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Journal: Hypertension research : official journal of the Japanese Society of Hypertension

28

In the presence of salt, aldosterone causes hypertension and organ damage via the mineralocorticoid receptor (MR) through various mechanisms. MR antagonists are considered to be potassium-sparing diuretics that exert their effect by blocking MR in the kidney, and they are not the first choice for treating hypertension. However, the importance and usefulness of inhibiting aldosterone in the management of hypertension have recently been revealed in both the basic and clinical fields. In Japan, both the selective MR antagonist eplerenone and the non-selective MR antagonist spironolactone are indicated for the treatment of hypertension. Although these drugs are generally used in the same manner, in some cases they require differentiation. This differentiation is divided into two types due to the differences in their features and differences in their contraindications in Japan. Based on a number of studies on MR antagonists that have been recently published, the diseases and clinical conditions targeted by MR antagonists appear to be likely to increase in the future. In Japan, we consider it necessary to carefully differentiate spironolactone from eplerenone in regard to their intended uses.Hypertension Research advance online publication, 22 November 2012; doi:10.1038/hr.2012.182.

Concepts: Hypertension, Aldosterone, Receptor antagonist, Spironolactone, Potassium-sparing diuretic, Diuretic, Aldosterone antagonist, Eplerenone

27

Enhanced external counterpulsation (EECP) is a FDA-approved treatment for patients with coronary artery disease and unstable angina. Although beneficial effects of EECP have been linked to central/cardiac adaptations, recent findings have shown peripheral/vascular effects. Here, we sought to determine EECP-induced blood flow patterns and their association with vascular function. The present study was designed to investigate endothelium-mediated arterial vasodilation changes after one 45-min session of either EECP or Sham EECP in 18 randomly assigned apparently healthy, young men (25±4 years). Brachial (b) and femoral (f) flow-mediated dilation (FMD) were assessed before and within 10 min after completing EECP or Sham. After 20 min of EECP, peak blood flow velocity (V) and brachial and femoral artery diameters (D) were recorded live for 2 min. In addition, a blood sample was drawn from the earlobe to determine hematocrit and then to calculate blood viscosity (μ) and density (ρ), Reynolds number (Re=V*D*ρ/μ), and endothelial shear stress (ESS=2μ*V/D). EECP increased retrograde shear stress and retrograde-turbulent blood flow in the femoral artery and antegrade-laminar shear stress in the brachial artery. fFMD was increased after EECP compared with Sham and baseline (fFMD=13.1±3.7 vs. 7.9±4.6% and 7.8±4.5%, respectively, P<0.05) and bFMD was increased after EECP compared with baseline (bFMD=10.6±4.8 vs. 7.0±3.5%, P<0.05), despite different blood flow patterns. These results provide novel evidence that a single session of EECP-induced blood flow patterns improve endothelial function in peripheral muscular conduit arteries.

Concepts: Blood, Atherosclerosis, Angina pectoris, Coronary artery disease, Heart, Artery, Coronary circulation, Viscosity

27

The effects of aldosterone and mineralocorticoid receptor (MR) blockers on presympathetic neurons in the rostral ventrolateral medulla (RVLM) are well studied. To directly investigate whether aldosterone, eplerenone (an MR blocker), FAD286 (an aldosterone synthase inhibitor) and benzamil (an epithelial sodium channel (ENaC) blocker) affect RVLM neurons, we examined changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole-cell patch-clamp technique during superfusion with these drugs to brainstem-spinal cord preparations. Aldosterone superfusion (0.1 μmol/l) depolarized the RVLM neurons. In contrast, eplerenone superfusion (1 μmol/l) hyperpolarized them. To evaluate the existence of aldosterone, FAD286 superfusion (10 μmol/l) was performed, and the RVLM neurons became hyperpolarized during FAD superfusion. These data suggest that MRs exist and that aldosterone is synthesized in the brainstem. Benzamil superfusion (1 μmol/l) hyperpolarized the RVLM neurons. To clarify whether aldosterone, eplerenone, FAD286 and benzamil acted directly on the RVLM neurons, a low-Ca(2+), high-Mg(2+) solution was used to block the synaptic input to the RVLM neurons, and the above-mentioned drugs were added during the low-Ca(2+) superfusion. During the aldosterone superfusion, the RVLM neurons became depolarized, and they became hyperpolarized during eplerenone, FAD286 or benzamil superfusion. Importantly, when aldosterone was superfused after the benzamil solution, the MPs of the RVLM neurons did not depolarize. These results suggest that MRs are present in the RVLM neurons and that aldosterone is synthesized in the RVLM. The RVLM neurons themselves possess ENaCs, and ENaCs are the underlying mechanism by which aldosterone activates RVLM neurons.Hypertension Research advance online publication, 31 January 2013; doi:10.1038/hr.2012.224.

Concepts: Action potential, Ion channel, Electrophysiology, Aldosterone, Sodium, Mineralocorticoid, Mineralocorticoid receptor, Epithelial sodium channel

23

Twenty-four-h blood pressure variability (BPV) predicts cardiovascular complications in hypertension, but its association with pulse wave indices (central arterial pressure, pulse wave velocity (PWV) and augmentation index (AIx)) is poorly understood. In the present study, we assessed the degree of the effect of 24-h BPV on 24-h pulse wave indices. Brachial blood pressure was measured non-invasively over the 24 h with an electronic, oscillometric, automated device (BPLab) in 661 uncomplicated treated or untreated hypertensive patients. Digitalized oscillometric waveforms were analyzed with a validated algorithm to obtain pulse wave indices. Twenty-four-h BPV was calculated as the unweighted (SDu) or weighted s.d. (SDw) of the mean blood pressure or as the average real variability (ARV). Twenty-four-h systolic BPV showed a direct and significant relationship with the central arterial systolic pressure (r=0.28 SDu, r=0.40 SDw, r=0.34 ARV), PWV (r=0.10 SDu, r=0.21 SDw, r=0.19 ARV) and AIx (r=0.17 SDu, r=0.27 SDw, r=0.23 ARV). After adjustment for age, sex, body mass index, antihypertensive treatment and 24-h systolic blood pressure, the relationship lost some power but was still significant for all measures, except for the AIx. Pulse wave indices were higher in patients with high BPV than in those with low BPV: after adjustment, these differences were abolished for the AIx. The diastolic BPV showed a weak association with the pulse wave indices. In conclusion, in hypertensive patients, 24-h systolic BPV is moderately and independently associated with 24-h central arterial pressure and stiffness.Hypertension Research advance online publication, 24 November 2016; doi:10.1038/hr.2016.156.

Concepts: Blood, Myocardial infarction, Hypertension, Blood pressure, Artery, Orthostatic hypotension, Mean arterial pressure, Brachial artery

5

We evaluated the associations of the ages at menarche and menopause with blood pressure (BP) and hypertension using the baseline data of 7893 women from the China Health and Retirement Longitudinal Study, a nationally representative survey among Chinese adults aged ≥45 years. Multivariate linear and logistic regression analyses were performed to evaluate the associations of the ages at menarche and men`opause with BP and hypertension, respectively. Nonlinear associations were evaluated using spline analyses. After controlling for age, education, marital status, living areas, smoking, drinking, and medication use if necessary, an early onset of menarche by 1 year was associated with a 6% (95% confidence interval [CI]: 3-9%) higher odds of hypertension and 0.82 mm Hg (P < 0.001) and 0.41 mm Hg (P < 0.001) higher systolic and diastolic BP, respectively. When further controlling for the body mass index (BMI), blood glucose, and lipids, the associations were still significant. Spline analyses did not support U-shaped relationships between menarche age and hypertension risk (P = 0.35), systolic BP (P = 0.60), or diastolic BP (P = 0.70). When stratified by location of residence, menarche age was only associated with BP and hypertension among women living in rural areas. The age of menopause was positively associated with hypertension (odds ratio [OR] = 1.02 per year delay of menopause, 95% CI: 1.01-1.03). However, when further controlling for BMI, such an association no longer existed (OR = 1.01, P = 0.32). These findings indicated that the associations of menarche age with BP and hypertension may be modified by factors related to the area of residence in China, and the association between menopause age and hypertension was driven by BMI.

3

The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.

3

The objective of our study was to examine the effects of isometric resistance training (IRT) on resting blood pressure in adults. We conducted a systematic review and meta-analysis of randomized-controlled trials lasting ⩾2 weeks, investigating the effects of isometric exercise on blood pressure in healthy adults (aged ⩾18 years), published in a peer-reviewed journal between 1 January 1966 to 31 January 2015. We included 11 randomized trials, totaling 302 participants. The following reductions were observed after isometric exercise training; systolic blood pressure (SBP) mean difference (MD) -5.20 mm Hg (95% confidence interval (CI) -6.08 to -4.33, P<0.00001); diastolic blood pressure (DBP) MD -3.91 mm Hg (95% CI -5.68 to -2.14, P<0.0001); and mean arterial blood pressure (MAP) MD -3.33 mm Hg (95% CI -4.01 to -2.66, P<0.00001). Sub-analyses showed males tended to reduce MAP MD -4.13 mm Hg (95% CI -5.08 to -3.18) more than females. Subjects aged ⩾45 years demonstrated larger reductions in MAP MD -5.51 mm Hg (95% CI -6.95 to -4.06) than those <45 years. Subjects undertaking ⩾8 weeks of IRT demonstrated a larger reduction in SBP MD -7.26 mm Hg (95% CI -8.47 to -6.04) and MAP MD -4.22 mm Hg (95% CI -5.08 to -3.37) than those undertaking<8 weeks. Hypertensive participants in IRT demonstrated a larger reduction in MAP MD -5.91 mm Hg (95% CI -7.94 to -3.87) than normotensive participants MD -3.01 mm Hg (95% CI -3.73 to -2.29). Our study indicated that IRT lowers SBP, DBP and MAP. The magnitude of effect may be larger in hypertensive males aged ⩾45 years, using unilateral arm IRT for >8 weeks.Hypertension Research advance online publication, 15 October 2015; doi:10.1038/hr.2015.111.

Concepts: Myocardial infarction, Hypertension, Blood pressure, Artery, Orthostatic hypotension, Prehypertension, Systole

2

Metformin is an antidiabetic drug. However, the pleiotropic beneficial effects of metformin in nondiabetic models still need to be defined. The objective of this study is to investigate the effect of metformin on angiotensin II (Ang II)-induced hypertension and cardiovascular diseases. Mice were infused with Ang II (400 ng/kg per min) with or without metformin for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure associated with enhanced vascular endoplasmic reticulum (ER) stress markers, which were blunted after metformin treatment. Moreover, hypertension-induced reduction in phosphorylated AMPK, endothelial nitric oxide synthase (eNOs) phosphorylation, and endothelium-dependent relaxation (EDR) in mesenteric resistance arteries (MRA) were rescued after metformin treatment. Infusion of ER stress inducer (tunicamycin, Tun) in control mice induced ER stress in MRA and reduced phosphorylation of AMPK, eNOS synthase phosphorylation, and EDR in MRA without affecting systolic blood pressure (SBP). All these factors were reversed subsequently with metformin treatment. ER stress inhibition by metformin improves vascular function in hypertension. Therefore, metformin could be a potential therapy for cardiovascular diseases in hypertension independent of its effects on diabetes.

2

The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.Hypertension Research advance online publication, 20 October 2016; doi:10.1038/hr.2016.124.

Concepts: Myocardial infarction, Atherosclerosis, Hypertension, Stroke, Blood pressure, Orthostatic hypotension, Prehypertension, Uric acid

1

It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27±0.19 vs. 0.44±0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78±0.27 vs. 0.79±0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00-0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98-1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD.Hypertension Research advance online publication, 7 January 2016; doi:10.1038/hr.2015.143.

Concepts: Regression analysis, Myocardial infarction, Atherosclerosis, Angina pectoris, Heart, Atheroma, Eicosapentaenoic acid, Docosahexaenoic acid