Sumiyo Yamashita

Increased oxidative stress impairs endothelial modulation of contractions in arteries from spontaneously hypertensive rats

Objectives The endothelium modulates vascular contractions. We investigated the effects of oxidative stress on endothelial modulation of contractions in hypertension. Methods Changes in isometric tension of femoral arterial rings from spontaneously hypertensive (SHR) and Wistar–Kyoto (WKY) rats were recorded. Results The contractile response to norepinephrine of arteries with endothelium was greater in SHR than in WKY rats (P < 0.0001). Endothelium removal augmented the norepinephrine-induced contraction (P < 0.05). The augmentation was more pronounced in WKY than in SHR, which resulted in comparable contraction of arteries without endothelium in both strains. Nω-nitro-L-arginine methyl ester (100 μmol/l) mimicked the effect of endothelium removal. Production of nitric oxide (NO, assessed by measuring nitrite/nitrate concentrations) during the contraction was not different between SHR and WKY. Vitamin C suppressed the contraction of arteries with endothelium from SHR but not from WKY (P < 0.05). Diphenyleneiodonium and apocynin, inhibitors of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase, attenuated the contraction of arteries with endothelium from SHR (P < 0.001) but not WKY, but did not affect contractions induced by serotonin. Superoxide generated by xanthine oxidase/hypoxanthine enhanced the norepinephrine-induced contraction of arteries with endothelium from WKY (P < 0.0001), and this effect was reversed by vitamin C. Conclusions In rat femoral arteries, NO released from the endothelium modulates vascular contraction. In SHR, production of superoxide by NADH/NADPH oxidase, which may be activated by norepinephrine, is enhanced, resulting in the inactivation of NO and impairment of endothelial modulation of vascular contractions. Vascular oxidative stress may contribute to the altered circulation in hypertension by impairing endothelial modulation of vascular contractions.

Increased reactive oxygen metabolites is associated with cardiovascular risk factors and vascular endothelial damage in middle-aged Japanese subjects

Background Vascular endothelium, a provider of nitric oxide, is essential for the maintenance of homeostasis in healthy vascular systems. Increased oxidative stress promotes vascular inflammation and is a common pathway involved in endothelial damage. The present study sought to investigate the usefulness of derivative reactive oxygen metabolites (d-ROM) as an oxidative stress marker for detecting endothelial damage in the clinical setting in subjects with early-stage atherosclerosis. Methods Study 1 investigated the relationship between serum d-ROM levels and cardiovascular risk factors in apparently healthy middle-aged subjects (n = 1992, 49 ± 8 years) who participated in our health checkup program. Study 2 analyzed the association between d-ROM levels and endothelial function assessed by flow-mediated dilation and that between d-ROM levels and high-sensitivity C reactive protein (hs-CRP) levels in middle-aged outpatients with mild-to-moderate cardiovascular risk (n = 43, 40 ± 5 years). Results In study 1, the d-ROM level was independently correlated with age, systolic blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, and brain natriuretic peptide in univariate and multivariate regression analysis. In study 2, the d-ROM level was correlated positively with the hs-CRP level and inversely with the flow-mediated dilation value. Patients in the highest tertile of d-ROM had significantly lower flow-mediated dilation values compared with patients in the other tertiles. Moreover, after subdivision of patients into four groups according to d-ROM and hs-CRP levels, patients with high levels of both d-ROM and hs-CRP showed significantly reduced flow-mediated dilation as compared with those with low levels of both indices. Conclusion The close relationship of d-ROM with cardiovascular risk factors, brain natriuretic peptide, inflammatory markers (hs-CRP), and endothelial function (flow-mediated dilation) suggest that d-ROM is a useful oxidative stress marker for detection of endothelial damage in the clinical setting. Assessment of d-ROM, especially combined with hs-CRP, may be a possible predictor of cardiovascular disease.

Serotonin in peripheral blood reflects oxidative stress and plays a crucial role in atherosclerosis: Novel insights toward holistic anti-atherothrombotic strategy.

We enrolled 132 outpatients with cardiovascular risk factors to evaluate the serotonin levels in platelet-poor plasma (PPP) and whole blood (WB). PPP serotonin levels and PPP/WB serotonin ratio were significantly correlated with levels of oxidative stress measured by derivative reactive oxygen metabolites (d-ROM). Twenty-five subjects were revealed to have stable coronary artery disease (CAD), and the levels CRP, d-ROM, and PPP/WB serotonin ratio were significantly higher in subjects with CAD than in those without CAD. Logistic regression analysis performed with the endpoint of having CAD revealed that the PPP/WB serotonin ratio was independently associated with CAD (odds ratio 3.37, 95% confidence interval 1.04-10.9, P = 0.04). Receiver operating characteristic (ROC) curve analyses to discriminate subjects with CAD from those without CAD indicated that combining PPP/WB serotonin ratio and d-ROM improved diagnostic utility. Targeting the serotonin-oxidative stress axis as part of a holistic anti-atherothrombotic strategy could be beneficial for patients with atherosclerosis.

Analytical evaluation of plasma serotonin and sphingosine 1-phosphate and their clinical assessment in early atherosclerosis.

ObjectivesSerotonin stored in platelets is released into plasma on aggregation and activation in atherosclerotic diseases. Sphingosine 1-phosphate (S1P) in plasma is mainly derived from red blood cells and is responsible for the production of nitric oxide in endothelial cells and protects vasculature. The purpose of this study was to investigate the plasma levels of serotonin, S1P, and their clinical relationships with vascular endothelial function in patients with early atherosclerosis. MethodsBlood was withdrawn from patients with low-to-moderate risks of atherosclerotic diseases (n=49, 39±7 years). Platelet-poor plasma was immediately centrifuged. Serotonin levels in plasma were measured with high-performance liquid chromatography. S1P levels in plasma were measured by high-performance liquid chromatography after fluorescent derivatization with o-phthaldialdehyde. Endothelial function was assessed by endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent dilation was measured by glycerol trinitrate-induced dilation using an ultrasound system. ResultsPlasma serotonin was inversely correlated with the FMD value (r=−0.287, P<0.05). Fourteen patients with dyslipidemia, who had not shown improvements after lifestyle modifications, were subsequently treated with rosuvastatin (2.5 mg/day). After 4 weeks of treatment, rosuvastatin improved lipid profiles. Rosuvastatin increased FMD, whereas glycerol trinitrate-induced dilation was unchanged. Notably, percentage decrease in plasma serotonin was inversely correlated with percentage increase in plasma S1P (r=−0.557, P<0.05). ConclusionPlasma serotonin was inversely correlated with FMD and a decrease in plasma serotonin was inversely correlated with an increase in plasma S1P after statin treatment. The results suggested that plasma levels of serotonin and S1P may be useful for the assessment of endothelial function of patients with low-to-moderate risks of atherosclerotic diseases.

Renoprotective Effect of Calcium Channel Blockers in Combination with an Angiotensin Receptor Blocker in Elderly Patients with Hypertension. A Randomized Crossover Trial Between Benidipine and Amlodipine

Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 ± 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4–8 mg/day) or amlodipine (5–10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 ± 16.7 (median ± median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 ± 23/87 ± 10 (mean ± SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 ± 22/75 ± 11 mmHg and 133 ± 17/72 ± 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 ± 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

Differential Response of Central Blood Pressure to Isometric and Isotonic Exercises

Central blood pressure may be more closely associated with cardiovascular events than peripheral blood pressure. The aim of the present study was to investigate central blood pressure responses to exercise. Apparently healthy 18 subjects were enrolled in the study (38 ± 6 years) and changes in central and brachial blood pressure were recorded in response to ergometer and hand-grip exercises. Central blood pressure was estimated using an automated device (Omron HEM-9000AI). Systolic brachial blood pressure was increased after both ergometer (from 119 ± 10 to 172 ± 16 mmHg; P < 0.001) and hand-grip (from 118 ± 8 to 122 ± 9 mmHg; P = 0.001) exercises, but central systolic blood pressure was increased only after hand-grip exercise (from 117 ± 11 to 121 ± 12 mmHg; P = 0.002). The radial augmentation index was increased after hand-grip exercise, whereas ergometer exercise reduced this index. Heart rate was increased only after ergometer exercise. Thus, isometric, but not isotonic, exercise may increase central blood pressure in overall healthy subjects. The response of central blood pressure, which is a better index of cardiac load than peripheral blood pressure, to hand-grip exercise may be useful in evaluating cardiovascular risk.

Central blood pressure reflects left ventricular load, while brachial blood pressure reflects arterial damage

Abstract Objectives. The present study investigated whether brachial and central blood pressures have differential impact on the cardiovascular system in the general population. Methods. The study included 706 subjects (59 ± 10 years) who visited our hospital for a physical check-up. Brachial blood pressure and radial artery pressure waveforms were recorded using an automated device, and the pressure corresponding to the radial late systolic peak (SBP2) was taken as central blood pressure. The concentration of B-type natriuretic peptide and the intima-media thickness of the carotid artery were measured and a cross-sectional analysis was performed. Results. Brachial blood pressure was 128 ± 18/74 ± 12 (mean blood pressure, 92 ± 13) mmHg and SBP2 was 120 ± 19 mmHg. Although both brachial systolic blood pressure and SBP2 correlated with B-type natriuretic peptide in a univariate analysis, only SBP2 independently correlated with B-type natriuretic peptide after adjustment for possible factors. In contrast, brachial systolic blood pressure, but not SBP2, independently correlated with carotid artery intima-media thickness. Conclusions. Central blood pressure is more closely associated with left ventricular load than brachial blood pressure, while brachial blood pressure is more strongly associated with vascular damage than central blood pressure.

Serum levels of Mac-2 binding protein increase with cardiovascular risk and reflect silent atherosclerosis

BACKGROUND AND AIMS Mac-2 binding protein (M2BP) was reported to be a useful biomarker for liver fibrosis and malignant tumors. We hypothesized that expression of M2BP might also change in the process of atherosclerosis. METHODS This study included subjects who visited our hospital for a physical checkup. RESULTS The M2BP levels in subjects with hypertension, dyslipidemia, or abnormal glucose metabolism were higher than those in subjects without such risk factors. Moreover, the M2BP levels were associated with severity of cardiovascular risk. Subdivision of M2BP levels into quartiles revealed that M2BP was significantly associated with reactive oxygen metabolites, central systolic blood pressure, and radial augmentation index (AI). Logistic regression analysis with the endpoint of high radial AI (above mean value) showed that high radial AI was independently associated with high M2BP. CONCLUSIONS Although the spectrum was narrow as compared to that in cases of hepatic fibrosis, serum M2BP may reflect silent atherosclerosis in apparently healthy subjects.

Oxidative Stress is Closely Associated with Increased Arterial Stiffness, Especially in Aged Male Smokers without Previous Cardiovascular Events: A Cross-Sectional Study

Aim: Cigarette smoking is one of the major risk factors for cardiovascular diseases and induces deleterious vascular damage. Oxidative stress is involved in vascular inflammation, the process of atherosclerosis. The purpose of the present study was to investigate whether the effects of oxidative stress on the arterial wall differ between smokers and non-smokers. Methods: Male smokers and non-smokers without physical deconditioning who visited Enshu hospital for an annual physical check-up were enrolled in the study. To assess oxidative stress, serum levels of derivative reactive oxygen metabolites (d-ROM) were measured. The radial augmentation index (RAI) was measured using an automated device and was used as an index for arterial stiffness. Results: Univariate and multivariate linear regression analysis showed that RAI was independently associated with d-ROM levels only in smokers. Moreover, RAI was significantly higher in smokers than in non-smokers. Logistic regression analysis with the endpoint of a higher RAI than the mean revealed that older age (> 65 years), hypertension, and smoking were independently associated with higher RAI. Similarly, logistic regression analysis with the endpoint of higher d-ROM levels than the mean showed that older age and smoking were independently associated with higher d-ROM levels. Conclusions: Increased RAI is significantly associated with smoking and, in smokers, with increased d-ROM levels. These results suggest that the effects of oxidative stress on arterial properties differ between smokers and non-smokers and that oxidative stress is closely associated with arterial stiffness, especially in smokers.

Use of Electrocardiography to Predict Future Development of Hypertension in the General Population.

AbstractCardiac muscle responds to increased afterload by developing hypertrophy. During the early stages of hypertension, the heart can be transiently, but frequently, exposed to increased afterload. This study was designed to test the hypothesis that left ventricular hypertrophy (LVH) assessed by electrocardiography (ECG) can be used to predict future development of hypertension.Sokolow–Lyon voltage and Cornell product were calculated using ECG in 5770 normotensive participants who visited our hospital for a physical checkup (age 52.7 ± 11.3 years). LVH was defined as a Sokolow–Lyon voltage of >3.8 mV or a Cornell product of >2440 mm × ms. After baseline examination, participants were followed up with the endpoint being the development of hypertension.During the median follow-up period of 1089 days (15,789 person-years), hypertension developed in 1029 participants (65.2/1000 person-years). A Kaplan–Meier analysis demonstrated a significantly higher incidence of hypertension in participants with LVH than in those without LVH as assessed by Sokolow–Lyon voltage or Cornell product (P < 0.0001 for both). The hazard ratios for incident hypertension in participants with LVH defined by Sokolow–Lyon voltage and Cornell product were 1.49 (95% confidence interval [CI] 1.16–1.90, P < 0.01) and 1.34 (95% CI 1.09–1.65, P < 0.01), respectively, after adjustment for possible risk factors. Furthermore, in multivariable Cox hazard analysis, where Sokolow–Lyon voltage and Cornell product were taken as continuous variables, both indices were independent predictors of future hypertension (P < 0.0001).Both Sokolow–Lyon voltage and Cornell product are novel predictors of future development of hypertension in the general population.