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Doxorubicin's (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic for the transition stage between the compensated and decompensated phases of HF. In conclusion, we suggest that DOX-induced HF in TGR is a suitable model to study the pathophysiological aspects of chemotherapy-induced HF and to evaluate novel therapeutic strategies to combat this form of HF, which are urgently needed.

Angiotensin (Ang)-(1-7) is a beneficial renin-angiotensin system (RAS) hormone that elicits protective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic syndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging, however, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related elevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged (16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a subcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body composition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment. Adipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene expression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic and mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved insulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body composition. The blood pressure-lowering effects of Ang-(1-7) in aged mice were associated with reduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic risk.

Diabetic nephropathy (DN) is a serious complication of diabetes, and its progression is influenced by factors like oxidative stress, inflammation, cell death, and fibrosis. Compared to drug treatment, exercise offers a cost-effective and low-risk approach to slowing down DN progression. Through multiple ways and mechanisms, exercise helps to control blood sugar and blood pressure and reduce serum creatinine and albuminuria, thereby alleviating kidney damage. This review explores the beneficial effects of exercise on DN improvement and highlights its potential mechanisms for ameliorating DN. In-depth understanding of the role and mechanism of exercise in improving DN would pave the way for formulating safe and effective exercise programs for the treatment and prevention of DN. [ABSTRACT FROM AUTHOR]

Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the renin–angiotensin–aldosterone system (RAAS). The new approach to the RAAS talks about two opposing pathways between which a state of equilibrium develops. One of them is a classical pathway, which is responsible for increasing blood pressure and is represented mainly by the angiotensin II (Ang II) peptide and, to a lesser extent, by angiotensin IV (Ang IV). The alternative pathway is responsible for the decrease in blood pressure and is mainly represented by angiotensin 1–7 (Ang 1–7) and angiotensin 1–9 (Ang 1–9). Our research study aimed to assess changes in angiotensin II, angiotensin IV, angiotensin 1–7, and angiotensin 1–9 concentrations in the plasma of adolescents with hypertension, with hypertension and obesity, and obesity patients. The Ang IV concentration was lower in hypertension + obesity versus control and obesity versus control, respectively p = 0.01 and p = 0.028. The Ang 1–9 concentration was lower in the obesity group compared to the control group (p = 0.036). There were no differences in Ang II and Ang 1–7 peptide concentrations in the hypertension, hypertension and obesity, obesity, and control groups. However, differences were observed in the secondary peptides, Ang IV and Ang 1–9. In both cases, the differences were related to obesity. [ABSTRACT FROM AUTHOR]

Arterial hypertension is one of the most common and significant cardiovascular risk factors. There are many well-known and identified risk factors for its development. In recent times, there has been growing concern about the potential impact of COVID-19 on the cardiovascular system and its relation to arterial hypertension. Various theories have been developed that suggest a connection between COVID-19 and elevated blood pressure. However, the precise link between SARS-CoV-2 infection and the long-term risk of developing hypertension remains insufficiently explored. Therefore, the primary objective of our study was to investigate the influence of COVID-19 infection on blood pressure elevation and the subsequent risk of developing arterial hypertension over an extended period. To accomplish this, we conducted a thorough search review of relevant papers in the PubMed and SCOPUS databases up to 3 September 2023. Our analysis encompassed a total of 30 eligible articles. Out of the 30 papers we reviewed, 19 of them provided substantial evidence showing a heightened risk of developing arterial hypertension following COVID-19 infection. Eight of the studies showed that blood pressure values increased after the infection, while three of the qualified studies did not report any notable impact of COVID-19 on blood pressure levels. The precise mechanism behind the development of hypertension after COVID-19 remains unclear, but it is suggested that endothelial injury and dysfunction of the renin–angiotensin–aldosterone system may be contributory. Additionally, changes in blood pressure following COVID-19 infection could be linked to lifestyle alterations that often occur alongside the illness. Our findings emphasize the pressing requirement for thorough research into the relationship between COVID-19 and hypertension. These insights are essential for the development of effective prevention and management approaches for individuals who have experienced COVID-19 infection. [ABSTRACT FROM AUTHOR]

Simple Summary: High blood pressure (hypertension) is a common medical issue in cats. Amlodipine is a medication used to treat hypertension, but it might activate hormone systems that can be harmful in the long term. This preliminary study evaluated a hormone system called the renin–angiotensin–aldosterone system (RAAS) in cats with high blood pressure being treated with amlodipine compared to healthy cats with normal blood pressure, and found that hypertensive cats treated with amlodipine were RAAS activated. Since RAAS activation can have harmful long-term effects, including cardiac fibrosis (scar formation in the heart) and salt and water retention, medications to suppress the RAAS might be helpful in cats with high blood pressure that are treated with amlodipine. Background: Chronic renin–angiotensin–aldosterone system (RAAS) activation is harmful. Amlodipine activates RAAS in humans and dogs, but contradictory data exist for systemically hypertensive (SHT) cats. Hypothesis: Cats with SHT and chronic kidney disease treated with amlodipine (SHT/CKD-A) are RAAS activated. Animals: Client-owned cats: unmedicated normotensive (NT) cats (n = 9); SHT/CKD-A cats (n = 5) with median systolic blood pressure of 170 mmHg (vs. 195 mmHg, pre-treatment), chronic kidney disease, and receiving no RAAS-suppressive therapy. Methods: Serum was frozen (−80 °C) until RAAS analysis via equilibrium analysis. The RAAS variables (reported as median (minimum–maximum)) were compared between groups, using Mann–Whitney U test. Results: Angiotensin 1, angiotensin 1,7, angiotensin III, and angiotensin 1,5, and angiotensin-converting enzyme (ACE)-2 activity were higher in SHT/CKD-A cats compared to NT cats, while ACE activity was lower in SHT/CKD-A cats compared to NT cats (p < 0.05 all). A marker for alternative RAAS influence (ALT-S) was significantly higher (69; 58–73 pmol/pmol) in SHT/CKD-A cats compared to NT cats (35; 14–63 pmol/pmol; p = 0.001). Aldosterone concentrations were significantly higher (393; 137–564 pmol/L) in SHT/CKD-A cats compared to NT cats (129; 28–206 pmol/L; p = 0.007). Conclusion and Clinical Importance: Circulating RAAS is activated in systemically hypertensive cats receiving amlodipine. Although this study did not parse out the individual contributions of SHT, chronic kidney disease, and amlodipine, the findings suggest that the use of concurrent RAAS-suppressant therapy, specifically aldosterone antagonism, in amlodipine-treated SHT cats with chronic kidney disease might be indicated. [ABSTRACT FROM AUTHOR]

Patients with arterial hypertension have an increased risk of developing tumors, particularly renal cell carcinoma. Arterial hypertension is linked to DNA damage via the generation of oxidative stress, in which an upregulated renin–angiotensin–aldosterone system plays a crucial role. The current study investigated surrogates of oxidative stress and DNA damage in a group of hypertensive patients (HypAll, n = 64) and subgroups of well (HypWell, n = 36) and poorly (HypPoor, n = 28) controlled hypertensive patients compared to healthy controls (n = 8). In addition, a longitudinal analysis was performed with some of the hypertensive patients. Markers for oxidative stress in plasma (SHp, D-ROM, and 3-nitrotyrosine) and urine (8-oxodG, 15-F2t-isoprostane, and malondialdehyde) and markers for DNA damage in lymphocytes (γ-H2AX and micronuclei) were measured. In HypAll, all markers of oxidative stress except malondialdehyde were increased compared to the controls. After adjustment for age, this association was maintained for the protein stress markers SHp and 3-nitrotyrosine. With regard to the markers for DNA damage, there was no difference between HypAll and the controls. Further, no significant differences became apparent in the levels of both oxidative stress and DNA damage between HypWell and HypPoor. Finally, a positive correlation between the development of blood pressure and oxidative stress was observed in the longitudinal study based on the changes in D-ROM and systolic blood pressure. In conclusion, we found increased oxidative stress in extensively treated hypertensive patients correlating with the level of blood-pressure control but no association with DNA damage. [ABSTRACT FROM AUTHOR]

Resistant hypertension (RH) is defined as the failure to achieve blood pressure control despite using triple combination therapy with a renin-angiotensin system inhibitor (RAS-i), a calcium antagonist, and a diuretic. The endothelin (ET) system is implicated in the regulation of vascular tone, primarily through vasoconstriction, intervenes in cardiac contractility with inotropic effects, and contributes to water and sodium renal reabsorption. ET inhibitors, currently approved for the treatment of pulmonary hypertension, seem to be also useful for essential hypertension and RH as well. Studies into the development of new dual ET inhibitors, which inhibit both type A and B ET (ETA and ETB) receptors, present initial results of managing RH. Aprocitentan (ACT-132577) is a novel, orally active and well tolerated dual ET receptor antagonist, which has been examined in several experimental studies and clinical trials with promising results for RH control. The recent publication of the large PRECISION study in The Lancet journal provides further reassurance regarding the efficacy and safety of aprocitentan for RH, with the aim of overcoming unmet needs in the management of this difficult group of patients. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system (RAS) inhibitors and calcium channel blockers (CCB) are often used together in chronic kidney disease (CKD). The PubMed, EMBASE, and Cochrane Library databases were searched to identify randomized controlled trials (RCTs) in order to explore better subtypes of CCB for the treatment of CKD. This meta-analysis of 12 RCTs with 967 CKD patients who were treated with RAS inhibitors demonstrated that, when compared with L-type CCB, N-/T-type CCB was superior in reducing urine albumin/protein excretion (SMD, −0.41; 95% CI, −0.64 to −0.18; p < 0.001) and aldosterone, without influencing serum creatinine (WMD, −3.64; 95% CI, −11.63 to 4.35; p = 0.37), glomerular filtration rate (SMD, 0.06; 95% CI, −0.13 to 0.25; p = 0.53), and adverse effects (RR, 0.95; 95% CI, 0.35 to 2.58; p = 0.93). In addition, N-/T-type CCB did not decrease the systolic blood pressure (BP) (WMD, 0.17; 95% CI, −1.05 to 1.39; p = 0.79) or diastolic BP (WMD, 0.64; 95% CI, −0.55 to 1.83; p = 0.29) when compared with L-type CCB. In CKD patients treated with RAS inhibitors, N-/T-type CCB is more effective than L-type CCB in reducing urine albumin/protein excretion without increased serum creatinine, decreased glomerular filtration rate, and increased adverse effects. The additional benefit is independent of BP and may be associated with decreased aldosterone (PROSPERO, CRD42020197560). [ABSTRACT FROM AUTHOR]

The prognosis of hypertension leads to organ damage by causing nephropathy, stroke, retinopathy, and cardiomegaly. Retinopathy and blood pressure have been extensively discussed in relation to catecholamines of the autonomic nervous system (ANS) and angiotensin II of the renin–angiotensin aldosterone system (RAAS) but very little research has been conducted on the role of the ECS in the regulation of retinopathy and blood pressure. The endocannabinoid system (ECS) is a unique system in the body that can be considered as a master regulator of body functions. It encompasses the endogenous production of its cannabinoids, its degrading enzymes, and functional receptors which innervate and perform various functions in different organs of the body. Hypertensive retinopathy pathologies arise normally due to oxidative stress, ischemia, endothelium dysfunction, inflammation, and an activated renin–angiotensin system (RAS) and catecholamine which are vasoconstrictors in their biological nature. The question arises of which system or agent counterbalances the vasoconstrictors effect of noradrenaline and angiotensin II (Ang II) in normal individuals? In this review article, we discuss the role of the ECS and its contribution to the pathogenesis of hypertensive retinopathy. This review article will also examine the involvement of the RAS and the ANS in the pathogenesis of hypertensive retinopathy and the crosstalk between these three systems in hypertensive retinopathy. This review will also explain that the ECS, which is a vasodilator in its action, either independently counteracts the effect produced with the vasoconstriction of the ANS and Ang II or blocks some of the common pathways shared by the ECS, ANS, and Ang II in the regulation of eye functions and blood pressure. This article concludes that persistent control of blood pressure and normal functions of the eye are maintained either by decreasing systemic catecholamine, ang II, or by upregulation of the ECS which results in the regression of retinopathy induced by hypertension. [ABSTRACT FROM AUTHOR]

Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension. [ABSTRACT FROM AUTHOR]

Hypertension leads to oxidative stress, inflammation, and fibrosis. The suppression of these indicators may be one treatment approach. Parboiled germinated brown rice (PGBR), obtained by steaming germinated Jasmine rice, reduces oxidative stress and inflammation in vivo. PGBR contains more bioactive compounds than brown rice (BR) and white rice (WR). Anti-hypertensive benefits of PGBR have been predicted, but research is lacking. The anti-hypertensive effects of PGBR were investigated in the downstream gene network of hypertension pathogenesis, including the renin–angiotensin system, fibrosis, oxidative stress production, and antioxidant enzymes in N-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. To strengthen our findings, the cardiac structure was also studied. PGBR-exposed rats showed significant reductions in systolic blood pressure (SBP) compared to the hypertensive group. WR did not reduce SBP because of the loss of bioactive compounds during intensive milling. PGBR also reduced the expression of the angiotensin type 1 receptor (AT1R), transforming growth factor-β (TGF-β), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), which contribute to the renin–angiotensin system, fibrosis, and oxidative stress production, respectively. Losartan (Los, an anti-hypertensive drug)-treated rats also exhibited similar gene expression, implying that PGBR may reduce hypertension using the same downstream target as Los. Our data also indicated that PGBR reduced cardiac lesions, such as the cardiomyopathy induced by L-NAME. This is the first report on the anti-hypertensive effects of PGBR in vivo by the suppression of the renin response, fibrosis, and improved cardiac structure. [ABSTRACT FROM AUTHOR]

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin–angiotensin–aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NPs) induce vasodilation, natriuresis, and diuresis, counteract the renin–angiotensin–aldosterone system and autonomic nervous system, and are key regulators of cardiovascular volume and pressure homeostasis. Baroreflex afferent pathway is an important reflex loop in the neuroregulation of blood pressure (BP), including nodose ganglion (NG) and nucleus tractus solitarius (NTS). Dysfunction of baroreflex would lead to various hypertensions. Here, we carried out functional experiments to explore the effects of NPs on baroreflex afferent function. Under physiological and hypertensive condition (high-fructose drinking-induced hypertension, HFD), BP was reduced by NPs through NG microinjection and baroreflex sensitivity (BRS) was enhanced via acute intravenous NPs injection. These anti-hypertensive effects were more obvious in female rats with the higher expression of NPs and its receptor A/B (NPRA/NPRB) and lower expression of its receptor C (NPRC). However, these effects were not as obvious as those in HFD rats compared with the same gender control group, which is likely to be explained by the abnormal expression of NPs and NPRs in the hypertensive condition. Our data provide additional evidence showing that NPs play a crucial role in neurocontrol of BP regulation via baroreflex afferent function and may be potential targets for clinical management of metabolic-related hypertension. [ABSTRACT FROM AUTHOR]

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is the primary pathway for regulating blood pressure in the body, and angiotensin-converting enzymes (ACEs) play a crucial role in it. Hirudo nipponia is an invertebrate that contains a variety of active peptides; however, there are no studies on the ACE inhibitory activity of hirudo. In the present study, our aim was to identify the active peptides in hirudo based on active peptide database analysis, unexpectedly filling the gap in hirudo ACE inhibitory activity research. Prep-HPLC was used to separate the part below 3 kD from hirudo. The peptide composition of the isolates was obtained based on Orbitrap LC-MS. The activity of each group of peptides was predicted by the database and the activity was determined by bioassay. Peptides with validation activity were screened through the database. In total, 337 peptides and 18 peptides matching the NCBI leech protein database were identified. All four fractions showed ACE inhibitory activity, and the IC50 was 0.8266, 0.2708, 0.4432, and 0.1764 mg/mL, respectively. Six screened peptides showed good affinity for ACE. This work reveals for the first time that low-molecular-weight peptides from H. nipponia have ACE inhibitory activity, which can provide a new explanation for leech treatment of hypertension. [ABSTRACT FROM AUTHOR]

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K+ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K+ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K+-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K+ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables. [ABSTRACT FROM AUTHOR]

This study investigated the vasoactive effects of des-aspartate-angiotensin-I (DAA-I) in male Wistar rats on whole body vascular bed, isolated perfused kidneys, and aortic rings. Dose–response curves to DAA-I were compared with those to angiotensin II (Ang II). The Ang II-type-1 (AT1) receptor blocker, losartan, was used to evaluate the role of AT1 receptors in the responses to DAA-I. Studies were also conducted of the responsiveness in aortic rings after endothelium removal, nitric oxide synthase inhibition, or AT2 receptor blockade. DAA-I induced a dose-related systemic pressor response that was shifted to the right compared with Ang II. Losartan markedly attenuated the responsiveness to DAA-I. DAA-I showed a similar pattern in renal vasculature and aortic rings. In aortic rings, removal of endothelium and nitric oxide inhibition increased the sensitivity and maximal response to DAA-I and Ang II. AT2 receptor blockade did not significantly affect the responsiveness to DAA-I. According to these findings, DAA-I increases the systemic blood pressure and vascular tone in conductance and resistance vessels via AT1 receptor activation. This vasoconstrictor effect of DAA-I participates in the homeostatic control of arterial pressure, which can also contribute to the pathogenesis of hypertension. DAA-I may therefore be a potential therapeutic target in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Dietary β-conglycinin has been shown to increase plasma adiponectin concentration and decrease visceral adipose tissue weight in rats. Since adiponectin is one of the factors regulating blood pressure, as well as modulating lipid metabolism, we examined whether dietary β-conglycinin affects blood pressure in spontaneously hypertensive rats. The experimental diets were prepared according to the AIN-93G formula containing 20% protein, either casein (Control) or casein replaced with soy protein isolate (SOY) or β-conglycinin (β-CON) at the proportion of 50%. Male rats (SHR/Izm, 6 wk-old) were fed the diets for 7 weeks. The SOY compared with the Control significantly suppressed the blood pressure both at week 4 (p = 0.011, Control vs. SOY) and thereafter, and β-CON had even higher suppression (p = 0.0002, Control vs. β-CON). SOY and β-CON increased plasma adiponectin concentration followed by an increase in plasma nitric oxide and possibly a decreasing trend of gene expressions of angiotensinogen in the liver and renin in the kidney. The results indicated suppression by β-conglycinin of increasing blood pressure through an enhancement of plasma adiponectin, probably in combination with a regulation of the renin–angiotensin system in spontaneously hypertensive rats. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of "checks and balances". It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the "crossroad" in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the "deleterious" Ang A as well as from the "protective" angiotensin 1-7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Hypertension remains the leading cause of disease burden worldwide. Hypertension can originate in the early stages of life. A growing body of evidence suggests that oxidative stress, which is characterized as a reactive oxygen species (ROS)/nitric oxide (NO) disequilibrium, has a pivotal role in the hypertension of developmental origins. Results from animal studies support the idea that early-life oxidative stress causes developmental programming in prime blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, leading to hypertension in adult offspring. Conversely, perinatal use of antioxidants can counteract oxidative stress and therefore lower BP. This review discusses the interaction between oxidative stress and developmental programming in hypertension. It will also discuss evidence from animal models, how oxidative stress connects with other core mechanisms, and the potential of antioxidant therapy as a novel preventive strategy to prevent the hypertension of developmental origins. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders. [ABSTRACT FROM AUTHOR]

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their own mechanism. Recently, firibastat, a new first-in-class antihypertensive drug has been developed. Firibastat is a prodrug that when crossing the blood-brain barrier, is cleaved into two active EC33 molecules. EC33 is the active molecule that inhibits the enzyme aminopeptidase A. Aminopeptidase A converts angiotensin II to angiotensin III. Angiotensin III usually has three central mechanisms that increase blood pressure, so by inhibiting this enzyme activity, a decrease in blood pressure is seen. Firibastat is an antihypertensive drug that affects the brain renin angiotensin system by inhibiting aminopeptidase A. Clinical trials with firibastat have been performed in animals and humans. No severe adverse effects related to firibastat treatment have been reported. Results from studies show that firibastat is generally well tolerated and safe to use in hypertensive patients. The aim of this review is to investigate the current knowledge about firibastat in the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, -12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients. [ABSTRACT FROM AUTHOR]

A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin–angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer's disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin–angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events. [ABSTRACT FROM AUTHOR]

Arterial hypertension (AH) is a major risk factor for the development of cardiovascular diseases. It is estimated that the disease affects between 10% and 20% of the adult population and is responsible for 5.8% of all deaths worldwide. Several pathophysiologic factors are crucial in AH, including inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress and inflammation. The heart, kidney, brain, retina and arterial blood vessels are prime targets of hypertensive damage. Uncontrolled and untreated AH accelerates the damage to these organs and could cause their failure. Damage to these organs could also manifest as coronary heart disease, cognitive impairment, retinopathy or optic neuropathy. For better understanding, it is important to analyze molecular factors which take part in pathogenesis of AH and hypertension-related target organ damage. In our paper, we would like to focus on molecular interactions of AH in the heart, blood vessels, brain and kidneys. We focus on matrix metalloproteinases, the role of immune system, the renin-angiotensin-aldosterone system and oxidative stress in hypertensive induced organ damage. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II–AT1R axis. [ABSTRACT FROM AUTHOR]

Obesity is a chronic state of energy imbalance that represents a major public health problem and greatly increases the risk for developing hypertension, hyperglycemia, and a multitude of related pathologies that encompass the metabolic syndrome. The underlying mechanisms and optimal treatment strategies for obesity, however, are still not fully understood. The control of energy balance involves the actions of circulating hormones on a widely distributed network of brain regions involved in the regulation of food intake and energy expenditure, including the arcuate nucleus of the hypothalamus. While obesity is known to disrupt neurocircuits controlling energy balance, including those in the hypothalamic arcuate nucleus, the pharmacological targeting of these central mechanisms often produces adverse cardiovascular and other off-target effects. This highlights the critical need to identify new anti-obesity drugs that can activate central neurocircuits to induce weight loss without negatively impacting blood pressure control. The renin–angiotensin system may provide this ideal target, as recent studies show this hormonal system can engage neurocircuits originating in the arcuate nucleus to improve energy balance without elevating blood pressure in animal models. This review will summarize the current knowledge of renin–angiotensin system actions within the arcuate nucleus for control of energy balance, with a focus on emerging roles for angiotensin II, prorenin, and angiotensin-(1–7) pathways. [ABSTRACT FROM AUTHOR]

Hypertension, causing cardiovascular disease, stroke, and heart failure, has been a rising health issue worldwide. Black soybeans and adzuki beans have been widely consumed throughout history due to various bioactive components. We evaluated the antihypertensive effects of black soybean and adzuki bean ethanol extracts on blood pressure, renin-angiotensin system (RAS), and aortic lesion in spontaneously hypertensive rats. A group of WKY (normal) and six groups of spontaneously hypertensive rats were administered with saline (SHR), 50 mg/kg of captopril (CAP), 250 and 500 mg/kg of black soybean extracts (BE250 and BE500), 250 and 500 mg/kg of adzuki bean extracts (AE250 and AE500) for eight weeks. BE250, BE500, AE250, and AE500 significantly (p < 0.05) reduced relative liver weight, AST, ALT, triglyceride, total cholesterol, systolic blood pressure, and angiotensin-converting-enzyme level compared to SHR. The angiotensin II level in AE500 and renin mRNA expression in BE500 and AE500 were significantly (p < 0.05) decreased compared to SHR. The lumen diameter was significantly (p < 0.05) reduced in only CAP. Furthermore, systolic and diastolic blood pressure and angiotensin II level in AE500 were lower than those of BE500. These results suggest that AE exhibit more antihypertensive potential than BE in spontaneously hypertensive rats. [ABSTRACT FROM AUTHOR]

High saturated fat diets have been associated with the development of obesity and hypertension, along with other pathologies related to the metabolic syndrome. In contrast, the Mediterranean diet, characterized by its high content of monounsaturated fatty acids, has been proposed as a dietary factor capable of positively regulating cardiovascular function. These effects have been linked to changes in the local renal renin angiotensin system (RAS) and the activity of the sympathetic nervous system. The main goal of this study was to analyze the role of two dietary fat sources on aminopeptidases activities involved in local kidney RAS. Male Wistar rats (six months old) were fed during 24 weeks with three different diets: the standard diet (S), the standard diet supplemented with virgin olive oil (20%) (VOO), or the standard diet enriched with butter (20%) plus cholesterol (0.1%) (Bch). Kidney samples were separated in medulla and cortex for aminopeptidase activities (AP) assay. Urine samples were collected for routine analysis by chemical tests. Aminopeptidase activities were determined by fluorometric methods in soluble (sol) and membrane-bound (mb) fractions of renal tissue, using arylamide derivatives as substrates. After the experimental period, the systolic blood pressure (SBP) values were similar in standard and VOO animals, and significantly lower than in the Bch group. At the same time, a significant increase in GluAP and IRAP activities were found in renal medulla of Bch animals. However, in VOO group the increase of GluAP activity in renal medulla was lower, while AspAP activity decreased in the renal cortex. Furthermore, the VOO diet also affected other aminopeptidase activities, such as TyrAP and pGluAP, related to the regulation of the sympathetic nervous system and the metabolic rate. These results support the beneficial effect of VOO in the regulation of SBP through changes in local AP activities of the kidney. [ABSTRACT FROM AUTHOR]

Resistant hypertension (R-HTN) implies a higher mortality and morbidity compared to non-R-HTN due to increased cardiovascular risk and associated adverse outcomes—greater risk of developing chronic kidney disease, heart failure, stroke and myocardial infarction. R-HTN is considered when failing to lower blood pressure below 140/90 mmHg despite adequate lifestyle measures and optimal treatment with at least three medications, including a diuretic, and usually a blocker of the renin-angiotensin system and a calcium channel blocker, at maximally tolerated doses. Hereby, we discuss the diagnostic and therapeutic approach to a better management of R-HTN. Excluding pseudoresistance, secondary hypertension, white-coat hypertension and medication non-adherence is an important step when diagnosing R-HTN. Most recently different phenotypes associated to R-HTN have been described, specifically refractory and controlled R-HTN and masked uncontrolled hypertension. Optimizing the three-drug regimen, including the diuretic treatment, adding a mineralocorticoid receptor antagonist as the fourth drug, a β-blocker as the fifth drug and an α1-blocker or a peripheral vasodilator as a final option when failing to achieve target blood pressure values are current recommendations regarding the correct management of R-HTN. [ABSTRACT FROM AUTHOR]

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures. [ABSTRACT FROM AUTHOR]

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin–angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP. [ABSTRACT FROM AUTHOR]

Hypertension can come from early life. N-acetylcysteine (NAC), a hydrogen sulfide (H2S) precursor as well as an antioxidant, has antihypertensive effect. We investigated whether maternal NAC therapy can protect spontaneously hypertensive rats (SHR) male offspring against hypertension. The pregnant rats were assigned to four groups: SHRs without treatment; Wistar Kyoto (WKY) without treatment; SHR+NAC, SHRs received 1% NAC in drinking water throughout pregnancy and lactation; and, WKY+NAC, WKY rats received 1% NAC in drinking water during pregnancy and lactation. Male offspring (n = 8/group) were killed at 12 weeks of age. Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR offspring at 12 weeks of age. Renal cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group. The protective effect of maternal NAC therapy against hypertension in SHR offspring is related to increased phylum Actinobacteria and genera Bifidobacterium and Allobaculum, but decreased phylum Verrucomicrobia, genera Turicibacter, and Akkermansia. Several microbes were identified as microbial markers, including genera Bifidobacterium, Allobaculum, Holdemania, and Turicibacter. Our results indicated that antioxidant therapy by NAC in pregnant SHRs can prevent the developmental programming of hypertension in male adult offspring. Our findings highlight the interrelationships among H2S-generating pathway in the kidneys and gut, gut microbiota, and hypertension. The implications of maternal NAC therapy elicited long-term protective effects on hypertension in later life that still await further clinical translation. [ABSTRACT FROM AUTHOR]

In Chronic Kidney Disease (CKD) patients, elevated blood pressure (BP) is a frequent finding and is traditionally considered a direct consequence of their sodium sensitivity. Indeed, sodium and fluid retention, causing hypervolemia, leads to the development of hypertension in CKD. On the other hand, in non-dialysis CKD patients, salt restriction reduces BP levels and enhances anti-proteinuric effect of renin–angiotensin–aldosterone system inhibitors in non-dialysis CKD patients. However, studies on the long-term effect of low salt diet (LSD) on cardio-renal prognosis showed controversial findings. The negative results might be the consequence of measurement bias (spot urine and/or single measurement), reverse epidemiology, as well as poor adherence to diet. In end-stage kidney disease (ESKD), dialysis remains the only effective means to remove dietary sodium intake. The mismatch between intake and removal of sodium leads to fluid overload, hypertension and left ventricular hypertrophy, therefore worsening the prognosis of ESKD patients. This imposes the implementation of a LSD in these patients, irrespective of the lack of trials proving the efficacy of this measure in these patients. LSD is, therefore, a rational and basic tool to correct fluid overload and hypertension in all CKD stages. The implementation of LSD should be personalized, similarly to diuretic treatment, keeping into account the volume status and true burden of hypertension evaluated by ambulatory BP monitoring. [ABSTRACT FROM AUTHOR]

Primary hypertension describes abnormally-high systolic/diastolic blood pressure in a resting condition caused by various genetic or environmental risk factors. Remarkably, severe complications, such as ischemic cardiovascular disease, stroke, and chronic renal disease have led to primary hypertension becoming a huge burden for almost one-third of the total population. Medication is the major regimen for treating primary hypertension; however, recent medications may have adverse effects that attenuate energy levels. Hence, the search for new hypotensive agents from folk or traditional medicine may be fruitful in the discovery and development of new drugs. This review assembles recent findings for natural antihypertensive agents, extracts, or decoctions published in PubMed, and provides insights into the search for new hypotensive compounds based on blood-pressure regulating mechanisms, including the renin-angiotensin-aldosterone system and the sympathetic/adrenergic receptor/calcium channel system. [ABSTRACT FROM AUTHOR]

Hypertension is one of the most frequent cardiovascular risk factors. The population of hypertensive patients includes some phenotypes whose blood pressure levels are particularly difficult to control, thus putting them at greater cardiovascular risk. This is especially true of so-called resistant hypertension (RH) and refractory hypertension (RfH). Recent findings suggest that the former may be due to an alteration in the renin–angiotensin–aldosterone axis, while the latter seems to be more closely related to sympathetic hyper-activation. Both these pathophysiological mechanisms are also activated in patients with obstructive sleep apnoea (OSA). It is not surprising, therefore, that the prevalence of OSA in RH and RfH patients is very high (as reflected in several studies) and that treatment with continuous positive airway pressure (CPAP) manages to reduce blood pressure levels in a clinically significant way in both these groups of hypertensive patients. It is therefore necessary to incorporate into the multidimensional treatment of patients with RH and RfH (changes in lifestyle, control of obesity and drug treatment) a study of the possible existence of OSA, as this is a potentially treatable disease. There are many questions that remain to be answered, especially regarding the ideal combination of treatment in patients with RH/RfH and OSA (drugs, renal denervation, CPAP treatment) and patients' varying response to CPAP treatment. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) plays an important role in regulating body fluids and blood pressure. However, inappropriate activation of the RAS contributes to the pathogenesis of cardiovascular and renal diseases. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used as anti-diabetic agents. SGLT2 inhibitors induce glycosuria and improve hyperglycemia by inhibiting urinary reabsorption of glucose. However, in the early stages of treatment, these inhibitors frequently cause polyuria and natriuresis, which potentially activate the RAS. Nevertheless, the effects of SGLT2 inhibitors on RAS activity are not straightforward. Available data indicate that treatment with SGLT2 inhibitors transiently activates the systemic RAS in type 2 diabetic patients, but not the intrarenal RAS. In this review article, we summarize current evidence of the diuretic effects of SGLT2 inhibitors and their influence on RAS activity. [ABSTRACT FROM AUTHOR]