential role of MAO-B related mechanisms in regulation of systemic blood pressure during anaesthesia.