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Hypertension (HTN) is a primary risk factor for cardiovascular (CV) events, target organ damage (TOD), premature death and disability worldwide. The pathophysiology of HTN is complex and influenced by many factors including biological sex. Studies show that the prevalence of HTN is higher among adults aged 60 and over, highlighting the increase of HTN after menopause in women. Estrogen (E2) plays an important role in the development of systemic HTN and TOD, exerting several modulatory effects. The influence of E2 leads to alterations in mechanisms regulating the sympathetic nervous system, renin-angiotensin-aldosterone system, body mass, oxidative stress, endothelial function and salt sensitivity; all associated with a crucial inflammatory state and influenced by genetic factors, ultimately resulting in cardiac, vascular and renal damage in HTN. In the present article, we discuss the role of E2 in mechanisms accounting for the development of HTN and TOD in a sex-specific manner. The identification of targets with therapeutic potential would contribute to the development of more efficient treatments according to individual needs. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease are at increased risk of cardiovascular disease and this often manifests clinically like heart failure. Conversely, patients with heart failure frequently have reduced kidney function. The links between the kidneys and cardiovascular system are being elucidated, with blood pressure being a key risk factor. Patients with heart failure have benefitted from many trials which have now established a strong evidence based on which to base management. However, patients with advanced kidney disease have often been excluded from these trials. Nevertheless, there is little evidence that the benefits of such treatments are modified by the presence or absence of kidney disease, but more direct evidence among patients with advanced kidney disease is required. Neprilysin inhibition is the most recent treatment to be shown to improve outcomes among patients with heart failure. The UK HARP-III trial assessed whether neprilysin inhibition improved kidney function in the short- to medium-term and its effects on cardiovascular biomarkers. Although no effect (compared to irbesartan control) was found on kidney function, allocation to neprilysin inhibition (sacubitril/valsartan) did reduce cardiac biomarkers more than irbesartan, suggesting that this treatment might improve cardiovascular outcomes in this population. Larger clinical outcomes trials are needed to test this hypothesis. [ABSTRACT FROM AUTHOR]

Inhibition of the renin-angiotensin system in early postnatal life is a potential therapeutic approach to prevent long-term cardiovascular and kidney diseases in individuals born small. We determined the long-term effects of juvenile losartan treatment on cardiovascular and kidney function in control male rat offspring and those exposed to uteroplacental insufficiency and born small. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed in late gestation in Wistar Kyoto rats. At weaning, male offspring were randomly assigned to receive losartan in their drinking water or drinking water alone from 5 to 8 weeks of age, and followed to 26 weeks of age. Systolic blood pressure and kidney function were assessed throughout the study. Pressure myography was used to assess passive mechanical wall properties in mesenteric and femoral arteries from 26-week-old offspring. Losartan treatment for three weeks lowered systolic blood pressure in both Control and Restricted groups but this difference was not sustained after the cessation of treatment. Losartan, irrespective of birth weight, mildly increased renal tubulointerstitial fibrosis when assessed at 26 weeks of age. Mesenteric artery stiffness was increased by the early losartan treatment, and was associated with increased collagen and decreased elastin content. Losartan also exerted long-term increases in fat mass and decreases in skeletal muscle mass. In this study, untreated Restricted offspring did not develop hypertension, vascular dysfunction or kidney changes as anticipated. Regardless, we demonstrate that short-term losartan treatment in the juvenile period negatively affects postnatal growth, and kidney and vascular parameters in adulthood, irrespective of birth weight. The long-term effects of early-life losartan treatment warrant further consideration in settings where the potential benefits may outweigh the risks; i.e. when programmed adulthood diseases are apparent and in childhood cardiovascular and kidney diseases. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS) is a major component of cardiovascular and renal homeostasis, maintaining blood pressure and water and electrolyte balance in health and disease. Whilst knowledge regarding the RAS in adult organisms has substantially increased over the last three decades, physiological effects and levels of functioning of the system during the perinatal period are poorly understood. It has been shown, however, that the RAS is subject to remarkable developmental changes that involve all system components, including the main active biologic peptide, angiotensin II (Ang II) and the receptors through which these effects are mediated, type 1 receptors (AT1Rs) and type 2 receptors (AT2Rs). The pattern of developmental changes suggests a relevant physiological role for the RAS in the critical cardio-renal adaptations to life after birth. In adulthood, the majority of the physiological functions of Ang II are mediated by activation of AT1Rs, whilst the roles for AT2Rs are less clear. Although the integrity of the AT1R signalling pathway is a pre-requisite for normal renal development, the physiological effects mediated by A1TRs during ontogeny are not well characterized. Much less is known regarding the roles that AT2Rs may play in regulating cardio-renal homeostasis in the newborn, despite the fact that the RAS appears to be a major player in fetal programming of disease. This article reviews current knowledge regarding the temporal and spatial expression pattern of ATRs during ontogeny, the cardiovascular and renal effects mediated by the ATRs early in life, as well as the clinical relevance for ATRs in the newborn period. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the roles of both angiotensin II (ANG II) receptors - type 1 (AT1Rs) and type 2 (AT2Rs) - separately and together in influencing hemodynamic effects of endogenously produced nitric oxide (NO) during postnatal development. In conscious, chronically instrumented lambs aged ~1 week (8 ± 1 days, N = 8) and ~6 weeks (41 ± 2 days, N = 8), systolic, diastolic, and mean arterial pressure (SAP, DAP, MAP) and venous pressure (MVP), renal blood flow (RBF), and renal vascular resistance (RVR) were measured in response to the l-arginine analog, l-NAME after pretreatment with either the AT1R antagonist, ZD 7155, the AT2R antagonist, PD 123319, or both antagonists. The increase in SAP, DAP, and MAP by l-NAME was not altered by either ATR antagonist in either age group. The increase in RBF after l-NAME was, however, altered by both ATR antagonists in an age-dependent manner, which was mediated predominantly through AT2Rs in newborn lambs. These findings reveal that there is an age-dependent interaction between the renin-angiotensin (RAS) and the NO pathway in regulating renal but not systemic hemodynamics through both ATRs, whereas AT2Rs appear to be important in the renal hemodynamic effects of NO early in life. [ABSTRACT FROM AUTHOR]

Background: Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines. Methods: Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data. Results: We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = −10.42, 95% CI −13.03∼−7.82, P<0.00001; DBP: WMD = −6.60, 95% CI −7.22∼−5.97, P<0.00001) or amlodipine (SBP: WMD = −4.85, 95% CI −6.88∼−2.81, P<0.00001; DBP: WMD = −2.91, 95% CI −3.85∼−1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66∼0.92, P = 0.004; RR = 0.51, 0.27∼0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m2) hypertensive and non-obese (body mass index <30 kg/m2) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups. Conclusion: We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events. [ABSTRACT FROM AUTHOR]

Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4–8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4–8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular function is affected by many mechanisms, including the autonomic system, the kallikrein–kinin system (KKS), the renin–angiotensin system (RAS) and the endothelin system. The function of these systems seems to be fairly well preserved throughout the vertebrate scale, but evolution required several adaptations. Snakes are particularly interesting for studies related to the cardiovascular function because of their elongated shape, their wide variation in size and length, and because they had to adapt to extremely different habitats and gravitational influences. To keep the normal cardiovascular control the snakes developed anatomical and functional adaptations and interesting structural peculiarities are found in their autonomic, KKS, RAS and endothelin systems. Our laboratory has characterized some biochemical, pharmacological and physiological properties of these systems in South American snakes. This review compares the components and function of these systems in snakes and other vertebrates, and focuses on differences found in snakes, related with receptor or ligand structure and/or function in autonomic system, RAS and KKS, absence of components in KKS and the intriguing identity between a venom and a plasma component in the endothelin system. [Copyright &y& Elsevier]

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]

Angiotensin II (ANG II) is part of the renin-angiotensin system (RAS) in vertebrates and exert vasoconstriction in all species studied. The present study examines the vasopressor effect of ANG II in the ball python (Python regius), and examines whether ANG II exert its effect through direct angiotensin receptors or through an activation of α-adrenergic receptors. The studies were conducted in snakes with chronic arterial catheters that had recovered from anesthesia. In addition to demonstrating a clear and pronounced dose-dependent rise in arterial blood pressure upon repeated injections of boluses with ANG II (0.001–1 μg/kg), we demonstrate that the pressor response persisted following α-adrenergic blockade using the α-adrenergic antagonist phentolamine (2.5 mg/kg). Unfortunately, it proved impossible to block the ANG receptors using losartan (1, 3 or even 10 mg/kg). The pressor response to ANG II was associated with a significant rise in heart rate at the higher dosages, pointing to a resetting of the barostatic mechanism for heart rate regulation. The responses were similar in fasting and digesting pythons despite the expected rise in baseline values for blood pressure and heart rate of the digesting snakes. Image 1 • Angiotensin II exerts a pronounced vasopressor action in ball pythons (Python regius) with small effects on heart rate. • The effects of angiotensin II (ANG II) are not altered by blockade of the α-adrenergic receptors. • Angiotensin II (ANG II) elicited similar in responses in fasting and digesting snakes. • Losartan could not block the cardiovascular responses to ANG II in Python regius. [ABSTRACT FROM AUTHOR]

Introduction: Vascular endothelial growth factor inhibition (VEGFi) in cancer treatment is associated with hypertension. Imbalance between the renin-angiotensin-aldosterone system (RAAS) and VEGF may contribute to VEGFi associated hypertension. We hypothesized that RAAS blockade at the time of VEGFi attenuates increases in blood pressure. Methods: Using de-identified medical records from 1085 outpatients with cancer on VEGFi, we extracted demographic, oncologic, anti-hypertensive medication exposure and comorbidity data between 2003-2017. Baseline blood pressure was estimated as the average of all outpatient blood pressures collected during 12-6 weeks prior to VEGFi. Response blood pressure was estimated as the average blood pressure collected from 0-6 weeks after VEGFi. We used non-parametric methods and adjusted regression models to assess associations in BP change between patients taking or not taking ACEi/ARB. Results: Patients where 48% male, 88% Caucasian, and had mean age of 64+13 years. Patients using ACEi/ARB therapy were older with a lower GFR, lower prevalence of hypertension, and a higher prevalence of diabetes and hyperlipidemia compared with patients not using ACEi/ARB therapy (Table 1). We observed a 2.6 + 16mmHg reduction in systolic blood pressure among patients exposed to ACEi/ARB prior to VEGFi compared with 1 + 15mmHg reduction in patients not exposed to an ACEi/ARB. ACEi/ARB exposure was associated with a reduction in BP at 6 weeks even after adjusting for age, gender, BMI, GFR, hyperlipidemia, hypertension, and diabetes (-3.3mmHg [95% CI -5.5, -1.1]; p =0.005). Conclusions: Our results suggest a protective effect of pre-VEGFi exposure to ACEi/ARB on blood pressure response. Future studies are warranted to determine whether RAAS blockade should be initiated prophylactically in patients receiving VEGFi. [ABSTRACT FROM AUTHOR]