First-line Treatment Of Hypertension Research Articles

Amlodipine increases risk of primary open-angle glaucoma

BackgroundThe use of calcium channel blockers is associated with primary open-angle glaucoma (POAG) in a statistically meaningful but minor way. In general, those who had received calcium channel blocker medication were at a 23% increased risk of developing glaucoma in comparison to those who had never taken the antihypertensive drugs. We wished to confirm this association and examine POAG genes that might be involved, since the genetics has not yet been analyzed.MethodsWe used MedWatch and UK Biobank data to evaluate the effects of amlodipine on POAG and intraocular pressure (IOP). We analyzed three POAG-associated single-nucleotide polymorphisms: rs9913911, an intron variant in growth arrest-specific 7 (GAS7), one of the genes that influences IOP; rs944801, an intron variant within CDKN2B-AS1, and rs2093210, an intron variant within SIX6, known to be associated with vertical cup-disc ratio, an important optic nerve head parameter that is often used to define or diagnose glaucoma.ResultsAmlodipine use in MedWatch doubled the prevalence of POAG, from 0.0805 to 0.177%, a small but significant increase. Multivariate analysis by logistic regression of UK Biobank data revealed that POAG risk was significantly increased with age, male sex, major alleles of rs9913911 (GAS7) and rs944801 (CDKN2B-AS1), and minor allele of rs2093210 (SIX6). Amlodipine increased POAG risk by 16.1% (P = 0.032). Amlodipine has not been associated with increased IOP. We confirmed this lack of association and in addition found that GAS7, associated with IOP, was not associated with POAG risk and amlodipine. But CDKN2B-AS1 and SIX6, POAG genes not associated with IOP, were associated with POAG and amlodipine.ConclusionsAmlodipine, a frequently prescribed drug and first line treatment for hypertension, has a potentially hazardous relationship with POAG. Knowledge of this link can guide the prescribing of alternate drugs for hypertensive individuals who have glaucoma or are at risk for it. Diuretics and β-blockers are not associated with POAG or increased IOP and could be substituted for amlodipine in hypertensive patients at risk POAG.Trial registrationNone.Graphical

Clinical outcome in hypertensive patients treated with amlodipine plus bisoprolol or plus valsartan

Objective Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V). Methods A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments. Results Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83–1.18), ASCVD event (aHR 0.97, 95% CI 0.84–1.12), and heart failure (aHR 1.06, 95% CI 0.87–1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52–0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups. Conclusions There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.

Thiazide-associated hyponatremia in arterial hypertension patients: A nationwide population-based cohort study.

Thiazides are the first-line treatment for hypertension, however, they have been associated with hospitalizations for thiazide-associated hyponatremia (TAH). The aim of this study was to evaluate the risk of TAH and other drug-associated hyponatremia in a Korean population. The study used big data from the National Health Insurance Sharing Service of 1,943,345 adults treated for hypertension from January 2014 to December 2016. The participants were divided into two groups based on the use of thiazides. Cox proportional hazard models were used to identify independent risk factors for the occurrence of hyponatremia. The study found that hyponatremia-related hospitalizations were significantly higher in the thiazide group than the control group (2.19%vs. 1.45%). The risk increased further with concurrent use of other diuretics or desmopressin, and thiazide+spironolactone+desmopressin and hospitalization risk further increased (4.0 and 6.9 times). Multivariate analysis showed that hyponatremia occurrence increased with age, diabetes mellitus, depression, and thiazide use (hazard ratio=1.436, p<0.001). The thiazide group had better 6-year overall survival than the control group but had more fractures and hyponatremia. Thiazide use is associated with an increased risk of hyponatremia and related complications. However, the mortality rate decreased in those who received thiazides, suggesting that thiazide use itself is not harmful and may help decrease complications and improve prognosis with proper, cautious use in high-risk patients.

DOCKING AND MD OF GOTU KOLA (Centella asiatica L.) COMPOUNDS TO AT1 RECEPTORS AS ANTIHYPERTENSIVES

Non-communicable diseases, including hypertension, are a significant source of health issues in developed nations[MOU1] . Angiotensin II Receptor Blocker (ARB) is frequently used as the first-line treatment for hypertension. ARB works by inhibiting Angiotensin II which can cause vasoconstriction of entire blood vessels[l2] . This study aimed to find lead compound of 54 compounds obtained from gotu kola (Centella asiatica L.) in order to determine the antihypertensive activity. The target of drug action chosen in this study was the type 1 angiotensin II receptors (AT1). Molecular docking and molecular dynamics simulation were chosen as the methods in this study to predict the interaction and the affinity and stability of the interaction. Based on the results of molecular docking, it was found that the compound of campesterol, centellasaponin B, and corosolic acid gave good affinity to the targets. The test ligand that the Ki and DG values were close to the natural ligand (Olmesartan) campesterol with a value of -10.79 kcal/mol and 12.28 nM. Meanwhile, in the molecular dynamics simulation test, it was found that corosolic acid has good interaction stability with the targets and was constant from the beginning of the simulation to 100 ns, while for MMGBSA centellasaponin B the lowest total energy value was -71.4347 kcal/mol. It was concluded that the gotu kola (Centella asiatica L.), compound corosolic acid, and centellasaponin B had the potential as a lead compound that had affinity and stability for the interaction with the AT1 receptor as antihypertensives.

Effects of Nebivolol therapy on hemodynamic parameters and lipid profile compared to other beta blockers in patients with essential hypertension: a systematic review and meta-analysis.

Besides being commonly used to treat high blood pressure, beta blockers are a family of drugs that are primarily used to regulate irregular cardiac rhythms. Nebivolol is a third generation of beta blockers, which is highly cardioselective, about three times as selective as bisoprolol. In this study, we aimed to evaluate Nebivolol's effectiveness and safety in comparison to other beta blockers. We searched the online databases PubMed, ScienceDirect, and Cochrane Library for relevant RCTs evaluating Nebivolol's effect on hypertension management. Relative risk (WRR) and weighted mean difference (WMD), with a 95% confidence interval (CI) were utilized to quantify the impact of nebivolol medication in the treatment of hypertension using a random effects model. Twelve RCTs are included in the study, the patient numbers in every attempt ranged from 42-273 and 1456 patients in all were included in this review. Nebivolol does not significantly reduce SBP, DBP and HR compared to other beta blockers (WMD -0.57 mmHg, 95% CI [-1.55; 0.42 mmHg] p=0.12; WMD -0.27 mmHg, 95% CI [-1.36; 0.82 mmHg] p=0.63 ; WMD 0.10 BPM, 95% CI [-4.11;1.31 BPM] p=0.96, respectively). Patients treated with Nebivolol has significantly lower LDL-C (WMD -8.88 mg/dL, 95% CI [-15.28; -2.48 mg/dL] p=0.007) and significantly higher HDL-C (WMD 2.30 mg/dL, 95% CI [0.75; 3.84 mg/dL] p=0.004. According to this study's findings, nebivolol is well tolerated and decreases LDL-C. And higher HDL-C than other beta blocker agents. This review does not recommend nebivolol as first-line treatment in hypertension as Nebivolol does not significantly reduce blood pressure and HR of patients.

β-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage.

Angiotensin receptor blockers (ARBs) are the first-line treatment for hypertension; they act by inhibiting signaling through the angiotensin 1 receptor (AT1R). Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the β-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication. Here, we explored the effects of TRV and associated β-arrestin signaling in podocytes, essential cells of the kidney filter. We used human podocyte cell lines to determine β-arrestin's involvement in calcium signaling and cytoskeletal reorganization and Dahl SS rats to investigate the chronic effects of TRV administration on glomerular health. Our experiments indicate that the TRV-activated β-arrestin pathway promotes the rapid elevation of intracellular Ca2+ in a dose-dependent manner. Interestingly, the amplitude of β-arrestin-mediated Ca2+ influx was significantly higher than the response to similar Ang II concentrations. Single-channel analyses show rapid activation of transient receptor potential canonical (TRPC) channels following acute TRV application. Furthermore, the pharmacological blockade of TRPC6 significantly attenuated the β-arrestin-mediated Ca2+ influx. Additionally, prolonged activation of the β-arrestin pathway in podocytes resulted in pathological actin cytoskeleton rearrangements, higher apoptotic cell markers, and augmented glomerular damage. TRV-activated β-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage.

Impact of amlodipine on clinical outcomes for heart failure in patients with dilated cardiomyopathy: a Korean nationwide cohort study.

Amlodipine, widely used as a first-line treatment for hypertension, has inconclusive clinical evidence regarding its efficacy in patients with heart failure. This retrospective cohort study aimed to investigate the clinical effectiveness of amlodipine treatment after hospitalization for heart failure in patients with dilated cardiomyopathy (DCMP). A total of 20,851 patients who were diagnosed with DCMP and admitted for heart failure between 2005 and 2016 according to Korean nationwide medical insurance service database were enrolled. Amlodipine use was defined as its prescription at the time of discharge and for at least 180 days within a year. The primary outcome was all-cause death, and the secondary outcome was heart failure rehospitalization during a 5-year period. The outcomes between patients who received amlodipine (n = 6,798) and those who did not (n = 14,053) were compared. During the 5-year follow-up, the group treated with amlodipine exhibited a significantly lower risk of all-cause death and heart failure rehospitalization than the group not treated with amlodipine [all-cause death: adjusted hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.59-0.70, p < 0.001; cardiovascular death: adjusted HR: 0.71, 95% CI: 0.62-0.81, p < 0.001; heart failure rehospitalization: adjusted HR: 0.92, 95% CI: 0.86-0.98, p = 0.006]. In a subgroup analysis, amlodipine had a significant impact on decreasing all-cause mortality in older adults, those with a higher systolic blood pressure, and those with a lower Charlson Comorbidity Index. In summary, amlodipine use after hospitalization for heart failure in patients with DCMP was associated with a lower risk of all-cause death and readmission for heart failure.

Abstract 11900: Potassium Magnesium Citrate is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone

Thiazide-type diuretics (TD) are the first-line treatment of hypertension in many guidelines because of its consistent benefit in lowering BP and cardiovascular risk. TD is also known to cause excess risk of diabetes mellitus (DM), which may limit its long-term use. Although hypokalemia was thought to be the main mechanism of TD-induced dysglycemia, potassium (K) supplementation alone does not consistently prevent TD-induced elevation in fasting plasma glucose (FPG). In addition to reducing serum K, TD triggers magnesium (Mg) depletion. However, it is unknown if Mg supplementation attenuates metabolic side effects of TD. Accordingly, we conducted a randomized double-blinded clinical trial in 60 hypertensive patients without DM to compare effects of KCl (40 meq daily) vs. KMgCitrate (Cit) powder containing identical amount of K, 20 meq of Mg, and 74 meq of Cit daily during chlorthalidone (CTD) treatment. Each patient received CTD alone (25 mg/day) for 3 weeks prior to randomization. The primary endpoint was the change in FPG after 4-month of treatment from baseline (CTD alone) after adjusting for baseline FPG as a covariate. The mean age of subjects was 59±11 years (45% Female, 30% Black participants). We found that CTD induced a significant rise in FPG, insulin, and a significant fall in serum K and 24-h urinary citrate excretion (all p &lt; 0.05). We found that KMgCit significantly increased serum K, 24-hour urinary Mg, and 24-hour urinary Cit excretion; and attenuated the rise in FPG which was not observed with KCl (Figure 1 A-C). There were no significant differences in liver fat by MRI or fasting plasma insulin between the 2 groups. In conclusion, our study showed beneficial effects of magnesium supplementation in maintaining serum K and reversing effects CTD on plasma glucose, which may improve safety profile and optimize long-term cardiovascular outcomes in hypertensive patients.

Estradiol modulation of behavioral and physiological body fluid control during repeated dietary sodium deprivation

The low salt diet is a first line treatment for hypertension, but it is a difficult diet to maintain. As a result, patients may alternate between periods of high and low salt intake, the effects of which are unclear. Importantly, blood pressure increases in women after menopause, suggesting that estrogen plays a role in preventing hypertension. At present, however, it is unknown if the behavioral and physiological impact of alternating episodes on the low salt diet may be altered by the presence of estrogen. Our goals were to assess salt intake and body fluid hormones with repeated dietary sodium deprivations. Using ovariectomized rats with (EB) and without (OIL) estrogen treatment, we subjected rats to one or two dietary sodium deprivations using low salt laboratory chow. 0.5 M NaCl and water intakes were recorded after each period of regular chow or deprivation. After deprivation, rats were sacrificed, and trunk blood was collected for analysis of vasopressin, norepinephrine, epinephrine, and aldosterone levels. Plasma sodium concentration, plasma protein concentration, body weight, and uterine weight were also measured. There was no difference in the salt intakes of OIL- or EB-treated rats after one or two dietary sodium deprivations. However, EB-treated rats drank a less concentrated solution overall, suggesting less overcompensation after dietary sodium deprivation. Additionally, after a single episode of dietary sodium deprivation, EB-treated rats’ consumption remained elevated above baseline even after returning to regular laboratory chow. These behavioral differences were not explained by alterations in vasopressin, norepinephrine, epinephrine, or aldosterone. Plasma sodium and plasma protein concentrations also did not show alterations related to the change in behavior. Further research is necessary to determine the mechanism behind these changes in intake in EB-treated rats, which may ultimately be clinically relevant for both pre- and postmenopausal women on the low salt diet.

Potassium Magnesium Citrate Is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone.

Thiazide diuretics (TD) are the first-line treatment of hypertension because of its consistent benefit in lowering blood pressure and cardiovascular risk. TD is also known to cause an excess risk of diabetes, which may limit long-term use. Although potassium (K) depletion was thought to be the main mechanism of TD-induced hyperglycemia, TD also triggers magnesium (Mg) depletion. However, the role of Mg supplementation in modulating metabolic side effects of TD has not been investigated. Therefore, we aim to determine the effect of potassium magnesium citrate (KMgCit) on fasting plasma glucose and liver fat by magnetic resonance imaging during TD therapy. Accordingly, we conducted a double-blinded RCT in 60 nondiabetic hypertension patients to compare the effects of KCl versus KMgCit during chlorthalidone treatment. Each patient received chlorthalidone alone for 3 weeks before randomization. Primary end point was the change in fasting plasma glucose after 16 weeks of KCl or KMgCit supplementation from chlorthalidone alone. The mean age of subjects was 59±11 years (30% Black participants). Chlorthalidone alone induced a significant rise in fasting plasma glucose, and a significant fall in serum K, serum Mg, and 24-hour urinary citrate excretion (all P<0.05). KMgCit attenuated the rise in fasting plasma glucose by 7.9 mg/dL versus KCl (P<0.05), which was not observed with KCl. There were no significant differences in liver fat between the 2 groups. KMgCit is superior to KCl, the common form of K supplement used in clinical practice, in preventing TD-induced hyperglycemia. This action may improve tolerability and cardiovascular safety in patients with hypertension treated with this drug class.

Beta-Blockers and Hypertension: Some Questions and Answers.

International guidelines have removed b-blockers from first-line treatment of hypertension, limiting their use to patients with compelling indications. The position of guidelines stems from the results of studies performed with the 1st and 2nd generation of b-blockers, which concluded that these drugs have lower cardiovascular protection, compared with other antihypertensive agents. The aim of our mini review is to answer to some questions about the effect of b-blockers on hypertension and cardiovascular protection and if these effects are different from those of other antihypertensive drugs, particularly in young and elderly patients. We evaluated the relevant systematic reviews and meta-analyses, which reported the effectiveness of b-blockers on blood pressure and cardiovascular outcomes, compared with placebo/no treatment and with other antihypertensive agents. Beta-blockers, decreased high blood pressure with no significant difference from other common antihypertensive agents. Moreover b-blockers, compared with placebo, lowered the risk of major cardiovascular outcomes, while, compared with other drug classes, the reported results are very heterogeneous. Therefore it is difficult, globally, to find a difference between b-blockers and other drug classes. Rather than looking for differences in the cardiovascular protective effect between b-blockers and other antihypertensive agents, we have to consider the different pathophysiology of hypertension in young [sympathetic hyperactivity] and elderly patients [arterial stiffness, high aortic systolic pressure]. Considering these aspects, non-vasodilating b-blockers are preferred, as first-line, in young/middle aged hypertensive subjects, while vasodilating b-blockers, are most appropriate, in elderly patients, for the favourable hemodynamic profile.

Beta-arrestin-biased agonism promotes TRPC6-mediated calcium influx in human podocytes

Background: Angiotensin Receptor blockers (ARBs) are the first-line treatment for hypertension and other chronic kidney diseases and act by inhibiting signaling through the angiotensin 1 receptor (AT1R). AT1R activation initiates signaling through G protein-coupled receptor (GPCR) effector signaling and β-arrestins. Recently, a novel AT1R agonist TRV120027 (TRV) that selectively activates the β-arrestin cascade without impacting the GCPR pathway has become available. Therefore, we hypothesized that β-arrestin and G-protein signaling pathways via AT1R have distinct downstream effects in podocytes. Furthermore, we propose that β-arrestin signaling initiates TRPC6-mediated Ca 2+ entry. Methods: We used a conditionally immortalized human podocyte cell line to determine β-arrestin’s involvement in podocyte calcium signaling and cytoskeletal reorganization. Intracellular Ca 2+ influx (Fluo-4 AM) and NO response (DAF-FM) to Ang II or TRV applications were analyzed with confocal microscopy. The role of TRPC channels was tested by single-channel electrophysiology and confocal imaging using a variety of commercially available inhibitors (AC1903 for TRPC5 and GSK283350A, SAR7334 for TRPC6). Western blotting for apoptosis-associated proteins, TUNEL staining to detect DNA cleavage, and actin cytoskeleton rearrangements were performed in podocytes exposed to TRV or Ang II treatment. Results: Our experiments determined that TRV-mediated β-arrestin pathway activation in podocytes promotes rapid elevation of intracellular Ca 2+ in a dose-dependent manner (IC 50 =15μM, ligand-receptor binding fit modeled with Levenberg–Marquardt algorithm, adj. R 2 =0.93). Interestingly, the amplitude of β-arrestin-mediated Ca 2+ influx was four times higher than the response to similar Ang II concentrations (t-test, n≥30, p&lt;0.05). Moreover, the TRV response was significantly increased under hyperglycemic stress conditions, and promoted rapid apoptosis in podocytes (one-way ANOVA, n≥21, p=0.003). The pharmacological blockade of TRPC6, but not TRPC5, significantly attenuated Ca 2+ influx in response to β-arrestin. In contrast to Ang II, TRV does not induce AT1R-mediated NO production, suggesting that β-arrestin activation only targets AT1R, and not AT2R. Single-channel analyses show rapid activation of TRPC activity in response to acute TRV application in podocytes (one-way ANOVA, n=8, p=0.004). Overall prolonged activation of the β-arrestin pathway in podocytes results in enhanced actin bundle thickness, abnormal actin cytoskeleton distribution, and increased apoptotic cell markers. Conclusions: TRV-mediated β-arrestin signaling in podocytes promotes high ionotropic TRPC6 channel-mediated Ca 2+ influx, cytoskeleton rearrangement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment is controversial and requires further investigation. DK126720 (to OP), DK129227 (to AS and OP), and NIH/NCATS/SCTR UL1TR001450/SCTR 2214 (to OP), endowed funds from the SC SmartState Centers of Excellence (to OP), Veterans Affairs Support Veterans Affairs (Merit Award I01 BX000820 to JL), research grant from Dialysis Clinic, Inc (to JL). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

RAG-AMERICAS-4: THE FUTURE OF HYPERTENSION RESEARCH: PRECISION MEDICINE

Outline: Medicine is transitioning from the traditional reactive care based on symptoms, diagnosis and treatment to a system that targets the disease before it occurs and when disease is present, then treats it in a personalized manner. Chronic diseases such as arterial hypertension are suitable for precision medicine since patients with the same blood pressure (BP) values differ from one another, for instance, in terms of arterial hemodynamics and therefore, respond differently to the same treatment. From an epidemiological perspective, BP lowering is broadly effective, requiring little or even no information about individuals. The success of public health interventions that do not involve personalized medicine raises the question to what extent will personalizing the treatment of hypertension impact the health of patients. In general, there is a trade-off between simplicity of one-drug for most hypertensive patients and the addition of more information about individuals for personalized clinical decision-making. More precise treatment strategies create the most value for patients in whom simple strategies with low information is ineffective. A usual clinical scenario is resistant hypertension. Our research has shown that when hypertension subtypes are considered, BP reduction with current antihypertensive medications considerably differs. Both systolic and diastolic hypertensives exhibit the best antihypertensive response to vasodilators while insolated forms of systolic or diastolic hypertension respond much less to this kind of first line treatment of hypertension. A new taxonomy based on patient's clinical information, BP subtypes, genetic and epigenetic factors will identify hypertensive phenotypes beyond classical BP based approach, which will lead to a more precise and effective hypertension treatment.

Comparative Analysis of Hypertension Guidelines: Unveiling Consensus and Discrepancies in Lifestyle Modifications for Blood Pressure Control.

Hypertension is a major global health concern, and lifestyle modifications have been recommended as first-line treatment for hypertension in many guidelines. However, different guidelines may recommend different types of lifestyle adjustment, and it is unclear which ones are most effective. In this review, we compared hypertension guidelines to identify any differences and/or consensus in content, efficacy, and timing of initiation of lifestyle modifications. We conducted a search of databases to identify hypertension guidelines available in English. We extracted and compared information about lifestyle modifications recommended by the guidelines. Five hypertension guidelines from America, Europe, the UK, Canada, and the International Society of Hypertension are included. They all recommend diet adaptation, sodium reduction, alcohol restriction, physical exercise, and weight reduction. Other lifestyle interventions emphasized by some guidelines, such as potassium supplementation, smoking cessation, and stress management, are not recommended by all the five guidelines. Among lifestyle changes, the dietary approaches to stop hypertension (DASH) diet may be considered the most effective treatment for reducing blood pressure. These guidelines recommend that for patients with high-normal blood pressure or grade 1 hypertension without high risk factors, lifestyle medicine should be used first for 3-6 months, if blood pressure is still not controlled, then start medication. For those patients who need drug treatment, lifestyle changes can also enhance the effects of antihypertensive therapy. Lifestyle modifications are crucial in the treatment of hypertension and should be recommended to most hypertensive patients. Among these lifestyle interventions, diet adaptation containing low sodium and alcohol restriction may be the most effective in reducing blood pressure. Physical exercise and weight reduction are also recommended. In some cases, lifestyle modifications should be tried first. They may also enhance the effects of antihypertensive drugs in other patients.

Page Kidney From Ruptured Mycotic Pseudoaneurysm of Renal Artery: An Unusual Complication of Infective Endocarditis

Page kidney is an uncommon but potentially reversible cause of secondary hypertension characterized by external compressive force leading to renal hypoperfusion and elevated renin level. Renal artery mycotic aneurysms from infective endocarditis are exceedingly rare. The most feared complication is rupture, which can result in subcapsular hematoma and Page kidney. Early recognition and treatment are crucial to preserving renal function. Imaging and clinical findings aid diagnosis. Angiotensin-converting enzyme inhibitors are usually the first-line treatment of hypertension. Here, we present a rare patient case of ruptured mycotic pseudoaneurysm of the renal artery that complicated infective endocarditis and resulted in Page kidney.

Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1–7) with selectivity for the C-terminal domain

The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from the action of angiotensin-I converting enzyme (ACE) on the decapeptide angiotensin-I. ACE possess two active sites (nACE and cACE) that have their own kinetic and substrate specificities. ACE inhibitors are widely used as the first-line treatment for hypertension and other heart-related diseases, but because they inactivate both ACE domains, their use is associated with serious side effects. Thus, the search for domain-specific ACE inhibitors has been the focus of intense research. Angiotensin (1–7), a peptide that also belongs to the RAS, acts as a substrate of nACE and an inhibitor of cACE. We have synthetized 15 derivatives of Ang (1–7), sequentially removing the N-terminal amino acids and modifying peptides extremities, to find molecules with improved selectivity and inhibition properties. Ac-Ang (2–7)-NH2 is a good ACE inhibitor, resistant to cleavage and with improved cACE selectivity. Molecular dynamics simulations provided a model for this peptide’s selectivity, due to Val3 and Tyr4 interactions with ACE subsites. Val3 has an important interaction with the S3 subsite, since its removal greatly reduced peptide-enzyme interactions. Taken together, our findings support ongoing studies using insights from the binding of Ac-Ang (2–7)-NH2 to develop effective cACE inhibitors.

Angiotensin II Receptor Blockers in the Management of Hypertension in Preventing Cognitive Impairment and Dementia-A Systematic Review.

Hypertension is a known risk factor for cognition-related pathologies including dementia. The National Institute of Health and Care Excellence (NICE) guidelines recommend angiotensin (Ang) II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) as a first-line treatment for hypertension. Although both ARBs and ACEIs show neuroprotective effects, ACEIs show contradictory side effects; therefore, ARBs may be a more viable option. However, trials assessing the effects of ARBs on cognition are scarce and conflicting. Therefore, the aim of this review is to conduct a systematic review and synthesise data on the influence of ARBs on cognition and dementia prevention. Five databases were searched from 1992–2022 to produce 13 randomised controlled trials (RCTs) involving 26,907 patients that compared associations of ARBs against placebos or other antihypertensives on cognition or probable dementia with a minimum duration of 3 months. ARBs showed greater cognitive benefits when compared to hydrochlorothiazide (HCTZ), beta blockers (BB), and ACEIs. Our findings showed that although ARBs are superior to some antihypertensives such as ACEIs, thiazide and beta blockers, they made no difference in comparison to the placebo in all but one sample of patients. The positive effects on cognitive performances are equal to calcium channel blockers (CCBs) and lower than statin. The neuroprotective effects of ARBs are also more beneficial when ARBs are taken at the same time as a statin. Due to these inconsistencies, robust conclusions cannot be made. Future trials are warranted and, if successful, could have positive economic implications and consequently improve quality of life.

Neonatal Reserpine Administration Produces Widespread Neuronal Losses and ⍺-Synuclein Inclusions in a Rat Model

Historically, reserpine was widely used as an antihypertensive drug. However, severe motor and non-motor symptoms such as dyskinesia and depression led to the discontinuation of reserpine as a first-line treatment for hypertension. Reserpine functions by inhibiting vesicular monoamine transporter 2 (VMAT2), reducing sequestration of monoamines into synaptic vesicles. The consequent reduction in monoamines, most notably dopamine, serotonin and norepinephrine, in the central nervous system, causes well-defined symptoms such as catalepsy, hypoactivity and sedation in animals, and these motor and non-motor symptoms are well defined for reserpine treatment. However, no gross neuropathological changes in response to reserpine treatment have been reported previously in any animal model. In contrast, reducing VMAT2 expression in genetically modified VMAT2 LO mice leads to the production of ⍺-synuclein-positive aggregates and progressive nigrostriatal neuronal loss. These VMAT2 LO mice have reduced VMAT2 functionality during critical brain developmental stages and this could be the key to producing a reserpine model with matching histopathologies. The aim of this study was therefore to investigate the effect of neonatal reserpine administration on brain histology. We report here that a single dose of 5mgkg-1 reserpine administered subcutaneously to neonatal rats on postnatal day 3 leads to widespread neuronal loss in various brain regions including the substantia nigra pars compacta, ventral tegmental area, striatum, hippocampus, locus coeruleus, amygdala and cerebral cortex, and the presence of ⍺-synuclein-positive inclusions in the substantia nigra pars compacta and the dorsal striatum within 30days of administration.

Comprehensive Comparative Effectiveness and Safety of First-Line β-Blocker Monotherapy in Hypertensive Patients: A Large-Scale Multicenter Observational Study.

[Figure: see text].

POS-157 ACUTE POST-INFECTIOUS GLOMERULONEPHRITIS IN CHILDREN: ABOUT A SERIES OF 83 CASES

Post-infectious acute glomerulonephritis (PI-AGN) is very common among Moroccan children. IT can be defined as an acute, non-suppurative, diffuse, generalized inflammation of the glomeruli of both kidneys. It occurs after an infection (of the skin or the upper respiratory tract). Group A beta-hemolytic (GABH) streptococcus is the most incriminated infectious agent. PI-AGN prognosis depends on the severity of renal involvement, with the possibility of chronic renal disease in the worst cases. The aim of our study is to determine the epidemiological, clinical, histological, and evolutive features of PI-AGN in children treated in our center. For that reason, we gathered retrospective data of 83 children. The study took place from January 2016 to June 2020. The median of age was 9 years. Distribution by sex was in favor of males with 65%. Most cases (91%) were seen in winter. The most involved infectious sites were the upper respiratory tract (74%), and the skin (24%). The infection was still active at diagnosis in 30% of cases, while the remaining cases had it at least one week before. Microscopic hematuria and proteinuria were always present. Gross hematuria, generalized edema, and hypertension were also very common (seen respectively in 77%, 82%, and 65% of the cases). Other symptoms reported at diagnosis of PI-AGN were abdominal pain and vomiting (71%), convulsions (17%), and oliguria (13.3%). Acute kidney failure was found at onset in 25 children, from whom two had dialysis. The C3 complement fraction was low in 68 patients, and the ASLO titers were high in 53% of cases. All patients were under water and salt restriction. Furosemide was the first-line treatment of hypertension and oliguria patients, and nicardipine was added when blood pressure targets were not achieved. Renal biopsy was performed on 14 children. The main indications were nephrotic syndrome, persistent proteinuria, rapidly progressive glomerulonephritis (respectively in 22, eight, four, and two patients). The renal biopsy findings were as follows: endocapillary GN with C3 deposits in 14 children, minimal change disease in four children, membranous GN in one patient, crescent GN in two children, and glomerulosclerosis with C3 deposits in one child. Oral steroids (nephrosis regiment) were prescribed in 40%. Meanwhile, intravenous methylprednisolone (1g/1.73m2 three days in a row) and cyclophosphamide (500 mg/m2/month for six months) was indicated in severe cases (respectively 23% and 9.6% of cases). All our 83 children had a good prognosis, and no cases of chronic kidney disease were noted at follow-up. PI-AGN is still very common in Morocco, mainly because GABH-streptococcus upper respiratory tract infections are still frequent in our children. However, the prognosis remains good if the appropriate management is started early.