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Background: The potential use of assays of N-terminal pro-brain natriuretic peptide for detection of diastolic abnormalities associated with alterations in blood pressure has not been elucidated. This study was designed to determine whether increased plasma concentrations of N-terminal pro-brain natriuretic peptide sensitively reflect abnormal diastolic function associated with hypertension., Methods: Concentrations of N-terminal pro-brain natriuretic peptide in plasma were assayed in 40 previously untreated hypertensive patients without overt congestive heart failure and in 20 age and sex-matched controls. Hypertensive patients were studied with the use of pulsed Doppler and color M-mode Doppler echocardiography for the evaluation of left ventricular diastolic function., Results: Concentrations of N-terminal pro-brain natriuretic peptide were elevated in hypertensive patients [75.1+/-75.2 (SD) pg/ml compared with 37.9+/-38.5 in controls, P<0.05]. In hypertensive patients, concentrations of N-terminal pro-brain natriuretic peptide were negatively correlated with the ratio of color M-mode flow propagation velocity to transmitral E velocity consistent with the view that increased concentrations of N-terminal pro-brain natriuretic peptide are indicative of alterations in diastolic function. Hypertensive patients with N-terminal pro-brain natriuretic peptide values above the mean value in the control group exhibited significantly increased brachial intimal-medial thickness and reduced wall stress, consistent with the view that increased N-terminal pro-brain natriuretic peptide was associated with favorable peripheral arterial remodeling., Conclusions: Elevated concentrations of N-terminal pro-brain natriuretic peptide in plasma reflect the presence of left ventricular diastolic abnormalities and peripheral arterial remodeling in asymptomatic patients with hypertension.

Acute myocardial infarction (AMI) has gradually been increasing in Japan; however, since the burden of Japanese residents for risk factors (RFs) of AMI, such as hypercholesterolemia, is chronologically less accumulated compared with American and European people, their RFs of AMI may be different from those in western countries. To answer this question, a retrospective community-based study was carried out enrolling 722 first time AMI patients in Hokkaido, the northern island of Japan. As controls, 1748 age-, sex- and residence-matched subjects were randomly chosen from a data-base of a health check-up organization. We assessed associations between premorbid variables and the RFs for AMI. In men, the most important predictor reflected by high odds ratio (OR) was low HDL-cholesterol (HDL-C). Hypertension (HT) and impaired glucose tolerance (IGT) were also independent RFs. In women, HT represented the highest OR, and low HDL-C, high triglyceride (TG) and IGT followed. Total cholesterol (TC) was a negative predictor for AMI in both sexes, because mean TC level of AMI patients was less than that of controls probably because of acute phase reaction. Thus, low HDL-C, HT, IGT and high TG, which represent the state of metabolic syndrome, were important predictors of AMI. And it was suggested that low HDL-C plays a pivotal role in a population whose TC level is not high.

Objectives: The efficacy of antihypertensive agents can vary in patients. Four to 8 weeks may be required before antihypertensive agents become fully effective. Predicting the efficacy can help agent selection and dose setting. This study determined whether nitroglycerin-induced vasodilation of brachial arteries can predict the antihypertensive action of angiotensin II receptor antagonist., Methods: Untreated uncomplicated patients with essential hypertension, who gave informed consent, were studied (n = 20, mean age 55 years). Before antihypertensive treatment, nitroglycerin-induced vasodilation of the brachial arteries was measured using a novel method of 15 MHz high-frequency high-frame-rate ultrasound imaging (Hitachi EUB8000). Diameter of the brachial artery at the end-systolic phase was measured before and after 0.3 mg nitroglycerin sublingual spray and percentage vasodilation (%D-N) was calculated. The reduction of mean blood pressure after nitroglycerin (%BP-N) was calculated. Valsartan monotherapy (40-80 mg/day)was administered for 3-6 months (mean 132 days). Reduction of mean blood pressure after valsartan monotherapy (%BP-V) was calculated., Results: Valsartan decreased systolic blood pressure from 138 +/- 13 to 130 +/- 17 mmHg, and diastolic blood pressure from 83 +/- 11 to 78 +/- 11 mmHg (p < 0.05). %D-N was correlated closely with %BP-V (r = - 0.70, p < 0.001). %BP-N had no correlation with %BP-V (r = 0.13, p = 0.58)., Conclusions: Direct vasodilatory action of nitroglycerin on vascular smooth muscle cells may predict the chronic antihypertensive effect of angiotensin II receptor antagonist.

Spontaneously hypertensive stroke-prone rats suffer spontaneous strokes partly as a result of abnormal cerebrovascular development. This model exhibits prehypertensive, typical hypertensive and malignant hypertensive stages. We had observed that vascular endothelial growth factor and its receptors, kinase domain region (KDR) and fms-like tyrosine kinase (Flt-1), were upregulated in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage. The current study therefore investigated whether the long-term treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting at the prehypertensive stage (6 weeks old) could reverse the upregulated vascular endothelial growth factor and its receptors; this upregulation is believed to be a compensatory adaptation for hypertension in the brain of spontaneously hypertensive stroke-prone rats. A 40% upregulation of vascular endothelial growth factor was observed in the brain of vehicle-treated spontaneously hypertensive stroke-prone rats compared with the age-matched genetic control, Wistar-Kyoto rat, and this upregulation was markedly reversed by endothelin antagonism. A similar change was found in KDR and Flt-1 expression. It is worth noting that the vascular endothelial growth factor/KDR signaling system was upregulated in the brain of spontaneously hypertensive stroke-prone rats treated with vehicle at the typical hypertensive stage, whereas the cerebral blood flow did not differ between Wistar-Kyoto and spontaneously hypertensive stroke-prone rats. We concluded that endothelin antagonism reversed the upregulated vascular endothelial growth factor and its receptors in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage, and it is suggested that endothelin antagonism can reverse the hypertension-induced neurovascular remodeling in the brain of these rats.

Spontaneously hypertensive stroke-prone rats (SHR-SP) suffer spontaneous stroke in part as a result of abnormal cerebrovascular development. Reduction of regional cerebral blood flow in this model has already been demonstrated. This model has three distinct stages of hypertension: pre-hypertensive, typical hypertensive and malignant hypertensive. We investigated the level of endothelin-1 and its receptor expression in the frontal cortex of SHR-SP at the malignant hypertensive stage (35-40 weeks of age), during which time the rats suffer strokes. The cerebral endothelin-1 level, as determined by enzyme-linked immunosorbent assay, was highly increased at this severely hypertensive stage compared to their genetic control, normotensive Wistar-Kyoto rats. This upregulation was associated with an increased expression of endothelin-A receptor, however, another endothelin-1 receptor, endothelin-B, was downregulated. The regional cerebral blood flow in the frontal cortex was reduced by 60% in 40-week-old malignantly SHR-SP as compared to age-matched Wistar-Kyoto rats. Thus, cerebral endothelin-1 expression increased in malignant hypertension in SHR-SP. The enhanced endothelin-1 may activate the endothelin-A receptor, which would, in turn, result in reduced cerebral blood flow. Downregulation of the endothelin-B receptor may cause suppression of endothelium-derived relaxing factors in the brain of SHR-SP and be an underlying factor in their stroke susceptibility.

Increased levels of endothelin-1 have been demonstrated in the ischemic brain, and endothelin receptor antagonism has been shown to improve the outcome of cerebral ischemia. However, it remains unknown what the relative receptor distribution in the brain of the spontaneously hypertensive stroke-prone rat (SHR-SP) is and whether it is changed by endothelin antagonism. The present study aimed to investigate the expression of the two endothelin receptors in the frontal cortex of SHR-SP after 12 weeks of treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting from the prehypertensive stage (6 weeks old). A 50% increase in the endothelin-A receptor was found in the vehicle-treated brain of SHR-SP compared with that of the age-matched Wistar-Kyoto control, but endothelin antagonism reversed this upregulation completely. A 20% decrease in endothelin-B receptor was found in the vehicle-treated brain of SHR-SP compared with Wistar-Kyoto and was recovered by endothelin antagonism. This is the first study to explore the relative endothelin receptor distribution in the frontal cortex of SHR-SP at the typical hypertensive stage and changes resulting from long-term endothelin antagonism starting from the prehypertensive stage.

It is already well known that alteration of angiotensin II (Ang II) receptors results in cardiac remodeling in different pathological states, and it is believed that Ang II stimulates the release of endothelin-1 (ET-1). The present study aimed at investigating the interaction between ET-1 and different Ang II receptors in the heart of stroke-prone spontaneously hypertensive rats (SHR-SP). These were treated for 3 months with SB209670, an endothelin-A/endothelin-B dual receptor antagonist, or saline (vehicle) starting from the prehypertensive stage (6 weeks of age). Blood pressure, body weight, heart weight and left ventricular weight were sufficiently decreased after treatment of SHR-SP with SB209670. Ang II type 1 receptor was significantly upregulated in the heart of vehicle-treated SHR-SP compared with the age-matched control, Wistar-Kyoto rat. After endothelin antagonism with SB209670, Ang II type 1 receptor in SHR-SP heart was markedly suppressed. On the other hand, Ang II type 2 receptor was approximately 45% downregulated in the heart of vehicle-treated SHR-SP compared with that of the control, and recovered after endothelin antagonism. The present study demonstrates for the first time the effects of endothelin antagonism on the differential expression and regulation of Ang II receptors in the malignant hypertensive model, SHR-SP, and suggests that the endothelin system may be able to function on the upstream of Ang II signaling.

Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and gender-based behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-beta levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD.

Increased carotid artery intima-media thickness (IMT), but not necessarily peripheral vessel IMT, accompanies atherosclerosis. We hypothesized that IMT in a peripheral, muscular artery known to be resistant to atherosclerotic changes would increase with hypertension, thereby limiting increases in wall stress and potentially preserving endothelial cell function reflected by flow-mediated dilation (FMD). Plasminogen activator inhibitor type-1 (PAI-1) can inhibit vascular smooth muscle cell migration contributing to increased IMT. Thus, increased PAI-1 may attenuate the mural adaptive response. A high-resolution scanner designed to delineate brachial artery FMD and IMT was used in studies of previously untreated patients with essential hypertension (n = 18) and age- and gender-matched normotensive subjects (n = 15). Brachial IMT was increased with hypertension (0.36 +/- 0.07 vs 0.27 +/- 0.03 mm in controls, p <0.01), and FMD was lower (3.6 +/- 1.5% vs 7.8 +/- 3.6, p <0.01). PAI-1 antigen in blood was increased (40.5 +/- 31.8 vs 26.3 +/- 11.6 ng/ml, p <0.05). IMT and FMD correlated positively (r = 0.63, p <0.05) in hypertensive patients. FMD correlated inversely with wall stress (r = -0.57, p <0.05). IMT correlated inversely with PAI-1 (r = -0.61, p <0.05). These observations support the hypothesis that increased PAI-1 attenuated increases in neointimal vascular smooth muscle cell cellularity. Thus, increased PAI-1 may attenuate a mural, adaptive response to hypertension associated with preservation of endothelial cell function.

Coronary vasodilator reserve (CVR) is reduced in patients with left ventricular hypertrophy (LVH). However, it is not clear whether there is any difference between the coronary blood flow increase in LVH caused by hypertension (HTH) and that caused by hypertrophic cardiomyopathy (HCM) when the heart rate increases. In this study, 16 subjects with HTH, 10 subjects with HCM, and 10 subjects with normotension (NT) were investigated. Average peak velocities at rest, at pacing, and at dilatation were measured using a Doppler catheter placed at the left descending coronary artery to calculate coronary blood flow (CBF) and CVR. CVR at rest was identical in the HTH and HCM groups, and in both cases was lower than the resting CVR in NT subjects. There were significant differences in the CVR values at a pacing rate of 120 beats/min among the groups. These values were lowest in HCM, highest in NT, and intermediary in HTH subjects. And the percent increase in CBF in HCM at that pacing rate was higher than that in HTH (p < 0.05) or NT (p < 0.05). There was no difference in the percent increase in CBF at this pacing rate between the HTH and NT groups. The effects of elevated heart rate on the percent increase in CBF were different between the HTH and HCM groups. We conclude that cardiac hypertrophy has qualitatively different effects on coronary circulation depending on whether patients have HTH or HCM.

Hypertension is an important risk factor for coronary atherosclerosis, which is accelerated by inflammation and diminished fibrinolysis. We have previously shown that levels of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis, are increased with atherogenic metabolic derangement. Because the liver is one of the major sources of circulating PAI-1, we here examined the effects of two proinflammatory cytokines, interleukin (IL)-1beta, and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1beta (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1beta: 2.1 +/- 0.2 (mean +/- SD) fold over the control; IL-6:1.4 +/- 0.2 fold; Western blot, p < 0.05). The increase in PAI-1 protein accumulation correlated with the increased expression of PAI-1 mRNA (Northern blot). An HMG-CoA reductase inhibitor (mevastatin, 10 micromol/l) attenuated the PAI-1 production induced by IL-1beta and IL-6. The plasma PAI-1 activity level was higher in hypertensives than in normotensives (10.0 +/- 9.8 AU/ml vs. 6.2 +/- 4.5 AU/ml, p < 0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9 +/- 22.4 ng/ml vs. 24.4 +/- 13.3 ng/ml, p < 0.05). Thus, 1) IL-1beta and IL-6 can increase PAI-1 production in hepatic cells and 2) mevastatin may exert anti-thrombotic effects by decreasing the PAI-1 protein production induced by these proinflammatory cytokines. These results provide further insights into how inflammation is involved in the atherothrombotic complications observed in hypertensives, which may be ameliorated by HMG-CoA reductase inhibitors.

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.

The article focuses on the studies related to signaling system in the heart of Stroke-prone spontaneously hypertensive rats (SHRSP). (SHRSP), a genetic animal model of malignant hypertension, demonstrate a remarkable hypertrophy of cardiomyocytes and a decreased capillary density in the left ventricular wall in the malignant hyertensive stage. The present study aimed to investigate the age-related changes in protein and mRNA expressions of a variety of molecules, that are pertinent as possible mediators of angiogenesis, in SHRSP heart with the development of malignant hypertension.