TLR4/MD-2 is a receptor for extracellular nucleophosmin 1.

Nucleophosmin 1 (NPM1) primarily localizes to the nucleus and is passively released into the extracellular milieu by necrotic or damaged cells, or is secreted by monocytes and macrophages. Extracellular NPM1 acts as a potent inflammatory stimulator by promoting cytokine production [e.g., tumor necrosis factor-α (TNF-α)], which suggests that NPM1 acts as a damage-associated molecular pattern. However, the receptor of NPM1 is unknown. Evidence indicates that DAMPs, which include high mobility group box 1 and histones, may bind Toll-like receptors (TLRs). In the present study, it was shown that NPM1 signaling was mediated via the TLR4 pathway, which suggests that TLR4 is an NPM1 receptor. TLR4 binds myeloid differentiation protein-2 (MD-2), which is essential for intracellular signaling. Furthermore, the TLR4 antagonist, LPS-Rhodobacter sphaeroides (an MD-2 antagonist) and TAK-242 (a TLR4 signaling inhibitor) significantly inhibited NPM1-induced TNF-α production by differentiated THP-1 cells as well as reducing ERK1/2 activation. Far-western blot analysis revealed that NPM1 directly bound MD-2. Thus, the results of the present study provide compelling evidence that TLR4 binds NPM1, and it is hypothesized that inhibiting NPM1 activity may serve as a novel strategy for treating TLR4-related diseases.

Relationship between casual serum triglyceride levels and the development of hypertension in Japanese.

OBJECTIVE: The purpose of the present study was to investigate the effects of serum triglyceride levels on the risk of new-onset hypertension in Japanese. METHODS: Five thousand nine hundred and thirty-three Japanese workers without hypertension at baseline, who participated in medical check-ups from 2006 to 2018, were followed retrospectively. The participants were divided into quartiles of casual serum triglyceride levels and were followed from the first to last visit of the study period. The outcome was development of hypertension. Risk estimates were computed using Cox's proportional hazards model. RESULTS: During the follow-up period (average: 6.7 years), 946 individuals developed hypertension. The crude incidence rates of hypertension (per 1000 person-years) increased with rising serum triglyceride levels: 10.1 for quartile 1 (<0.76 mmol/l), 19.6 for quartile 2 (0.76-1.17 mmol/l), 26.0 for quartile 3 (1.18-1.84 mmol/l), and 36.5 for quartile 4 (>1.84 mmol/l) (P < 0.0001 for trend). These associations remained significant even after adjustment for other risk factors: the multivariable-adjusted hazard ratio was 1.29 (1.01-1.66) for the second quartile, 1.27 (0.99-1.63) for the third quartile, and 1.39 (1.09-1.77) for the highest quartile compared with the lowest. There were comparable effects of serum triglyceride levels for incidence of hypertension between subgroups defined by sex, obesity, and diabetes (all P > 0.1 for interaction), whereas stronger associations were observed for participants under 40 years of age than for those aged 40 or above (P = 0.002 for interaction). CONCLUSION: Serum triglyceride levels were significantly associated with development of hypertension in a Japanese worksite population.

Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists.

White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.

C-reactive protein and incident hypertension in a worksite population of Japanese men.

Inflammation plays a key role in the pathogenesis of cardiovascular diseases via the development of atherosclerosis. Here, we evaluated the impact of serum C-reactive protein (CRP) and the white blood cell (WBC) count on the risk of hypertension in middle-aged Japanese men at a work site. We evaluated a total of 2991 Japanese male workers without hypertension who ranged in age from 18 to 64 years (mean age 40.4 ± 0.2 years) at a worksite in 2010. The hazard ratio (HR) for incident hypertension was estimated according to quartile levels of serum high-sensitivity CRP (hs-CRP) or WBC count. These men were followed up for 5 years from 2010 to 2015. During the follow-up period, 579 (19.4%) subjects developed hypertension. In a multivariable analysis, the risk of incident hypertension was significantly increased with higher hs-CRP levels: HR 1.00 (reference) for the lowest quartile, 1.39 (1.04-1.85) for the 2nd quartile, 1.46 (1.08-1.98) for the 3rd quartile, and 1.57 (1.17-2.11) for the highest quartile. In contrast, the WBC count was not associated with a greater risk of incident hypertension after multivariable adjustment. These findings suggest that higher levels of serum hs-CRP, but not the WBC count, are associated with the future incidence of hypertension in middle-aged Japanese men.

Impact of obstructive sleep apnea on long-term blood pressure variability in Japanese men: a cross-sectional study of a work-site population.

Blood pressure variability (BPV) has been shown to be associated with cardiovascular diseases. The effects on long-term BPV of obstructive sleep apnea (OSA) are not yet known. We evaluated a total of 1653 Japanese male workers (18-69 years) at a work site to diagnose OSA, and we divided them into three groups: non-OSA (apnea-hypopnea index (AHI): < 5, n = 1414), mild-to-moderate OSA (5 ≤ AHI < 30: n = 131) and severe OSA (AHI ≥ 30: n = 108). The standard deviation and coefficient of variation of the subjects' BPV were calculated by using their annual blood pressure measurements at routine physical examinations from 2012 to 2015 (four measurements). The multivariable-adjusted BPV of systolic blood pressure (SBP) was significantly higher in the severe-OSA group compared to the non-OSA group. A multiple regression analysis also revealed that OSA was positively associated with BPV of SBP. We focused on the mild-to-moderate OSA group to evaluate the association of OSA treatment with BPV, because most of the severe-OSA subjects were being treated with continuous positive airway pressure or an oral appliance. The BPV of both systolic and diastolic blood pressure was significantly decreased in the treated subjects. These findings suggest that OSA is associated with increases in long-term BPV which was improved by the treatment of OSA in Japanese men of a work-site population.

Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism.

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.

Impact of serum uric acid on incident hypertension in a worksite population of Japanese men.

OBJECTIVE: Higher levels of serum uric acid are associated with an increased risk of cardiovascular diseases, which may be confounded by comorbidities. We investigated the effects of serum uric acid on the risk of hypertension in Japanese men at a worksite. METHODS: We evaluated a total of 2335 Japanese male workers without hypertension who ranged in age from 18 to 64 years at a worksite in 2009. These men were followed for 6 years from 2009 to 2015. RESULTS: During the follow-up period, 380 individuals developed hypertension. The odds ratio for the incident hypertension was estimated according to quartiles of serum uric acid levels of 5.1 or less, 5.2-5.8, 5.9-6.6, and at least 6.7 mg/dl. The multivariable-adjusted risk of incident hypertension was significantly higher in the highest serum uric acid quartile than in the lowest: odds ratio 1.00 (reference) for the lowest quartile, 1.34 (0.91-1.97) for the second quartile, 1.42 (0.97-2.06) for the third quartile, and 1.65 (1.14-2.40) for the highest quartile. In stratified analyses, the association between serum uric acid and incident hypertension was significant in the patients of aged below 45 years and without comorbidities, namely diabetes and low levels of high-density lipoprotein-cholesterol. CONCLUSIONS: Serum uric acid levels were associated with the future incidence of hypertension, and the association was observed in the younger individuals, those without diabetes, and those with preserved high-density lipoprotein cholesterol levels in a worksite population of Japanese men.

Accurate Depth of Radiofrequency-Induced Lesions in Renal Sympathetic Denervation Based on a Fine Histological Sectioning Approach in a Porcine Model.

BACKGROUND: Ablation lesion depth caused by radiofrequency-based renal denervation (RDN) was limited to <4 mm in previous animal studies, suggesting that radiofrequency-RDN cannot ablate a substantial percentage of renal sympathetic nerves. We aimed to define the true lesion depth achieved with radiofrequency-RDN using a fine sectioning method and to investigate biophysical parameters that could predict lesion depth. METHODS AND RESULTS: Radiofrequency was delivered to 87 sites in 14 renal arteries from 9 farm pigs at various ablation settings: 2, 4, 6, and 9 W for 60 seconds and 6 W for 120 seconds. Electric impedance and electrode temperature were recorded during ablation. At 7 days, 2470 histological sections were obtained from the treated arteries. Maximum lesion depth increased at 2 to 6 W, peaking at 6.53 (95% confidence interval, 4.27-8.78) mm under the 6 W/60 s condition. It was not augmented by greater power (9 W) or longer duration (120 seconds). There were statistically significant tendencies at 6 and 9 W, with higher injury scores in the media, nerves, arterioles, and fat. Maximum lesion depth was positively correlated with impedance reduction and peak electrode temperature (Pearson correlation coefficients were 0.59 and 0.53, respectively). CONCLUSIONS: Lesion depth was 6.5 mm for radiofrequency-RDN at 6 W/60 s. The impedance reduction and peak electrode temperature during ablation were closely associated with lesion depth. Hence, these biophysical parameters could provide prompt feedback during radiofrequency-RDN procedures in the clinical setting.

Quantitative angiographic anatomy of the renal arteries and adjacent aorta in the swine for preclinical studies of intravascular catheterization devices.

Swine are the most common animal model in preclinical studies of cardiovascular devices. Because of the recent trend for development of new devices for percutaneous catheterization, especially for the renal arteries (RAs), we examined the quantitative anatomical dimensions of the RAs and adjacent aorta in swine. Angiographic images were analyzed in 66 female Yorkshire/Landrace crossbred swine. The diameter of both the right and left main RA was 5.4 ± 0.6 mm. The length of the right main RA was significantly longer than that of the left (29.8 ± 7.5 mm vs. 20.6 ± 5.4 mm, respectively; P<0.001). The diameter of both the right and left branch RA with diameters ≥3 mm (the target vessel diameter of recently developed devices) was 3.8 ± 0.5 mm. The right branch RA was significantly longer than that of the left (18.9 ± 7.8 mm vs. 16.4 ± 7.4 mm, respectively; P<0.05). The branching angle of the right RA from the aorta was significantly smaller than that of the left (91 ± 12° vs. 103 ± 15°, respectively; P<0.001). The diameters of the suprarenal and infrarenal aorta were 10.6 ± 1.1 mm and 9.7 ± 0.9 mm, respectively. In conclusion, because of their similar dimensions to human, swine are an appropriate animal model for assessing the safety of, and determining optimal design of, catheter devices for RAs in simulated clinical use. However, there were species differences in the branching angle and adjacent aorta diameter, suggesting that swine models alone are inadequate to assess the delivery performance of catheter devices for RAs.

Impact of obstructive sleep apnea on blood pressure and cardiovascular risk factors in Japanese men: A cross-sectional study in work-site group.

It has been shown that obstructive sleep apnea (OSA) is related to hypertension and cardiovascular disease; however, the prevalence of OSA in general population and the impact of it on blood pressure especially in Japan has not been well determined. We have conducted a screening test for OSA from 2003 to 2011. In addition, a cross-sectional analysis was performed in 2012 to determine the association of OSA and cardiovascular risk factors in Japanese men (18-69 years of age; mean age, 44.4 ± 0.2). The study group consisted of 2208 male employees, and OSA was evaluated by using the 4% oxygen desaturation index and apnea-hypopnea index (AHI). The prevalence of mild-to-moderate (5≤AHI<30) and severe (AHI≥30) OSA in the studied subjects were 7.1%, and 6.1%, respectively. Among the 135 severe OSA subjects, 105 (77.8%) had been treated with continuous positive airway pressure. Both systolic and diastolic blood pressures (DBP) were significantly increased in the subjects with severe OSA compared with those without OSA. These associations in DBP remained observed after adjustment for age, body mass index (BMI), estimated glomerular filtration rate, HbA1c, current alcohol intake, current smoking habits, and OSA treatment. DBP in severe OSA subjects were significantly increased in 1807 subjects who were not treated for hypertension or OSA. However, the levels of blood pressures were not decreased by OSA treatment. These results suggest that the prevalence of OSA is relatively high in middle-aged Japanese men and that blood pressures were elevated in the subjects with severe OSA.

Role of renin-angiotensin aldosterone system on short-term blood pressure variability in hypertensive patients.

The relationship between the renin-angiotensin aldosterone system and short-term blood pressure variability has not been well elucidated. Here, we investigated whether blood pressure variability determined by ambulatory blood pressure monitoring differed among patients with primary aldosteronism (PA), renovascular hypertension (RVHT), and essential hypertension (EHT). We examined 25 patients with PA, 28 patients with RVHT, and 18 patients with EHT. Ambulatory blood pressure monitoring was conducted in all patients. Short-term blood pressure variability was evaluated by calculating the standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of 24-h, daytime, and nighttime blood pressure values. Day-night differences in blood pressure were also determined. The mean 24-h systolic blood pressure (SBP) and the mean diastolic blood pressure (DBP) in the PA and RVHT groups were found to be comparable to those in the EHT group. The SD, the CV, nor the ARV of the 24-h, daytime, and nighttime blood pressures showed any significant differences among the three groups. The day-night differences in blood pressure were comparable among the three groups. The short-term blood pressure variabilities evaluated by ambulatory blood pressure monitoring were comparable among the patients with EHT, RVHT, and PA. The results suggest that the renin-angiotensin aldosterone system may contribute little to short-term blood pressure variability in individuals with hypertension.

Angiotensin II Receptor-Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats.

BACKGROUND: We have previously demonstrated that antihypertensive treatment with renin-angiotensin system inhibitors restores the impaired endothelium-dependent hyperpolarization (EDH)-mediated responses in spontaneously hypertensive rats (SHRs). Herein, we investigated whether the angiotensin II receptor-neprilysin inhibitor sacubitril/valsartan (LCZ696) would improve reduced EDH-mediated responses and whether LCZ696 would exert additional effects on endothelium-dependent and endothelium-independent vasorelaxation compared with an angiotensin II type 1 receptor blocker alone during hypertension. METHODS AND RESULTS: SHRs were treated for 3 months with either LCZ696 or valsartan, from the age of 8 to 11 months. Age-matched, untreated SHRs and Wistar-Kyoto rats served as controls. Membrane potentials and contractile responses were recorded from the isolated superior mesenteric arteries. Acetylcholine-induced, EDH-mediated responses were impaired in untreated SHRs compared with Wistar-Kyoto rats. EDH-mediated responses were similarly improved in the LCZ696- and valsartan-treated SHRs. No difference was observed in acetylcholine-induced, nitric oxide-mediated relaxations among the 4 groups. Endothelium-independent relaxations in response to a nitric oxide donor, sodium nitroprusside, and those to levcromakalim, an ATP-sensitive K+-channel opener, were similar among the 4 groups; however, the sensitivities to levcromakalim were significantly higher in both LCZ696- and valsartan-treated SHRs. CONCLUSIONS: LCZ696 appears to be as effective as valsartan in improving the impaired EDH-mediated responses during hypertension. LCZ696 and valsartan exert similar beneficial effects on endothelium-independent relaxation via enhanced sensitivity of the ATP-sensitive K+ channel. However, the dual blockade of renin-angiotensin system and neutral endopeptidase with LCZ696 does not appear to provide additional benefit over valsartan alone on vasomotor function in mesenteric arteries of SHRs.

Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice.

AIMS: We examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. MAIN METHODS: XOR+/+ and XOR+/- mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-α and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. KEY FINDINGS: The BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/-IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/-IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-α mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/-IR mice. The histological analysis revealed that the XOR+/-IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SIGNIFICANCE: Both the disruption of XOR gene in XOR+/- mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR mice attenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target.

Acute changes in histopathology and intravascular imaging after catheter-based renal denervation in a porcine model.

OBJECTIVES: We first aimed to identify the histopathological changes occurring immediately after renal denervation (RDN) with radiofrequency energy, and then to assess the feasibility of determining procedural success using currently available clinical intravascular imaging techniques. BACKGROUND: Catheter-based RDN has been used as an alternative therapy for hypertension. However, no practical endpoint to determine procedural success during treatment has been established. METHODS: A total of 39 ablation lesions were induced in vivo in eight porcine renal arteries and a total of 15 ablation lesions were induced ex vivo in five excised porcine renal arteries with a radiofrequency delivery device. Acute histological changes and appearance on intravascular imaging of the lesions were investigated with light microscopy, transmission electron microscopy, intravascular ultrasound (IVUS), and optical frequency domain imaging (OFDI). RESULTS: Marked changes were noted in media, adventitia, and perirenal-arterial nerves immediately after in vivo ablation. Changes visualized on IVUS were characterized by focal adventitial thickening comprising a relatively echogenic layer around a heterogeneously hypoechoic interior region, and on OFDI as disappearance of the external elastic membrane signals with high scattering of signals in the surface layer. The changes after ex vivo ablation were histopathologically identical to those from in vivo ablation. There were statistically significant positive correlations in measured dimensions (area, depth, width, and diameter) of ablation lesions between histopathology and IVUS/OFDI findings (Pearson correlation coefficients = 0.69-0.77). CONCLUSIONS: These findings suggest that observation of treated renal arteries by IVUS or OFDI immediately after RDN improves the success rate of RDN.

Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension.

Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. The activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa) underpins EDH-mediated responses. It was recently reported that Ca2+ influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SKCa/IKCa in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IKCa, using isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDH-mediated responses were reduced by a combination of SKCa/IKCa blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl)diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SKCa protein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IKCa were preserved in SHRSP arteries. These findings suggest that EDH-mediated responses are impaired in superior mesenteric arteries of SHRSP because of a reduction in both TRPV4 and SKCa input to EDH.

Salt Intake, Home Blood Pressure, and Perinatal Outcome in Pregnant Women.

BACKGROUND: The relationship between salt (sodium chloride) intake and pregnancy-induced hypertension (PIH) remains unclear. The aim of this study was therefore to investigate the current status of salt intake during pregnancy and identify effective predictors for PIH. METHODS AND RESULTS: Participants were 184 pregnant women who collected 24-h home urine as well as early morning urine samples. We investigated urinary salt excretion, home blood pressure (HBP) measurements for 7 consecutive days before the 20th and after the 30th gestational week, and the development of PIH. Urinary salt excretion according to early morning urine before the 20th gestational week was 8.6±1.7 g/day, and was significantly correlated with that measured from 24-h collected urine. Early morning urine estimated urinary salt excretion was slightly but significantly increased during pregnancy. HBP was 102±10/63±8 mmHg before the 20th gestational week and 104±12/64±10 mmHg after the 30th gestational week. On multiple regression analysis, serum uric acid and body mass index, but not urinary salt excretion, contributed to HBP both before the 20th and after the 30th gestational week. Fourteen participants (7.6%) developed PIH. On multivariate analysis, higher HBP and older age, but not urinary salt excretion, were significantly associated with PIH. CONCLUSIONS: Higher HBP and older age, but not urinary salt excretion, are predictors of PIH. (Circ J 2016; 80: 2165-2172).

Trends in blood pressure control and medication use during 20 years in a hypertension clinic in Japan.

Guidelines for the management of hypertension have recommended strict control of blood pressure to help prevent cardiovascular disease. The aim of the present study was to evaluate the current status of blood pressure control and trends over the past two decades. Four hundred patients treated for hypertension at Kyushu University Hospital were included in the present study. Blood pressure levels and prescribed antihypertensive drugs were examined in 2011. The average blood pressure was 129/74 mmHg, and the number of prescribed antihypertensive drugs was 2.2. Angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, alpha-blockers, and beta-blockers were prescribed in 66%, 5%, 78%, 21%, 12%, and 27% of the cases, respectively. Systolic blood pressure was significantly higher, and diastolic blood pressure was significantly lower in patients aged 80 years or older compared with the younger patients (<80 and ≥80 years, 128/75 mmHg and 133/68 mmHg, respectively). The number of prescribed antihypertensive drugs was similar between the two groups. Sixty-five patients were continuously treated for 20 years. The average blood pressure of these patients significantly decreased from 142/87 mmHg in 1991 to 128/71 mmHg in 2011, accompanied with an increase in the number of antihypertensive drugs from 1.6 in 1991 to 2.7 in 2011. These findings suggest that the revised guidelines for the management of hypertension may have contributed to increased awareness and better management of blood pressure levels.

Bromoenol Lactone, an Inhibitor of Calcium-Independent Phospholipase A2, Suppresses Carrageenan-Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw.

Prostaglandin (PG) E2 and PGI2 are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2 (PLA2). Which isozyme of PLA2 is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation-induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2 isozyme-specific inhibitors on carrageenan-induced production of PGE2 and PGI2 in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2 (iPLA2), significantly reduced carrageenan-induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2 ß, iPLA2 γ, cyclooxygenase-2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2 is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci.

Prostaglandin transporter in the rat brain: its localization and induction by lipopolysaccharide.

Prostaglandin E2 (PGE2) is produced in the brain during infectious/inflammatory diseases, and it mediates acute-phase responses including fever. In the recovery phase of such diseases, PGE2 disappears from the brain through yet unidentified mechanisms. Rat prostaglandin transporter (PGT), which facilitates transmembrane transport of PGE2, might be involved in the clearance of PGE2 from the brain. Here, we examined the cellular localization of PGT mRNA and its protein in the brains of untreated rats and those injected intraperitoneally with a pyrogen lipopolysaccharide (LPS) or saline. PGT mRNA was weakly expressed in the arachnoid membrane of untreated rats and saline-injected ones, but was induced in blood vessels of the subarachnoidal space and choroid plexus and in arachnoid membrane at 5 h and 12 h after LPS injection. In the same type of cells, PGT-like immunoreactivity was found in the cytosol and cell membrane even under nonstimulated conditions, and its level was also elevated after LPS injection. PGT-positive cells in blood vessels were identified as endothelial cells. In most cases, PGT was not colocalized with cyclooxygenase-2, a marker of prostaglandin-producing cells. The PGE2 level in the cerebrospinal fluid reached its peak at 3 h after LPS, and then dropped over 50% by 5 h, which time point coincides with the maximum PGT mRNA expression and enhanced level of PGT protein. These results suggest that PGT is involved in the clearance of PGE2 from the brain during the recovery phase of LPS-induced acute-phase responses.