The syndrome of primary aldosteronism is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. The most common clinical subtypes of primary aldosteronism are aldosterone-producing adrenocortical adenoma (APA) and bilateral adrenal cortical hyperplasia (idiopathic hyperaldosteronism, or IHA). It has been reported that renin suppression and aldosterone levels are lower and hypokalemia milder in patients with IHA than in patients with APA. In the present study, we investigated the genetic analysis of aldosterone synthase gene, CYP11B2 in patients with primary aldosteronism and review the recent studies. The chimeric CYP11B1/CYP11B2 gene, which is a candidate gene for glucocorticoid-remediable hyperaldosteronism, was not found in either the DNA from aldosteronoma or in the genomic DNA from patients with APA or IHA. Mutations in the CYP21 or CYP11B1 gene were not present in patients with APA. No mutations in the coding region of the CYP11B2 gene were found in patients with IHA or APA. The level of CYP11B2 messenger RNA (mRNA) was much higher in the aldosteronoma portion than in nonadenomatous portion. The overexpression of CYP11B2 mRNA seen in the mononuclear leukocytes of patients with IHA suggests that unidentified aldosterone-stimulating factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA. The variants of the CYP11B2 gene may also contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.(Hypertens Res 2001; 24: 469-474)

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A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.(Hypertens Res 2001; 24: 475-480)

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The purpose of this study was to investigated the effect of weight loss on blood pressure and its related variables in moderately obese Japanese females, including an investigation of the rebound phenomenon. Study I examined the effects of weight loss on blood pressure in 138 moderately obese, nondiabetic females (BMI 29.3±0.3 kg/m²; age, 46.3±0.8 years) during a 3-month therapeutic dietary and exercise program. Study II investigated the effect of weight rebound on blood pressure over an additional 21 months of exercise in 48 subjects from Study I subjects. After 3 months, the BMI significantly decreased to 27.9±0.3 kg/m². Abdominal total fat, visceral fat (V), and subcutaneous fat (S) also decreased significantly. In addition, the summation of insulin (ΣIRI), plasma glucose (ΣPG) and HOMA during 75 g oral glucose tolerance test also all significantly decreased. Significant decreases in both the SBP and DBP were observed after the 3 month weight reduction program. Multiple regression analysis revealed that the reduction in SBP was significantly and positively associated with the reduction in log ΣIRI and the reduction in log 24h-urinary norepinephrine excretion at the end of Study I. The DBP showed a significantly positive association with the log ΣIRI. With regard to the weight rebound phenomenon, Study II showed that the SBP, DBP and ΣIRI all increased significantly, and a positive correlation was observed between the changes in the SBP and those in the log ΣIRI. However, no such correlation was observed regarding the abdominal total fat and visceral fat during both periods. These results suggest that weight loss therefore caused the BP to decrease due to both an improvement in hyperinsulinemia and a decrease in the adrenergic activity which may be involved in the urinary catecholamine. As a result, hyperinsulinemia is thus considered to play an important role in the pathogenesis of blood pressure due to obesity not only during weight loss, but also during the weight rebound phenomenon. (Hypertens Res 2001; 24: 481-487)

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The aim of the present study is to investigate the pathophysiological characteristics of a number of recent cases of malignant hypertension (MHT) and to compare them to the characteristics of earlier cases. Patients with MHT (age 25-76, mean 44±2 years) who were admitted to our hospital from 1984-1999 were retrospectively studied. All of the patients had either grade III or IV retinopathy and diastolic blood pressure levels higher than 120 mmHg. The observations in this study were compared to previously reported findings regarding 59 MHT patients who were admitted from 1971-1983. Of the 37 recent MHT patients, 20 had essential hypertension (EHT) as the underlying disease, 13 had chronic glomerulonephritis (CGN), and the remaining 4 presented with other diseases including pyelonephritis and renovascular hypertension. A positive family history of hypertension was more prevalent in the EHT patients than in other patients, and persistent proteinuria, microhematuria, and anemia were more prevalent in the CGN patients. These characteristics were similar between the recent and previous cases. Within 4 weeks after admission, hemodialysis was initiated in 3 of the 13 patients (23%) with CGN and 2 of the 20 (10%) patients with EHT. The prevalence of renal death at 1 year after admission was 30%, which was lower than the prevalence in the previous cases (42%). Grade IV retinopathy was seen in 45% of the patients admitted from 1984-1999, significantly less than in the patients admitted from 1971-1983 (66%, p<0.05). In addition, left ventricular hypertrophy was less frequently observed on electrocardiogram in the recent cases (67%) than in the previous cases (88%, p<0.05). Our results suggest that the recent cases of MHT demonstrate less severe organ damage.
(Hypertens Res 2001; 24: 489-492)

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The objective of this study was to elucidate the relationship between left ventricular geometry and left ventricular (LV) function in patients with untreated essential hypertension. We evaluated LV systolic and diastolic functions by M-mode echocardiography in 24 normotensive control subjects (NC) and 129 patients with essential hypertension. Patients were divided into four groups according to the relative wall thickness and LV mass index: a normal left ventricle (n=57), a concentric remodeling (n=7), a concentric hypertrophy (n=31), and an eccentric hypertrophy (n=34) group. LV systolic function as measured by midwall fractional shortening (FS) was significantly decreased in both the concentric remodeling and concentric hypertrophy groups; no differences were observed for endocardial FS. LV diastolic function as measured by isovolumic relaxation time (IRT) was also decreased in both the concentric remodeling and concentric hypertrophy groups. In multivariate analysis, relative wall thickness (p<0.0001), end-systolic wall stress (p<0.0001), and systolic blood pressure (p=0.002) were independently associated (r²=0.72) with midwall FS in a model including age, LV mass index, body mass index, diastolic blood pressure and IRT. In addition, relative wall thickness (p=0.0008) and age (p<0.0001) were independently associated (r²=0.31) with IRT in a model including LV mass index, end-systolic wall stress, body mass index, systolic and diastolic blood pressures and midwall FS. We conclude that LV geometry as evaluated by relative wall thickness may provide a further independent stratification of LV systolic and diastolic functions in essential hypertension.
(Hypertens Res 2001; 24:493-499)

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The association of the angiotensinogen (AGT) gene variation at codon 235, the T235 variant, with hypertension induced by erythropoietin (Epo) was investigated in patients with progressive renal disease requiring treatment for renal anemia with Epo. The subjects for the study were patients with renal diseases with serum creatinine concentration exceeding 2 mg/dl and a hematocrit (Ht) of less than 30%. During the run-in period, blood pressure was well controlled with an appropriate salt restricted diet and/or antihypertensive treatment. The patients were then given 6,000 lU of Epo once a week until the Ht rose by 5%. For the overall patient group, AGT gene polymorphism analysis revealed T235T (T/T) in 31 cases (61%), M235T (M/T) in 19 cases (37%), and M235M (M/M) in 1 case (2%). In response to treatment with Epo, hypertension (defined as an increase in mean blood pressure greater than 10 mmHg) was found in 11 cases (22%), all of who carried the homozygous T allele (T/T). On the other hand, the frequency of T/T in patients who did not develop hypertension was 50% (T/T:T/M=20:19 cases), indicating a significant difference (p=0.003 by Chi-square). Variables estimated to be associated with Epo-induced hypertension were the T allele, gender (male), and the degree of increase in Ht, in descending order. Our preliminary research indicates that individuals who carry two copies of the T allele, i.e., who are homozygous for T, are highly susceptible to development of hypertension when subjected to Epo. These results suggest that the AGT T235 variant may be the primary gene responsible for the development of Epo-induced hypertension. (Hypertens Res 2001; 24: 501-505)

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Although left ventricular hypertrophy (LVH) is a common complication which contributes substantially to high cardiovascular mortality and morbidity in end-stage renal failure, whether changes in blood pressure and alterations of circadian variation of blood pressure occur between the hemodialysis (HD) day and the interdialytic day, and if so, whether they influence the left ventricular mass (LVM) remain unknown. Thirty-five consecutive stable patients who had had a hematocrit value greater than 25% for the previous 6 months, who had been on the same antihypertensive drugs during this period, and who underwent HD 3 times a week were included. Echocardiograms were recorded after HD and then ambulatory blood pressure monitoring was recorded every hour for 48 h. The mean interdialytic body weight gain was less than 5% of dry weight. Patients with LVH had a higher average systolic blood pressure (SBP) at predialysis, postdialysis, on the HD day and on the interdialytic day than those without LVH despite the higher antihypertensive therapy rate. The majority of patients with LVH showed concentric hypertrophy and higher plasma natriuretic peptide levels. Irrespective of the presence of LVH, the average blood pressure value did not change between the HD day and the interdialytic day, and a loss of circadian blood pressure variation was observed on both the HD and interdialytic days. Univariate analysis revealed that LVM was significantly correlated with the average SBP at predialysis, postdialysis, on the HD day, on the interdialytic day and over 48 h(r=0.48, r=0.61, r=0.67, r=0.67, r=0.73, respectively; all p<0.05). Multiple regression analysis revealed that 48-h SBP was independently associated with the LVM index. These results suggest that neither the loss of circadian blood pressure variation nor the changes of blood pressure between the HD and interdialytic days was of major etiologic importance in the development of LVH, and that the absolute value of the 48-hour average SBP may be an important risk factor for concentric LVH in stable HD patients.
(Hypertens Res 2001; 24: 507-514)

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It remains to be defined whether molecular variants of the genes underlying Mendelian forms of hypertension play some etiological role in essential hypertension. To pursue this issue, we focused on the following three genes: the epithelial sodium channel (ENaC), 11β-hydroxysteroid dehydrogenase type 2, and mineralocorticoid receptor genes. Five sequence variations of these genes, which were either previously reported to show significant association with hypertension or identified as “mild” molecular variants, were chosen for our study. Each variation was screened in 247 severe hypertensive patients with early onset (<45 years) and any detectable variations were subsequently characterized in 291 older normotensive subjects (>60 years) for the case-control comparison. We also investigated the significance of association between the tested variants and biochemical parameters reflecting sodium-water homeostasis, such as plasma aldosterone concentration (PAC) and renin activity (PRA). Only the T663A variant (α-subunit of ENaC) turned out to be polymorphic in the Japanese population. In disagreement with positive associations previously reported in white and black subjects, we observed no significant association between T663A and hypertension, while allele frequencies of A663 were higher in Japanese (58-64%) compared with a reported prevalence of 29% in whites and 15% in blacks. T663A showed a borderline association (p=0.02) with the PAC/PRA ratio but not with PAC or PRA in the multivariate analysis. Our data did not support the association between Mendelian disease gene variants and essential hypertension in the Japanese. However, the present study did not definitively resolve this issue and further investigation is certainly warranted.
(Hypertens Res 2001; 24: 515-521)

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We evaluated the association between the phenotypes or alleles of apolipoprotein E and hypertension in Japanese-Americans living in Hawaii or Los Angeles. The study consisted of 932 nondiabetic participants aged 40-79 years. Of these participants, 315 were hypertensive, while the remainder were normotensive. The prevalence of hypertension was higher in subjects with the ε2 allele than in those without. Using a multivariable prediction model that included age, serum glucose, insulin, lipids, and body mass index, we found the ε2 allele to be associated with hypertension in men (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.05-2.24) and for both sexes combined (OR, 1.35; 95% CI, 1.05-1.73). In a follow-up study, 37 of the 352 (11%) normotensive subjects had developed hypertension 4 years after the baseline examination. The frequencies of the apolipoprotein E phenotype E3/2 and the ε2 allele were higher in the subjects who became hypertensive than in those who remained normotensive. The E3/2 phenotype was associated with incidence of hypertension after adjustment for age, sex, baseline body mass index, and systolic blood pressure (OR, 1.75; 95% CI, 1.01-2.90). When serum lipids, glucose, and insulin were included in this analysis, the E3/2 phenotype tended to be associated with the incidence of hypertension. In conclusion, the ε2 allele of apolipoprotein E was associated with hypertension in Japanese-Americans. This association may be mediated via high levels of serum triglycerides that in turn are mediated in part by the ε2 allele. Nonlipid mechanisms may also be responsible for the effect of the ε2 allele on hypertension.
(Hypertens Res 2001; 24: 523-529)

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The present study was to assess the association of metabolic factors including hyperinsulinemia, with the development of hypertension in Japanese-Americans. One hundred forty normotensive (<140/90 mmHg) subjects aged 40 to 69 years old from the Hawaii-Los Angeles-Hiroshima study were followed for 15 years. Patients with cardiovascular disease were excluded. Body mass index (BMI), blood pressure (BP), serum total cholesterol (TC), triglycerides (TG), uric acid (UA), and glucose and insulin responses at baseline, 1 h, and 2 h after a glucose load were analyzed. Seventeen subjects became hypertensive (systolic BP ≥ 160 mmHg, diastolic BP ≥ 95 mmHg, or received drug treatment) during follow-up. Age- and sex-adjusted BMI, BP, serum UA, TG, insulin, and changes in fasting glucose during follow-up were higher in subjects who later became hypertensive than in those who did not. There was no difference in the change in BMI. Age- and sex-adjusted relative risks for the development of hypertension by quartiles of BMI, serum UA, TG, and the sum of insulin values (Σinsulin) during a glucose load were highest in highest quartile of the distribution. When age, sex, systolic BP, BMI, serum UA, TC, TG, fasting glucose, Σinsulin, and the change in BMI were used in a proportional hazard analysis, hyperinsulinemia, hyperuricemia, and systolic BP were found to be significant risk factors for hypertension. In conclusion, hyperinsulinemia, as well as obesity, hyperuricemia, and hypertriglyceridemia were associated with hypertension in Japanese-Americans. Hyperinsulinemia and hyperuricemia were independent predictors of the development of hypertension.
(Hypertens Res 2001; 24: 531-536)

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This study was designed to clarify the effects of orally administered eicosapentaenoic acid (EPA) on blood pressure, intracellular sodium content, and cell membrane fatty acid composition in patients with essential hypertension. After a 4-week run-in period, a study group of 17 male patients was assigned to an 8-week treatment with EPA (2.7 g/day) or placebo in a randomized, double-blind fashion with a crossover at week 4. Systolic blood pressure (SBP) was lower after treatment with EPA than after treatment with placebo (152.9 ± 17.3 vs. 162.6 ± 20.6 mmHg; p<0.01), while diastolic blood pressure was not statistically different. Compared with the placebo treatment, EPA supplementation resulted in a decrease in intraerythrocyte sodium content (R-Na; 11.17 ± 0.63 vs. 10.44 ± 1.28 nmol/l cells; p<0.05) accompanied by an increase (p<0.001) in erythrocyte membrane EPA content. The increase in membrane EPA content was related to the decrease in SBP (r=−0.52, p<0.05) and the decrease in R-Na (r=−0.57, p<0.02) during EPA treatment. The decrease in R-Na correlated positively with the decrease in SBP (r=0.54, p<0.05), and correlated negatively with the change in Na⁺-K⁺ ATPase activity (r=−0.59, p<0.02). However, the change in Na⁺-K⁺ ATPase activity did not directly correlate with the change in membrane EPA content. In conclusion, oral EPA supplementation increased membrane EPA content and reduced SBP in patients with essential hypertension. Based on the association between the increase in membrane EPA content and the decrease in intracellular sodium concentration, EPA may lower blood pressure by altering the activities of the membrane sodium transport systems. (Hypertens Res 2001; 24: 537-542)

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To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP—as well as the tissue expression of proadrenomedullin (proAM) mRNA—in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.
(Hypertens Res 2001; 24: 543-549)

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Recent studies have demonstrated that cytochrome P450-dependent metabolites of arachidonic acid (CYP450-AA) play important roles in the control of renal vascular resistance (RVR). In the present study, we examined the possible involvement of CYP450-AA in the vasoconstrictor action of angiotensin II (Ang II) on the afferent arterioles (Af-Arts), a vascular segment crucial to the control of RVR. Rabbit Af-Arts were microperfused at 60 mmHg in vitro, and the vasoconstrictor action of Ang II (10⁻¹¹-10⁻⁸ M, added to both the bath and lumen) was examined with or without blocking the activity of CYP450 epoxygenase or hydroxylase. Ang II decreased the luminal diameter of Af-Arts in a dose-dependent manner (34±2% of control diameter at 10⁻⁸ M, n=9, p<0.0001). Pretreatment with miconazole, an inhibitor of CYP450 epoxygenase, at 10⁻⁶ M decreased the basal diameter by 14±1% (n=6, p<0.01) and augmented the vasoconstrictor action of Ang II (7±3% of control diameter at 10⁻⁸ M, p<0.001 vs. without miconazole). This augmentation was abolished by blocking the Ang II type 2 (AT₂) receptor with PD 123319 at 10⁻⁷ M. In contrast, pretreatment with 17-octadecynoic acid (17-ODYA, 10⁻⁶ M), which inhibits both epoxygenase and hydroxylase activity, had no effect on the basal diameter but attenuated the vasoconstrictor action of Ang II (46±2% of control diameter at 10⁻⁸ M, p<0.01 vs. without 17-ODYA). Our results demonstrate that in the Af-Art, endogenous CYP450-AA are involved not only in the control of basal tone but also in the action of Ang II. Further, it appears that the CYP450 epoxygenase pathway attenuates Ang II action via AT₂ receptors. (Hypertens Res 2001; 24: 551-557)

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It remains to be clarified whether ACE inhibitors extend the lifespan in cases of severe hypertension. In the present study, we examined whether inhibition of angiotensin-converting enzyme (ACE) would affect mortality in a very severe hypertensive model. Twelve-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto rats (WKY) were used, and measurements at this age were taken as the basal values. At this age, the systolic blood pressure of SHR-SP was 219±4 mmHg, while that of WKY was 102±3 mmHg. After 12 weeks of sodium loading, the systolic blood pressure in the placebo-treated SHR-SP reached to 251±4 mmHg. At 4 weeks of sodium loading, 85% of the placebo-treated SHR-SP had died, and the systolic blood pressure of the surviving rats was 249±26 mmHg. In the trandolapril-treated SHR-SP, the systolic blood pressure was gradually increased to 293±5 mmHg at 16 weeks, and none of the mice had died at this time point (0% mortality). The ACE activities of the aorta, brain, heart and kidney were increased in the surviving placebo-treated SHR-SP at 4 weeks compared with the basal levels, while they were significantly decreased in the trandolapril-treated SHR-SP at 16 weeks. These data demonstrate that trandolapril extends the lifespan of this severe hypertensive model, even in cases in which the blood pressure cannot be lowered. (Hypertens Res 2001; 24: 559-564)

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The aim of this study was to examine the roles of muscle fiber composition, capillary density and muscle blood flow in insulin resistance (IR) and the effect of cilnidipine, a calcium channel blocker in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks, the rats were treated by gavage with a vehicle (Control and FFR groups) or with cilnidipine (FFR+Cil group). Blood pressure (BP) and insulin sensitivity were assessed in the sixth week. Muscle fiber composition, capillary density and blood flow in the soleus muscle were evaluated. BP of FFR was significantly higher than that of the controls. Cilnidipine significantly lowered BP in FFR. Insulin sensitivity was significantly lower in FFR than in the controls. Cilnidipine significantly improved IR in FFR. The composite ratio of type I fibers in the soleus muscle was significantly lower in FFR than in the controls, but that of type II fibers was significantly higher in FFR. Treatment with cilnidipine resulted in recovery of this ratio to that of the controls. Insulin sensitivity was found to be significantly correlated with the composite ratio of either type I fibers or type II fibers. There were no intergroup differences in capillary density. Muscle blood flow in the FFR+Cil group was higher than that in the Control of FFR groups. These results suggest that muscle fiber composition is linked to IR and that clinidipine may improve IR in FFR either by modulating muscle fiber composition or by increasing muscle blood flow.(Hypertens Res 2001;24:565-572)

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Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors can protect the myocardium against ischemic injury, the mechanisms of their effect have not yet been characterized at the cellular level. Therefore, we investigated the role of cardiac ATP-sensitive K⁺ (K_ATP) channels induced by the HMG-CoA reductase inhibitor known as pravastatin on the myocardial metabolism during ischemia by phosphorus 31-nuclear magnetic resonance (³¹P-NMR) in isolated rabbit hearts. Forty-five min of continuous normothermic global ischemia was carried out. Pravastatin with or without the K_ATP channel blocker glibenclamide or the nitric oxide synthase inhibitor L-NAME was administered beginning 60 min prior to the global ischemia. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each: the control group, the P group consisting of pravastatin treatment, the P+G group consisting of pravastatin treatment with glibenclamide, and the P+L group consisting of pravastatin treatment with L-NAME. During ischemia, the decreases in adenosine triphosphate (ATP) and intracellular pH (pHi) were significantly inhibited in the P group in comparison with Control group (at end of ischemia, respectively; both p<0.01), as was the increase in inorganic phosphate (Pi)(at end of ischemia, p<0.01). However, the decreases in ATP and pHi and the increase in Pi were not inhibited in the P+G group during ischemia. The P+L group also showed no inhibition of the aforementioned parameters during the same period. These results suggest that pravastatin has a significant beneficial effect for improving the myocardial energy metabolism, which is provided by K_ATP channels and nitric oxide (NO), during myocardial ischemia. The cardioprotection of HMG-CoA reductase inhibitor may be caused by the K_ATP channels that are mediated by the NO.
(Hypertens Res 2001;24:573-577)

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Retinoids have been shown to promote vascular smooth muscle cell differentiation, although the underlying mechanism is unclear. In fact, treatment of rat aortic smooth muscle cells with all-trans retinoic acid (ATRA) has been shown to markedly elevate the mRNA and protein levels of smooth muscle α-actin. Considering that an exit from the cell cycle is a prerequisite for cell differentiation, we examined the effect of ATRA on cellular events during the progression from G₀ to S phase. Pretreatment with ATRA dose-dependently inhibited DNA synthesis induced by basic fibroblast growth factor. However, ATRA did not inhibit transient activation of mitogen-activated protein kinase (MAPK) in response to mitogenic stimulation. And ATRA consistently failed to influence the phosphorylation of MAPK kinase (MEK) and the expression of MAPK-specific dual phosphatase (MKP-1). ATRA did not interfere with other early mitogenic signals either, such as the phosphorylation of FGF-1 receptor or the induction of immediate early genes c-fos, c-jun, and c-myc. In contrast, ATRA strongly suppressed the pRb kinase activities of the cyclin-dependent kinases (Cdks) Cdk4, Cdk6, and Cdk2. ATRA did not influence the expressions of Cip/Kip family Cdk inhibitors or those of cyclins D1 and D2, whereas it strongly inhibited the expressions of cyclins D3 and E, Cdk4, Cdk6, and Cdk2. These results suggest that ATRA targets multiple genes essential for entry into the cell cycle and for the subsequent progression to G₁ phase, but without interrupting early mitogenic signals upstream of MAPK.
(Hypertene Res 2001;24: 579-588)

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We report a Japanese family with glucocorticoid-remediable aldosteronism (GRA) in whom gene abnormality was identified by the long-polymerase chain reaction (PCR) method. The proband was a 21-year-old female incidentally found to have high blood pressure (173/107 mmHg). Laboratory tests showed hypokalemia (3.7 mmol/l), and high plasma aldosterone concentration (PAC, 234 pg/ml) with suppressed plasma renin activity (PRA, <0.1 ng/ml/h). The circadian rhythm pattern and the results of a rapid adrenocorticotrophic hormone (ACTH) test indicated ACTH-dependent changes in PAC. Imaging studies showed no adrenal mass on either side. A dexamethasone (Dexa) suppression test (1.0 mg/day orally for 7 days) showed a marked decrease of PAC 2 days after administration, and this decreased level was maintained throughout Dexa administration. High blood pressure and hypokalemia also improved during Dexa treatment. The proband’s younger sister was 19 years old and had hypertension, PAC of 231 pg/ml, and PRA <0.1 ng/ml/h. The mother was 53 years old and had hypertension, PAC of 98.5 pg/ml, and PRA <0.1 ng/ml/h. The proband’s elder sister was a 22-year-old normotensive with PAC of 110 pg/ml and PRA of 0.1 ng/ml. Long-PCR was performed for detection of the chimeric gene associated with GRA, using DNA samples from all four cases and two normal control subjects. Although the aldosterone synthase gene was expressed among all DNA samples, the chimeric gene was detected only in the proband, her younger sister and her mother. Our clinical data and genetic investigation confirmed the presence of GRA in this Japanese family.
(Hypertens Res 2001; 24: 589-594)

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In a patient who was taking an angiotensin-converting-enzyme inhibitor, low-density lipoprotein (LDL) apheresis with dextran-sulfate cellulose provoked hypotension accompanied by lacrimation and blurred vision. Hypotension was eliminated by changing the anticoagulant from heparin to a protease inhibitor, nafamostat mesilate. A study was undertaken to clarify whether an antagonist of angiotensin type 1-receptor, losartan, could be safely used in the same patient during LDL apheresis treatment. Blood pressure and humoral factors were compared between the apheresis sessions with losartan and those without. Although angiotensin II and bradykinin plasma levels during LDL apheresis were significantly greater with losartan than without, blood pressure reduction by losartan was mild and unpleasant symptoms were not induced. Losartan was thus safely used for this patient during treatment by LDL apheresis. The greater rise in bradykinin levels during apheresis with losartan might be ascribable to angiotensin type 2-receptor stimulation.(Hypertens Res 2001;24: 595-598)

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To evaluate the alteration of cardiac function in hypertensive patients with different left ventricular geometric patterns. Echocardiography was used to study left ventricular geometry and cardiac diastolic function in 117 cases of essential hypertension, with 45 normal cases as controls. Echocardiographic date were used to calculated the left ventricular mass index (LVMI) and relative wall thickness (RWT), which values in turn were used to divide the subjects into four groups. The left atrial dimension of the group, with the exception of these hypertensives who showed normal geometry, was larger than that of the control group. The damage of peak of E velocity, peak of A velocity, E/A and the slope between the E and F points (E to F slope) were greater than in hypertension than in the control group. The concentric hypertrophy group and eccentric hypertrophy group suffered more serious damage of left ventricular diastolic function than the concentric remodeling group, and damage of left ventricular diastolic function in the concentric remodeling group was greater than that in the normal geometry group. The degree of cardiac diastolic function damage differed among patients with different left ventricular geometric patterns, when the cardiac structure was changed, the degree of cardiac diastolic function damage increased.(Hypertens Res 2001; 24: 601-604)

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To compare the effects of an α, β blocker, arotinolol, in the treatment of essential hypertension between patients with a dipper and those with a non-dipper profile by means of 24-h ambulatory blood pressure monitoring (ABPM), a multicenter single blind parallel trial was carried out in five clinical centers. After a one-week single blind placebo run-in period, the patients underwent ABPM if their clinic diastolic blood pressure (DBP) ranged from 90-109 mmHg and their clinic systolic blood pressure (SBP) was < 180 mmHg. They were divided into two groups according to the absence (non-dipper group, 24 cases) or presence (dipper group, 23 cases) of nocturnal BP reduction ≥ 10% of daytime BP. ABPM was measured again at the end of the active treatment phase. All patients were given Arotinolol 10-20 mg twice daily for 4 weeks. Twenty four-hour systolic and diastolic average BPs (MSBP, MDBP), 24-h systolic and diastolic blood pressure load (LS BP, LDBP), daytime systolic and diastolic average BPs (dMSBP, dMDBP), daytime systolic and diastolic blood pressure load (dLSBP, dLDBP), nighttime systolic and diastolic average BPs (nMSBP, nMDBP) and nighttime systolic and diastolic blood pressure load (nLSBP, nLDBP) were calculated. Arotinolol was effective in 78.2% of dippers and 54.2% of non-dippers, but the difference in effectiveness between these groups was not statistically significant. After treatment, SBP and DBP-including 24-h, daytime and nighttime systolic and diastolic BPs- were significantly reduced in both groups. During the daytime period, the systolic and diastolic blood pressures were significantly reduced in both dippers and non-dippers, while nighttime systolic and diastolic blood pressures were significantly reduced only in the non-dipper group. No significant changes were found in the dipper group over this period. In conclusion, Arotinolol, which can be dosed twice daily, is an effective antihypertensive agent which effectively lowers blood pressure during the day while reducing nighttime blood pressure more in non-dippers than in dippers, without excessive lowering blood pressure in the latter. (Hypertens Res 2001; 24: 605-610)

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