Vascular hypertrophy, which is characterized by proliferation of vascular smooth muscle cells (VSMC) and accumulation of extracellular matrix (ECM), is a major pathological change in blood vessels after chronic exposure to hypertension. Blood pressure is transmitted to the arterial walls and counterbalanced by mechanical stress, leading to stretching of circumferentially oriented VSMC, which may play some role in the pathogenesis of vascular hypertrophy. The present study was designed, therefore, to investigate the effect of mechanical stretch on the expression of ECM components and transforming growth factor-β (TGF-β), a potent stimulator for ECM production, and to examine the signal transduction mechanisms of the induction of TGF-β in cultured rat VSMC. VSMC were subjected to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles per minute for up to 24h. Mechanical stretch stimulated TGF-β1 mRNA expression in a time- and elongation-dependent manner. Indeed, the secretion of TGF-β proteins into the culture media was increased after stretch. Stretch also stimulated mRNA expression of the ECM components, type I and type IV collagen, and fibronectin, which was largely inhibited by addition of neutralizing antibody against TGF-β. The tyrosine kinase inhibitors genistein and herbimycin A blocked the induction of TGF-β1 and type I collagen by stretch, while protein kinase C inhibitors, the calcium channel blockers nitrendipine and gadolinium, or Ca removal from the media had no effect. These results suggest that stretch-induced, tyrosine kinase-mediated autocrine/paracrine production of TGF-β may play a critical role in the progression of vascular remodeling associated with high blood pressure. (Hypertens Res 2000; 23: 91-99)

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The aim of this study was to determine the effect of Tang-Shen-Jiao-Nang (TSJN), a Chinese medicine used to treat diabetes mellitus, on insulin resistance and hypertension in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or a fructose-rich chow (FFR) for 6wk. For the last 2 or 4wk of a 6-wk period of either diet, the rats were treated by gavage with gum arabic solution as a vehicle (control or FFR) or TSJN (800mg/kg/d; FFR+TS), and then we performed the euglycemic hyperinsulinemic glucose clamp technique to estimate insulin sensitivity. Systolic blood pressure was measured weekly for 6wk. At the end of the glucose clamp, the soleus muscle was dissected out for determination of muscle fiber composition by ATPase methods. Systolic blood pressure was elevated at 2wk after the start of the fructose-rich chow feeding and persisted thereafter throughout the study. Systolic blood pressure during the glucose clamp in the FFR group was significantly higher than that in the control group.
Although there was no effect on systolic blood pressure in rats treated with TSJN for the last 2wk of their 6-wk diet, those treated with TSJN for the last 4wk of their 6-wk diet had lower systolic blood pressure than did the rats in the FFR group. The average rate of glucose infusion during the glucose clamp, as a measure of insulin sensitivity (M value), was significantly lower in the FFR than in the controls (10.9±0.6 and 15.4±0.4, mg/kg/min, for FFR and controls, respectively; p<0.01). Treatment with TSJN for 2wk significantly improved the M value compared to that of the control level (15.1±0.5mg/kg/min). The composite ratio of type I fibers in the soleus muscle was significantly decreased in the FFR compared to controls (75.0±1.7 and 81.7±1.5%, for FFR and controls, respectively; p<0.01), and treatment with TSJN for 2wk led to a recovery composite ratio of type I fiber to the same level as that of the control group (78.7±1.7% in FFR+TS). The M value was significantly correlated with the compositions of type I and type II fibers (for type I fibers, r=0.45, p<0.01, for type II fibers, r=-0.44, p<0.05). These results suggest that the Chinese medicine TSJN may improve insulin resistance, lower the systolic blood pressure, and modulate muscle fiber composition in hypertensive and insulin-resistant fructose-fed rats. (Hypertens Res 2000; 23: 101-107)

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It has been established that deoxycorticosterone acetate (DOCA)-salt hypertensive rats have an overactive brain angiotensin-system. The purpose of the present study was to identify the brain sites showing enhanced angiotensin-system activity responsible for the pathogenesis of hypertension in DOCA-salt hypertensive rats. The angiotensin receptor antagonist, losartan, was injected into brain ventricles or into tissues around the rostral parts of the third ventricle in conscious DOCA-salt hypertensive rats. Losartan (1μg) injection into the lateral ventricle or into the rostral parts of the third ventricle produced a depressor response, whereas the agent did not affect blood pressure when injected into the caudal parts of the third ventricle or into the fourth ventricle. Losartan (0.1μg) injection into the anterior hypothalamic preoptic area, anterior (AHA) produced a depressor response. Angiotensin II (0.1-1ng) injection into the AHA produced a pressor response in sham-operated and DOCA-salt hypertensive rats, and the pressor response to angiotensin II (1ng) was greater in DOCA-salt hypertensive rats than that in sham-operated rats. Release of angiotensin peptides in the AHA was greater in DOCA-salt hypertensive rats than that in sham-operated rats. These findings suggest that the angiotensin-system in the AHA is enhanced, and that this enhancement is involved in the maintenance of hypertension in DOCA-salt hypertensive rats. Both increased pressor reactivity to angiotensin II and increased release of angiotensin peptides in the AHA appear to be related to this enhancement of the angiotensin-system in DOCA-salt hypertensive rats. (Hypertens Res 2000; 23: 109-118)

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We report the case of a 68-yr-old woman who, upon standing, experienced dizziness in association with increased blood pressure (BP) and heart rate (HR). We made a diagnosis of orthostatic hypertension and examined the BP response to postural change using the head-up tilt test. Positional change resulted in a 20-mmHg increase in systolic BP and a 15-bpm increase in HR. A 24-h ambulatory BP recording showed daytime hypertension that decreased at night, along with a nocturnal decrease in HR. Based on these post-diagnostic results, the patient was rediagnosed as an extreme dipper with silent lacunar infarction as the only complication of orthostatic hypertension. We suggest that, in our patient, the mechanism of orthostatic hypertension was hypersensitivity of cardiovascular responsiveness to endogenous vasoconstrictors. This was evidenced by increased pressure sensitivity to isoproterenol as well as phenylephrine. We thus selected carvedilol, a β-blocker with slight α-blocking action, and were more effective in abolishing the hypertension. (Hypertens Res 2000; 23: 119-123)

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We performed a cross-sectional survey of the incidence of stroke and acute myocardial infarction (AMI) in Okinawa, Japan, with a census population of about 1.2million. A total of 3, 644 cases of first-ever stroke and 898 cases of initial AMI were detected. The age-adjusted annual incidence rate of stroke was 105 per 100, 000 of the standard population of Japan based on census population taken in 1985, and that of AMI was 26 per 100, 000. The case-fatality rate of stroke within 28 days of onset was 12.8%, and that of AMI was 22.2%. Of the stroke cases, 51.4% were diagnosed as brain infarctions, 38.7% as brain hemorrhages, and 9.3% as subarachnoid hemorrhages. The diagnoses of stroke subtypes were confirmed by computed tomography or magnetic resonance imaging in 98.4% of all stroke cases. TThe long-term prognosis of patients with stroke and AMI was studied by examining their 10-yr survival rates (follow-up rate 89.8%). The cumulative survival rate was 38.2% in brain infarction cases, 40.4% in brain hemorrhage cases, and 38.2% in AMI cases. The 50% reduction of survival had occurred at 2, 880 days after onset in brain infarction cases, at 2, 764 days in brain hemorrhage cases, and at 2, 658 days in AMI cases. In Okinawa, the incidence rate of AMI was still considerably lower than that in the Western population, and the rate of stroke was similar to that in the Western population. The ten-year survival rates were quite similar in AMI and stroke, and both were unexpectedly high. (Hypertens Res 2000; 23: 127-135)

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The study of the effect of autocrine-paracrine vasoactive modulators on cardiovascular biology is very difficult in vivo, because in vivo studies are limited. In particular, characterization of the role of components of the renin-angiotensin system (RAS) in vivo is limited by the difficulty in manipulating individual components of the RAS as well as by methodological limitations in studying the function of a local RAS in the absence of any contribution by the circulatory system. Recent progress in in vivo gene transfer technologies has provided us with the opportunity to study cellular responses to the manipulation of the individual components (i.e., by overexpression or inhibition). Many researchers have recently developed various in vivo gene transfer techniques for cardiovascular applications. Using in vivo gene transfer approaches, the roles of various tissues in the RAS, such as cardiac angiotensin, have been identified. Such an approach may increase our understanding of the biology and pathobiology of the autocrine-paracrine system. This review discusses the potential utility of in vivo gene transfer methods. (Hypertens Res 2000; 23: 137-141)

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Hypertension is a known risk factor for cardiovascular disease, but few epidemiological studies have examined simultaneously the effect of baseline blood pressure on the development of stroke, acute myocardial infarction (AMI), and end-stage renal disease (ESRD). In 1983, a large, community-based mass screening covered about 14% of the adult population in Okinawa, Japan. The total number of people screened was 107, 192 (51, 122 men, 56, 070 women). We had access to two independent registries of end-organ damage: the Co-operative Study Group of Morbidity and Mortality of Cardiovascular Diseases in Okinawa (COSMO) registry for stroke and AMI, and the Okinawa Dialysis Study (OKIDS) registry for ESRD. The total number of people registered was 4, 756 with stroke, 1, 059 with AMI, and 641 with ESRD during the study period from April 1, 1988, to March 31, 1991. By using the name, sex, birth date, and ZIP code of registrants, we identified those registrants who were screened in 1983 and had developed stroke, AMI, or ESRD. Hypertension was defined as systolic blood pressure (SBP) of 140mmHg or higher or diastolic blood pressure (DBP) of 90mmHg or higher. Other readings were regarded as normotensive. The prevalence of hypertension was 35.8% (N=37, 299). The cumulative incidence of stroke, AMI, and ESRD was 154, 21, and 19 subjects among those with SBP_??_119mmHg, and 1933, 315, and 71 subjects among those with SBP_??_160mmHg. Similarly, the incidence of stroke, AMI, and ESRD was 234, 44, and 25 subjects among those with DBP_??_69mmHg and 1980, 381, and 364 subjects among those with DBP_??_110mmHg. Hypertension was prevalent in the adult population in Okinawa, Japan, and was a significant predictor of stroke, AMI, and ESRD. However, the effect of blood pressure on target organs differed and was more evident in those with stroke than in those with AMI and ESRD. (Hypertens Res 2000; 23: 143-149)

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We examined the associations between sodium and blood pressure (BP), and between 3-methylhistidine (3MH)(a marker of animal protein intake) and BP in four Chinese population samples (Guiyang, Guangzhou, Shanghai and Shijiazhuang). This work was a constituent part of the World Health Organization (WHO) Cardiovascular Disease and Alimentary Comparison (CARDIAC) Study. Each population sample consisted of 100 men and 100 women aged 48-56yr and randomly selected using a cross-sectional study design. Twenty-four hour urine samples were collected. Urinary sodium and potassium excretion levels were measured by the flame photometry method, and 3MH was measured using a Hitachi Amino Acid Analyzer 835 (Hitachi, Ibaraki, Japan). After excluding subjects who did not complete the 24-h urine collection (as assessed by urinary creatinine excretion in relation to weight), the total study group included 314 men and 355 women. The results showed that (1) Sodium was positively, and 3MH negatively associated with systolic and diastolic BP (SBP, DBP) in both the total sample and in those who were not administered anti-hypertensive drugs; these associations were all significant (p<0.05), and remained so after adjustment for age, sex, body mass index [BMI, weight (kg)/height (m²)], alcohol intake and potassium excretion. Sodium and 3MH were also observed to exert a combined effect on BPs. In general, subjects who had higher sodium and lower 3MH levels had higher mean SBP and DBP. This combined effect was particularly clear on SBP. (3) A positive association between sodium and BP, and a negative association between 3MH and BP were also shown in subjects who had BMI less than 26kg/m². In conclusion, the study confirmed and further extended previous observations on the study of salt and animal protein intake in relation to BP in middle-aged Chinese. The results support recommendations for a reduction in high salt intake for the control of high BP in the general population and in those with lower BMI. The results also provide important evidence that adequate animal protein intake may have a favorable effect on BP. (Hypertens Res 2000; 23:151-157)

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In patients with accelerated (malignant) hypertension, end-organ damage is the determinant factor for prognosis. Although recent advances in antihypertensive therapy have improved the outcome of patients with accelerated hypertension, the effectiveness of antihypertensive therapy still remains less convinced. In this study, we followed 13 patients clinically diagnosed with accelerated hypertension (defined as diastolic blood pressure>130mmHg, retinopathy with K-W IV and accelerated renal impairment) for 3yr. One patient died due to acute myocardial infarction arising from poor compliance with antihypertensive therapy. One patient was maintained on hemodialysis for 3yr. One patient was introduced for continuous ambulatory peritoneal dialysis (CAPD) for a year and then lived without dialysis therapy. The remaining 10 patients were followed for 3yr. All patients were initially treated with intravenous administration of calcium antagonist for reduction of blood pressure, followed by hemodialysis therapy if needed. After stabilization of blood pressure, combination therapy with extended release nifedipine (40 to 80mg daily) and arotinolol (20mg daily) was started. The targets for blood pressure control were a systolic pressure of 135mmHg and a diastolic pressure of 80mmHg. If blood pressure control was unsatisfactory, guanabenz (2 to 4mg before bedtime), a central acting drug, was added. At presentation, the mean diastolic blood pressure (mDBP) among the 10 remaining patients was 134±2mmHg, the mean serum creatinine (mScr) was 4.5±0.7mg/dl and the left ventricular mass index (LVMi) as measured by echocardiography was 150±9 g/m². At 1yr, the mDBP was reduced to 90±3mmHg, the mScr to 2.9±0.9mg/dl and the LVMi to 140±9g/m². At 3yr, the mDBP was stabilized at 79±3mmHg, the mScr maintained at 2.2 ±0.4mg/dl, and the LVMi reduced to 128±9g/m². These results indicate that appropriate blood pressure control is important for improvement of renal impairment and cardiac damage in patients with accelerated hypertension. Moreover, combination therapy with arotinolol and extended release nifedipine may be beneficial for this purpose. (Hypertens Res 2000; 23: 159-166)

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Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n=25; 157/86mmHg) and normotensive (n=11; 116/66mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139± 14.8/76±2.5mmHg vs. 110±5.1/66.7±3.1mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27±8% vs. -17±5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4±8.7%), whereas it remained stable in hypertensives (0.2±5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure. (Hypertens Res 2000; 23: 167-171)

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The natriuretic peptide (NP) system may play a crucial role in the development of cardiovascular and renal diseases. C-type NP dilates arteries and lowers blood pressure, and it inhibits the proliferation of vascular smooth muscle cells via the type B NP receptor (NPRB). We determined and analyzed the structure of the NPRB gene and found an insertion/deletion (I/D) polymorphism in intron 18. In this experiment, we studied this I/D polymorphism in the NPRB gene in 241 subjects, including 118 patients with cerebral infarction (the CI group) and 123 control subjects (the non-CI group). Our goal was evaluate the association of this polymorphism with cerebral infarction. Our findings showed that genotype frequencies of the I/D polymorphism were in Hardy-Weinberg equilibrium. The frequencies for the II, ID, and DD alleles were 0.569, 0.374, and 0.057, respectively, in the non-CI group and 0.576, 0.356, and 0.068, respectively, in the CI group. No association was found between this polymorphism and cerebral infarction. These results suggest that this polymorphism in the NPRB gene is not linked to a pathogenic CI gene. (Hypertens Res 2000; 23: 173-176)

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The Uygur in Hotan (Xinjiang, China) are reported to have a long life expectancy. The purpose of this study was to clarify the relationship between variations in blood pressure (BP) and longevity. Cross-sectional surveillance was carried out in both Hotan and Barkol. The subjects were divided into five groups: 1. Uygur longevity subjects in Hotan (103 subjects, age>90yr); 2. Uygur elderly subjects in Hotan (107 subjects, age 65-70yr); 3. Han elderly subjects in Hotan (41 subjects, age 65-70yr); 4. Kazakh elderly subjects in Barkol (117 subjects, age 65-70yr); 5. Han elderly subjects in Barkol (50 subjects, age 65-70yr). BP was monitored and analyzed using the fourteen devices of ambulatory BP monitoring. The prevalence of hypertension was lowest in the Uygur (16.2% in Uygur elderly subjects in Hotan; 23.7% in Uygur longevity subjects in Hotan; 27.0% in Han elderly subjects in Hotan; 42.0% in Han elderly subjects in Barkol; 50.0% in Kazakh elderly subjects in Barkol). The ratio of dips in BP was largest in the Han (57% in Han elderly subjects in Barkol; 50% in Han elderly subjects in Hotan; 50% in Uygur longevity subjects in Hotan, 49% in Uygur elderly subjects in Hotan; 17% in Kazakh elderly subjects in Barkol). The 24-h mean systolic BP in Uygur longevity subjects in Hotan was not different from those in Uygur elderly subjects and Han elderly subjects in Hotan, nor did the 24-h mean diastolic BP differ from those in Uygur elderly subjects and Han elderly subjects in Hotan respectively. In conclusion, Uygur subjects seem to be less hypertensive, compared to Kazakh subjects. Uygur longevity subjects had more dipping in their BP variation than did the Kazakh subjects in Xinjiang, China. (Hypertens Res 2000; 23: 177-185)

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Statins are lipid-lowering agents which act by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is responsible for the conversion of HMG-CoA to mevalonate. Products of mevalonate metabolism are critical for several cellular processes of eukaryotic cells, and inhibition of the mevalonate pathway by statins has pleiotropic effects. It has been reported that statins inhibit the migration and proliferation of vascular smooth cells (VSMCs) and macrophages, decrease interleukin-6 and inducible nitric oxide synthase expression in VSMCs, improve endothelial function and up-regulate endothelial nitric oxide synthase expression. The above effects of statins are independent of plasma cholesterol levels, and are completely blocked by exogenous mevalonate and some isoprenoids. These findings suggest that, in addition to their effects on plasma lipids, statins exert direct antiatherosclerotic effects on the cells primarily involved in atherosclerosis. (Hypertens Res 2000; 23: 187-192)

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