Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. Here, we aimed to determine whether reactive oxygen species (ROS) reduction by resveratrol in the brain leads to cognitive impairment reduction in rats with angiotensin II (Ang-II)-induced early AD. Male Wistar Kyoto (WKY) rats with Ang-II-induced AD were treated with losartan or resveratrol for two weeks. Our results show decreased blood pressure, increased hippocampal brain-derived neurotrophic factor (BDNF) level, and decreased nucleus tractus solitarius (NTS) ROS production in the Ang-II groups with losartan (10 mg/kg), or resveratrol (10 mg/kg/day) treatment. Furthermore, losartan inhibition of hippocampal TauT231 phosphorylation activated AktS473 phosphorylation, and significantly abolished Ang-II-induced Aβ precursors, active caspase 3, and glycogen synthase kinase 3β (GSK-3β)Y216 expressions. Consistently, resveratrol showed similar effects compared to losartan. Both losartan and resveratrol restored hippocampal-dependent contextual memory by NADPH oxidase 2 (NOX2) deletion and superoxide dismutase 2 (SOD2) elevation. Our results suggest that both losartan and resveratrol exert neuroprotective effects against memory impairment and hippocampal damage by oxidative stress reduction in early stage AD rat model. These novel findings indicate that resveratrol may represent a pharmacological option similar to losartan for patients with hypertension at risk of AD during old age.

BackgroundFew studies have examined the relationship between the amounts of heavy metal and stroke incidence. The aim of this study was to explore the relationship between levels of heavy metals, including Pb, Hg, As, and Cd, in patients with acute ischemic stroke (AIS).MethodsWe selected patients with first-ever AIS onset within 1 week as our study group. Healthy controls were participants without a history of stroke or chronic disease, except hypertension. The serum levels of Pb, Hg, As, and Cd in participants in the experimental and control groups were determined. All participants received a 1-g infusion of edetate calcium disodium (EDTA). Urine specimens were collected for 24 h after EDTA infusion and measured for heavy metal levels.ResultsIn total, 33 patients with AIS and 39 healthy controls were enrolled in this study. The major findings were as follows: (1) The stroke group had a significantly lower level of serum Hg (6.4 ± 4.3 μg/L vs. 9.8 ± 7.0 μg/L, P = 0.032, OR = 0.90, 95% CI = 0.81–0.99) and a lower level of urine Hg (0.7 ± 0.7 μg/L vs. 1.2 ± 0.6 μg/L, P = 0.006, OR = 0.27, 95% CI = 0.11–0.68) than the control group. (2) No significant difference in serum Pb (S-Pb), As (S-As), and Cd (S-Cd) levels and urine Pb (U-Pb), As (U-As) and Cd (U-Cd) levels was observed in either group.ConclusionsOur study found low levels of serum and urine Hg in first-ever patients with AIS, providing new evidence of dysregulated heavy metals in patients with AIS.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0446-0) contains supplementary material, which is available to authorized users.

G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and μ-opioid receptor (μOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased μOR and adrenergic receptor α2A (α2A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, and nNOSS1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of μOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. μOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and μOR, and α2A-AR and μOR, heterodimers. Losartan also significantly increased the levels of nNOSS1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and μOR heterodimers in the NTS, leading to progressive hypertension.

Resveratrol is a polyphenol with pleiotropic effects against oxidative damage that has been widely implicated in lowering hypertension risk. The purpose of this study was to determine whether improve nitric oxide (NO) release in the brain, either through the activation of AMP-activated protein kinase (AMPK) or reduced Ras-related C3 botulinum toxin substrate 1 (Rac1)-induced reactive oxygen species (ROS) generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The rats were fed with 10% fructose or Crestor (rosuvastatin; 1.5 mg·kg·day) and resveratrol (10 mg·kg·day) treatment for 1 wk, then the systolic blood pressure of the rats was measured by tail-cuff method. Endogenous in vivo superoxide radical production in the nucleus tractus solitarii (NTS) was determined with dihydroethidium. Immunoblotting analyses were used to quantify protein expression levels. Oral resveratrol treatment for 1 wk decreased BP and increased NO production in the NTS of fructose-fed rats but not in the control Wistar-Kyoto rats. The effect of Crestor is opposite that of resveratrol. Fructose induced hypertension by inactivating AMPK, which in turn enhanced the generation of ROS and reduced manganese superoxide dismutase by increasing the activity of Rac1-induced NADPH oxidase, abolishing the activity of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and neuronal nitric oxide synthase (nNOS) phosphorylation signaling pathway in the brain. However, resveratrol had the opposite effect in the fructose-fed rats. Overall, we show that the resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-RSK-nNOS pathway by activating AMPK to downregulate Rac1-induced NADPH oxidase levels in the NTS during oxidative stress-associated hypertension. NEW & NOTEWORTHY 1) Evidence showed that the Ras-related C3 botulinum toxin substrate 1 (Rac1) augmented by Crestor (rosuvastatin) did not result in a significant change in blood pressure (BP) in fructose-induced hypertension. 2) Fructose induced hypertension by inactivating AMP-activated protein kinase (AMPK), which in turn enhanced the generation of reactive oxygen species (ROS) and reduced manganese superoxide dismutase in the brain. 3) Resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-ribosomal protein S6 kinase-neuronal nitric oxide synthase pathway by activating AMPK to negatively regulate Rac1-induced NADPH oxidase levels in the nucleus tractus solitarii during oxidative stress-associated hypertension.

Hypertension development with an increased intake of added sugar, especially excessive fructose intake, was shown in the National Health and Nutrition Examination Survey (NHANES) data. However, the mechanism underlying blood pressure (BP) elevation with increased fructose intake is still unclear. First, the present study showed that in rats fed 10% fructose for one week, BP and fructose/glucose levels increased in the central and peripheral nervous system. Furthermore, increased fructose intake resulted in an upregulation of fructose concentration in the cerebrospinal fluid. Second, consumption of excess fructose increased serum triglycerides. However, the inhibition of triglyceride production did not mitigate sympathetic nerve hyperactivity, but contributed to an insignificant decrease in BP. Finally, increased fructose intake reduced nitric oxide (NO) levels in the nucleus tractus solitarii (NTS) and reduced baroreflex sensitivity within a week. Collectively, the data suggested that fructose intake reduced NO levels in the NTS and caused baroreflex dysfunction, which further stimulated sympathetic nerve activity and induced the development of high BP.

Autonomic dysfunctions including impaired baroreflex sensitivity (BRS) can develop after acute ischemic stroke (AIS) and may predispose patients to subsequent cardiovascular adverse events and serve as potential indicators of long-term mortality. This study aimed to determine the potential short-term prognostic significance of BRS after AIS. All patients admitted to Kaohsiung Veterans General Hospital within 72 h after onset of first-ever AIS between April 2008 and December 2012 were enrolled. Autonomic evaluation with continuous 10-minute monitoring of beat-to-beat hemodynamic and intracranial parameters was performed within 1 week after stroke by using the Task Force Monitor and transcranial Doppler. The 176 enrolled AIS patients were divided into high-BRS and low-BRS groups. All but two enrolled patients (who died within 3 months after stroke) attended scheduled follow-ups. The high-BRS group had significantly lower National Institutes of Health Stroke Scale (NIHSS) scores at 1 and 2 weeks after stroke and at discharge; lower modified Rankin scale (mRS) scores 1, 3, 6, and 12 months after stroke; and lower rates of complications and stroke recurrence compared to the low-BRS group. This study provides novel evidence of the utility of BRS to independently predict outcomes after AIS. Furthermore, modifying BRS may hold potential in future applications as a novel therapeutic strategy for acute stroke.

Scope In the Natural Medicines database, coenzyme Q10 (CoQ10) is classified as possibly effective for the treatment of hypertension. Patients with hypertension frequently have a significant deficiency of the antioxidant CoQ10. Furthermore, reactive oxygen species are overproduced in the nucleus tractus solitarii (NTS) during the cardiovascular regulation of hypertension in vivo. However, the molecular mechanisms by which CoQ10 modulates cardiovascular functions in the NTS are unclear. In this study, the effects of CoQ10 on superoxide generation, downstream NO signaling in the NTS, and blood pressure were evaluated in rats with fructose‐induced hypertension. Methods and Results Treatment with oral CoQ10 for 4 weeks abolished nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH oxidase) activation, decreased p38 phosphorylation, and increased superoxide dismutase 2 production in the NTS of fructose‐fed rats. The serum levels of uric acid decrease in response to CoQ10 treatment in fructose‐fed rats. Oral CoQ10 reduced blood pressure by inducing Akt and nNOS phosphorylation in NTS of fructose‐induced hypertensive rats. Conclusion Oral CoQ10 decreases blood pressure by negatively regulating fructose‐induced NADPH oxidase levels, abolishing ROS generation, reducing p38 phosphorylation, and enhancing the Akt‐nNOS pathway in the NTS. These results support the beneficial effects of CoQ10 in oxidative stressassociated hypertension.

While catecholamines like epinephrine (E) and norepinephrine (NE) are commonly used in emergency medicine, limited studies have discussed the harm of exogenously induced catecholamine overdose. We investigated the possible toxic effects of excessive catecholamine administration on cardiopulmonary function and structure via continuous 6 h intravenous injection of E and/or NE in rats. Heart rate, echocardiography, and ventricular pressure were measured throughout administration. Cardiopulmonary structure was also assessed by examining heart and lung tissue. Consecutive catecholamine injections induced severe tachycardia. Echocardiography results showed NE caused worse dysfunction than E. Simultaneously, both E and NE led to higher expression of Troponin T and connexin43 in the whole ventricles, which increased further with E+NE administration. The NE and E+NE groups showed severe pulmonary edema while all catecholamine-administering groups demonstrated reduced expression of receptor for advanced glycation end products and increased connexin43 levels in lung tissue. The right ventricle was more vulnerable to catecholamine overdose than the left. Rats injected with NE had a lower survival rate than those injected with E within 6 h. Catecholamine overdose induces acute lung injuries and ventricular cardiomyopathy, and E+NE is associated with a more severe outcome. The similarities of the results between the NE and E+NE groups may indicate a predominant role of NE in determining the overall cardiopulmonary damage. The results provide important clinical insights into the pathogenesis of catecholamine storm.