To evaluate the optimal BP control for patients with IgA nephropathy (IgAN) based on the histologic severity of the nephropathy and the degree of renal dysfunction. We analyzed 332 consecutive renal biopsy specimens and clinical data from patients with IgAN. Patients were divided into three groups based on their BP at the time of biopsy: an optimal BP (SBP<120 mmHg and DBP<80 mmHg), a hypertensive BP (SBP≥140 mmHg and/or DBP≥90 mmHg), and an intermediate BP group. Each biopsy specimen was evaluated for mesangial proliferation, degree of sclerosis and/or hyalinosis of the arterioles and the interlobular artery using a semiquantitative method. Creatinine clearance and the percentage of sclerosed glomeruli were also determined. Both the degree of renal dysfunction and the histologic changes correlated significantly with BP, even in patients with a BP<140/90 mmHg. The patients with an optimal BP at the time of biopsy had significantly less histologic damage with respect to mesangial proliferation and vessel changes than those with an intermediate or hypertensive BP. In the patients with a hypertensive BP, the percentage of sclerotic glomeruli was significantly higher and the creatinine clearance was significantly lower. The optimal BP proposed by the WHO in 1999 prevents histologic evidence of renal damage for patients with IgAN. (Hypertens Res 2001; 24: 89-92)

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We sought to determine whether a family history of hypertension is quantitatively associated with the prevalence of hypertension and blood pressure in a screened cohort. Clinical data and family (parents and siblings) histories regarding hypertension were collected from 9,914 individuals (probands) who were interviewed and examined during a one-day clinic by the Okinawa General Health Maintenance Association in 1997. We used logistic analysis to calculate odds ratios with adjustments for age, sex, body mass index, total cholesterol, presence of diabetes mellitus, alcohol use, cigarette smoking, and status of physical exercise. The age- and sex-adjusted hypertension prevalences in probands were 29.0% for those with 1 family member with a history of hypertension (n=2,112), 37.6% for those with 2 hypertensive family members (n=374), and 47.3% for those with 3 or more hypertensive family members (n=68). In contrast, only 16.4% of probands who reported no family history of hypertension (n=7,360) were hypertensive themselves. The trend of the prevalence according to the number of family members with a history of hypertension was significantly positive (p=0.003). The adjusted odds ratios (95% confidence interval) of hypertension were 2.74 (2.43-3.10) for 1 member, 4.62 (3.62-5.90) for 2 members, and 6.04 (3.51-10.4) for 3 or more members with a history of hypertension. In patients without antihypertensive medication (n=9,009), systolic/diastolic blood pressure (mean±SD) was 121±17/75±11 for 1 member, 124±18/77±12 for 2 members, and 127±17/78±11 for 3 or more members with a history of hypertension. In contrast, the mean systolic/diastolic blood pressure of probands who reported no family history of hypertension (n=7,360) was 119±15/74±10 mmHg, which was significantly (p<0.05) lower than that of any of the groups with hypertensive family members. In conclusion, an increase in the number of family members with hypertension was associated with an increasing prevalence of hypertension and blood pressure in the probands, independent of conventional risk factors for hypertension. Family members of hypertensive subjects may need to be treated in primary prevention efforts related to hypertension. (Hypertens Res 2001; 24: 93-98)

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We recently demonstrated that spironolactone may have beneficial effects on left ventricular hypertrophy in selected patients with essential hypertension undergoing treatment with an angiotensin-converting enzyme (ACE) inhibitor. To clarify the possible mechanisms by which spironolactone improves cardiac hypertrophy, we investigated the change in serum procollagen type III amino-terminal peptide (PIIINP) in 11 patients with essential hypertension treated with spironolactone and an ACE inhibitor for 24 weeks. Both blood pressure and serum PIIINP levels were significantly decreased by treatment. There was a statistical significant correlation between the changes in LVMI and those in PIIINP. The reduction in PIIINP was significant in patients whose initial serum PIIINP levels were above the normal range. Before treatment, there were no statistically significant correlations between serum PIIINP levels and either LVMI, blood pressure, or plasma aldosterone concentration. Essential hypertensive patients matched in terms of duration of therapy, blood pressure and LVMI and treated with an ACE inhibitor alone showed no change in serum PIIINP levels. In conclusion, the results of the present study demonstrate that patients with essential hypertension and high serum levels of PIIINP are particularly responsive to MR blockade in terms of left ventricular hypertrophy. Moreover, these results suggest that spironolactone limits cardiac collagen turnover in such patients. Larger studies may provide definitive evidence for the involvement of aldosterone in left ventricular hypertrophy in patients with abnormally high PIIINP levels. (Hypertens Res 2001; 24: 99-104)

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Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(−344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the T(−344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population. (Hypertens Res 2001; 24: 105-109)

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This study investigates the circadian blood pressure variation of non-diabetic chronic hemodialysis (HD) patients on both HD and non-HD days as well as the factors affecting diurnal BP variation. Forty-nine HD patients aged 61.8±12.9 years who were on daytime HD for 97±68 months were studied. No significant difference was found in every daytime and nighttime BP between the first (HD) and the second (non-HD) day. However, the ratio nighttime/daytime BP was significantly higher on the second day. Each BP diurnal variability pattern was classified as either Dipper (D: the ratio nighttime/daytime mean BP 0.8-0.9), non-dipper (0.9<ND<1.0), or inverted dipper (ID>1.0). More than 75% of the cases were classified as ND (26 cases) or ID (11 cases). The ultrafiltration rate in D was significantly less than that in ND and ID. The difference of plasma renin activity between pre- and post-HD (dRen) was significantly higher in ID than in D and ND. The amount of dialysis (Kt/V) was found to be significantly correlated with nighttime BP fall. Ultrafiltration, dRen and Kt/V were independent factors for the abnormal BP diurnal variability. In conclusion, the decreased nocturnal BP fall seen in non-diabetic HD patients is associated with increased extracellular fluid even in the patients without overt overhydration, whereas relatively insufficient amount of dialysis (low Kt/V) may be another possible cause. The increased dRen observed only in ID patients may reflect occult cardiovascular damage or functional disturbances in aortic and carotid baroreflexes caused by arterial structural changes. (Hypertens Res 2001; 24: 111-117)

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Endothelin (ET)-1, a potent vasoconstrictor peptide derived from the endothelium, is markedly increased in endotoxic shock, although the pathophysiological role of ET-1 under septic conditions remains obscure. To delineate the role of ET-1 and its receptor subtype in endotoxic shock, we here attempted to determine the changes of circulating levels of ET-1 and its biosynthetic intermediate big ET-1 in endotoxic shock rats, to evaluate the gene expression of ET-1 as well as the ET-1 receptor subtypes (ET_A and ET_B) in the heart, lung and liver, and to study the effects of ET receptor antagonists on systemic arterial blood pressure, heart rate and survival rate. Administration of bacterial lipopolysaccharide (LPS) caused profound hypotension, increased heart rate and death, and these effects were blocked by a nonselective ET_A/ET_B receptor antagonist (TAK044), but not by an ET_A selective antagonist (BQ123). Administration of exogenous ET-1 caused a profound pressor response in control rats, but not in the LPS-pretreated rats. Injection of LPS caused marked elevation of plasma levels of both ET-1 and big ET-1, which were not affected by treatment with either ET receptor antagonist. Administration of LPS caused up-regulation of ET-1 and ET_B receptor mRNA in the heart, whereas ET_A receptor mRNA was markedly down-regulated in the heart, lung and liver. These data suggest differential gene regulation of ET-1 and its receptor subtypes in various organs from endotoxic shock rats, and that nonselective ET_A/ET_B receptor antagonist, but not ET_A receptor antagonist, ameliorates endotoxin-induced hypotension and death. (Hypertens Res 2001; 24: 119-126)

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Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10^-5 M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting. (Hypertens Res 2001; 24: 127-135)

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We previously demonstrated that endothlin-1 (ET-1) augments and ET_A receptor antagonist attenuates excitatory neuronal response to glutamate (Glu) in brainstem slices from normotensive rats. The aim of this study was to determine which type of Glu receptor is responsible for the stimulatory effects of ET-1 on neurons of the nucleus tractus solitarii (NTS). Single unit discharges were recorded extracellularly from rat brainstem slice preparations. Seven NTS neurons that were excited by solitary tract (ST) stimulation responded to iontophoretically applied ET-1 with neuronal activity. An N-methyl-D-aspartate (NMDA) receptor antagonist, non-NMDA, 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX), or DL-2-amino-5-phosphonovaleric acid (AP-5) was perfused over the slices with Kreb’s-Ringer solution. The increase in neuronal activity evoked by iontophoretically applied ET-1 was nearly abolished by CNQX but not by AP-5. CNQX but not AP-5 decreased the basal spontaneous neuronal activity of NTS neurons. These results suggest that non-NMDA receptors play a role in mediating the stimulatory effect of ET-1 on neuronal activity in the NTS. (Hypertens Res 2001; 24: 137-142)

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To examine physical activity at work and during leisure-time as well as other factors related to blood pressure (BP) in Japanese-Americans living in Hilo, Hawaii, USA, we performed a population-based cross-sectional study with a sample of 238 participants aged 42-64 years old. This survey was carried out between 19 February and 1 March 2000 in Hilo. All participants were invited to Hilo Medical Center for a free physical examination and experimental tests including an examination of blood and urine samples. A self-administered health questionnaire was used that included items related to demographics, smoking, alcohol consumption, and habitual physical activity at work and during leisure-time. A summary score of physical activity (PA) was calculated. BP was measured using an automated BP measurement system (Khi machine, VINE Co., Ltd., Kyoto, Japan). The results showed the following. 1) Mean (SD) PA scores at work (WPA) and during leisure-time (LTPA) were 2.9 (0.5) and 2.5 (0.5) in men, and 3.0 (0.5) and 2.4 (0.3) in women, respectively; 2) Pearson correlation analyses (adjustment for age) indicated that WPA and LTPA in men show significant negative associations with SBP and DBP (p<0.05 and p<0.01), while LTPA shows significant negative associations with SBP and DBP in women (p<0.05 and p<0.01). After further adjustment for education, occupation, smoking, and alcohol consumption status, LTPA continued to show significant and negative associations with both SBP and DBP in men (p<0.01) and with DBP alone in women (p<0.01). 3) Hypertensive subjects had significantly lower mean LTPA scores than normotensive men (2.39 vs. 2.61, p<0.05) and women (2.32 vs. 2.45, p<0.05). 4) Body mass index and the ratio of sodium to potassium excretion showed significant and positive associations with SBP and DBP in multiple linear regression analyses. In conclusion, the results further emphasize that the health benefits of LTPA, control of body weight, and reduction in salt intake should continually receive strong attention in population-based high BP control. (Hypertens Res 2001; 24: 145-151)

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The aim of this study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor and αβ blocker in combination with a calcium antagonist on the progression of renal function and left ventricular hypertrophy (LVH) in patients with chronic renal insufficiency and hypertension. The 65 subjects in this study were recruited from a cohort of 316 patients. The main criteria for inclusion were echocardiographic diagnosis of LVH (posterior wall thickness >12 mm) and serum creatinine of more than 1.5 mg/dl. Antihypertensive treatments were switched to the combination of amlodipine at a dose of 5 mg and benazepril at a dose of 2.5 mg daily or the combination of amlodipine at a dose of 5 mg and arotinolol at a dose of 20 mg daily at random irrespective of whether or not patients had been previously treated. The follow-up period was 2 years. Systolic and diastolic blood pressure were significantly reduced from 150/90±15/11 mmHg to 130/75±11/9 mmHg (ACE) and the levels of serum creatinine were increased significantly from 1.8±0.3 to 2.0±0.4 mg/dl (ACE). In the αβ-blocker group, these two values were similar and no significant changes were found. PWT was decreased from 14.2±0.6 to 12.9±0.3 cm in αβ blocker but was not significantly decreased in the ACE inhibitor group. In conclusion, combination therapy with a calcium antagonist and αβ blocker might be effective treatment for hypertensive patients with chronic renal insufficiency and left ventricular hypertrophy. (Hypertens Res 2001; 24: 153-158)

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To investigate the relationship between the A-6G variant in the promoter of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations. All patients with essential hypertension were selected by WHO criteria. And the polymorphism of the A-6G variant was determined by PCR/RFLP. The data were analyzed by t test and χ² test. There was no significant difference in the genotype or allele frequencies between normotensives and hypertensives in the Han, Tibetan, and Yi populations, respectively. However, when the subjects were divided into male and female subgroups, the genotype distributions among hypertensives and normotensives of the Tibetan female group were as follows: AA, 37% vs. 48%; AG, 52% vs. 48%; GG, 11% vs. 4%, respectively and the frequency of the G allele was significantly higher in hypertensives than in normotensives in the Tibetan female group (0.37 vs. 0.28, χ²=4.25, p<0.05). In addition, we observed that there was a significant difference between the Han and Tibetan normotensive groups in the distributions of the allele and genotype frequencies of the A-6G variant. The frequency of the G allele was 0.29 and 0.17 in the Tibetan normotensive and Han groups, respectively (p<0.001). The G allele of the A-6G variant was associated with hypertension in the Tibetan females, but not in the Yi or Han females. And we confirmed that there was a significant difference in the prevalence of the allele frequencies of the A-6G variant between the Han and Tibetan normotensive groups. (Hypertens Res 2001; 24: 159-163)

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Proteoglycans are an important component of the extracellular matrix, and are thought to play multiple roles not only in kidney remodeling, but also in regulating glomerular permeability, and in modulating the activity of other cytokines and growth factors. The aim of this study was to examine the gene expressions of proteoglycan core proteins in hypertensive rat kidneys, and their modulation by AT1 receptor antagonist. SHRSP/Izm rats and normotensive control WKY/Izm rats on a normal salt diet were treated with or without the AT1 receptor antagonist candesartan cilexetil (1 mg/kg/day) from 10 weeks to 22 weeks. At the end of the treatment period, renal tissue was excised, and gene expressions of the proteoglycan core proteins versican, perlecan, decorin, and biglycan were examined by Northern blot analysis and RT-PCR. Treatment with candesartan cilexetil caused significant decreases in blood pressure and amelioration of proteinuria and renal histological scores in the SHRSP/Izm rats. Compared to WKY/Izm rats, expression of biglycan mRNA showed a small increase in SHRSP/Izm rats which did not attain statistical significance. On the other hand, treatment with candesartan caused significant reductions in biglycan and decorin mRNA in the SHRSP/Izm rats. In contrast, the level of versican mRNA appeared to be increased after candesartan treatment. These results suggest that treatment with AT1 receptor antagonist was associated with diverse changes in renal proteoglycan gene expression in SHRSP/Izm rats. These changes could contribute to the beneficial effects of AT1 receptor antagonist on tissue remodeling and inhibition of disease progression in hypertensive rat kidneys. (Hypertens Res 2001; 24: 165-172)

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We examined the influence of chronic antihypertensive treatment on the central pressor response in SHR. Adult male SHR were divided into 5 groups, i.e., those receiving 1) enalapril (Enal: 25 mg/kg/day in drinking water, n=12); 2) losartan (Los: 40 mg/kg/day, n=11); 3) candesartan (Cand: 4 mg/kg/day, n=12); 4) hydralazine+hydrochlorothiazide (H&H: 50+7.5 mg/kg/day, n=9); 5) vehicle (Control: n=9). At 4 weeks of treatment, hypertonic saline (0.25, 0.5 M) was intracerebroventricularly (i.c.v.) injected into conscious rats. Plasma catecholamines were measured before and after i.c.v. injection. On completion of the experiment, heart weight was measured, and angiotensin-converting enzyme (ACE) activity of the cerebrum was determined. All antihypertensive drugs elicited comparable reductions in systolic blood pressure, while heart rate was significantly higher in the H&H group than in the other groups during treatment. Pressor response to i.c.v. hypertonic saline (0.5 M) was significantly smaller in the Enal (12±3 mmHg) and Cand (11±2 mmHg) groups than in the Los (22±2 mmHg), H&H (16±2 mmHg), and Control (29±5 mmHg) groups. Plasma catecholamines did not differ among the groups. Heart weight was lowest in the Enal group, followed by the Los and Cand groups. ACE activity of the cerebrum was significantly decreased in the Enal group. The results suggest that chronic treatment with various antihypertensive drugs differentially alters the central pressor response in SHR, and enalapril and candesartan are effective in attenuating this response. (Hypertens Res 2001; 24: 173-178)

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Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle c, angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT₁-A), angiotensin II type 2 receptor antagonist (AT₂-A) or ACE-I plus bradykinin B₂ antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated Dutp nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH₂-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT₂-A and ACE-I, and increased by AT₁-A and ACE-I+icatibant. ACE-I and AT₂-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT₁-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT₂ receptor are cardioprotective against IR injury through the activation of ERK, but not JNK. (Hypertens Res 2001; 24: 179-187)

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