Showing papers in "Hypertension Research in 2002"
TL;DR: In this article, the authors evaluated the validity and reproducibility of noninvasive brachial-ankle pulse wave velocity (baPWV) measurements and examined the alteration of BAWV in patients with coronary artery disease (CAD).
Abstract: The present study was conducted to evaluate the validity and reproducibility of noninvasive brachial-ankle pulse wave velocity (baPWV) measurements and to examine the alteration of baPWV in patients with coronary artery disease (CAD). Simultaneous recordings of baPWV by a simple, noninvasive method and aortic pulse wave velosity (PWV) using a catheter tip with pressure manometer were performed in 41 patients with CAD, vasospastic angina, or cardiomyopathy. In 32 subjects (15 controls and 17 patients with CAD), baPWV was recorded independently by two observers in a random manner. In 55 subjects (14 controls and 41 patients with CAD), baPWV was recorded twice by a single observer on different days. baPWV were compared among 172 patients with CAD (aged 62 +/- 8 years); 655 age-matched patients without CAD but with hypertension, diabetes mellitus, or dyslipidemia; and 595 age-matched healthy subjects without these risk factors. baPWV correlated well with aortic PWV (r=0.87, p<0.01). Pearson's correlation coefficients of interobserver and intraobserver reproducibility were r=0.98 and r=0.87, respectively. The corresponding coefficients of variation were 8.4% and 10.0%. baPWV were significantly higher in CAD patients than in non-CAD patients with risk factors, for both genders (p<0.01). In addition, baPWV were higher in non-CAD patients with risk factors than in healthy subjects without risk factors. Thus, the validity and reproducibility of baPWV measurements are considerably high, and this method seems to be an acceptable marker reflecting vascular damages. baPWV measured by this simple, noninvasive method is suitable for screening vascular damages in a large population.
1,487 citations
TL;DR: It is indicated that oral ingestion of GCE or 5-CQA decreases blood pressure in SHR, and that FA, which is a metabolite of 5- caffeoylquinic acid, is a candidate hypotensive component.
Abstract: The effects of a water-soluble green coffee bean extract (GCE) on blood pressure were investigated using spontaneously hypertensive rats (SHR). There was a dose-dependent reduction in blood pressure after a single ingestion (180 to 720 mg/kg, p.o.) or long-term ingestion (0.25 to 1% diet for 6 weeks) of GCE. A single oral ingestion (50 to 200 mg/kg) of 5-caffeoylquinic acid (5-CQA), the major component of GCE, dose-dependently decreased blood pressure, suggesting that 5-CQA is involved in the hypotensive effect of GCE in SHR. Because significant increases in caffeic acid (CA) or ferulic acid (FA) were detected in plasma after oral ingestion of 5-CQA in SHR, these acids (2.5, 5,10 micromol/kg) were intravenously injected into SHR under anesthesia and the carotid arterial pressure was measured. Of the two components, FA had a stronger depressor effect than CA. The depressor effect of FA (50 mg/kg, p.o.) was attenuated by the concurrent injection of atropine sulfate (5 mg/kg, s.c.), suggesting that the hypotensive effect of FA in SHR might be mediated via the muscarinic acetylcholine receptors. These findings indicate that oral ingestion of GCE or 5-CQA decreases blood pressure in SHR, and that FA, which is a metabolite of 5-CQA, is a candidate hypotensive component.
158 citations
TL;DR: The ALDH2 Lys/Lys genotype is a risk factor for myocardial infarction in Japanese men due to its influence on HDL cholesterol level.
Abstract: In epidemiological studies, moderate alcohol consumption has been consistently associated with a reduced risk of myocardial infarction (MI). About half of Japanese show an extremely high sensitivity to alcohol (ethanol), which is due to a missense mutation from glutamic acid (Glu) to lysine (Lys) at codon 487 in an isoenzyme of aldehyde dehydrogenase (ALDH2) with a low Km. We obtained a preliminary result that subjects homozygous for the Lys 487 allele had higher risk for myocardial infarction. The purpose of the present study was to assess this hypothesis by employing a larger cohort of subjects with MI. The experimental group consisted of 342 male subjects with demonstrated MI who were selected randomly from our outpatient clinic. As controls, we employed 1,820 male subjects with no cardiovascular complications who were selected from the Suita Study. All subjects provided their written informed consent to participate in the genetic analyses. Subjects with MI were older and had higher body mass index, higher prevalence of diabetes mellitus, higher prevalence of smoking habit, higher prevalence of the Lys/Lys genotype (homozygous for Lys 487 allele), and lower high density lipoprotein (HDL) cholesterol level (HDL-C). The ALDH2 genotype affected the level of alcohol consumption, and HDL-C. Multiple logistic analyses indicated that the odds ratio of the Lys/Lys genotype to the Lys/Glu+Glu/Glu genotype was 1.56 (p=0.0359). Inclusion of HDL-C as one of the independent variables downplayed the importance of the ALDH2 genotype. This may indicate that the ALDH2 genotype affects MI via its effects on HDL-C. In conclusion, the ALDH2 Lys/Lys genotype is a risk factor for myocardial infarction in Japanese men due to its influence on HDL cholesterol level.
140 citations
TL;DR: Simply measured PWVs and %MPVR are easier to determine than conventional PWV and may be useful as new indices of age-related changes in arterial distensibility.
Abstract: Recently, oscillometric devices have been developed that can measure blood pressure in the extremities and analyze pulse volume record. On the basis of the extremity pulse volume record, these devices can automatically determine three types of simply measured pulse wave velocity (PWV) (brachial PWV: heart to right upper arm; R-PWV: right upper arm-right ankle; and L-PWV: right upper arm-left ankle). The percent mean pulse volume record (%MPVR=the height that bisects the area of the pulse volume record/pulse pressure X100), a quantitative index of right brachial pulse volume record, can also be determined. To evaluate the usefulness of these new indices, we studied 1,067 consecutive subjects undergoing health checkups (648 men, 419 women; mean age, 50 +/- 9 years). In both sexes, age correlated positively with simply measured PWVs (men, brachial PWV: r=0.46, p<0.0001; R-PWV: r=0.46, p<0.0001; L-PWV: r=0.47, p<0.0001; women, brachial PWV: r=0.37, p<0.0001; R-PWV: r=0.47, p<0.0001; L-PWV: r=0.48, p<0.0001) and correlated negatively with %MPVR (men: r=-0.40, p<0.0001; women: r=-0.45, p<0.0001). Simply measured PWVs and %MPVR were significantly correlated with mean blood pressure. In a separate group of 60 patients, simply measured PWVs correlated positively with carotid PWV (heart to carotid) derived from an elastic vessel (brachial PWV: r=0.76, p<0.0001; R-PWV: r=0.43, p<0.01; L-PWV: r=0.43, p<0.01). %MPVR correlated negatively with carotid PWV (r=-0.35, p<0.01). In conclusion, simply measured PWVs and %MPVR are easier to determine than conventional PWV and may be useful as new indices of age-related changes in arterial distensibility.
118 citations
TL;DR: The findings showed that the frequencies of autoantibodies against AT1-receptor and alpha1-adrenergic receptor were higher in patients with hypertension, particularly in those with refractory hypertension, and that these autoant ibodies might play a role in the pathogenesis of hypertension.
Abstract: This study will explore the autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with hypertension. Forty normotensives and 194 patients with hypertension were recruited for participation in this study. All patients accepted systemic combination drug treatment for antihypertension. According to the treatment results and the definition of refractory hypertension, the patients were divided into two groups: a refractory hypertension group and a non-refractory hypertension group. The epitope of the 2nd extracellular loop of type 1 angiotensin (AT1) receptor and alpha1-adrenergic receptor were synthesized and used as antigens to screen the autoantibodies against AT1-receptor and alpha1-adrenergic receptor by ELISA. The plasma renin activity and concentration of angiotensin II and catecholamine were also examined. The positive rates of the autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with hypertension, 26.8% (52/194) and 25.3% (49/194), respectively, were higher than those in normotensives (7.5% and 5%)(p < 0.01). Further investigation showed that the frequencies of the autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with refractory hypertension, 42.9% (42/98) and 36.7% (36/98), respectively, were higher than those in patients with non-refractory hypertension under systematic treatment (10.4% and 13.5%)(p < 0.01). The levels of circulating angiotensin II, catecholamine, proteinuria and serum creatine were also higher in the refractory hypertension group than in the non-refractory hypertension group. The findings showed that the frequencies of autoantibodies against AT1-receptor and alpha1-adrenergic receptor were higher in patients with hypertension, particularly in those with refractory hypertension, and that these autoantibodies might play a role in the pathogenesis of hypertension.
104 citations
TL;DR: It is concluded that the AT1-mediated Ang II signaling pathway plays an important role in Doxorubicin-induced cardiac impairment, suggesting that an AT1 antagonist can be used to prevent DOX-induced cardiomyopathy.
Abstract: Although the serious cardiotoxicity of doxorubicin (DOX), a useful chemotherapeutic agent, limits the use of this agent, the mechanism of DOX-induced cardiomyopathy remains unclear. Since accumulating evidence suggests that activation of the renin-angiotensin system is involved in the development of various types of cardiovascular remodeling, we examined the role of angiotensin II (Ang II) in DOX-induced cardiotoxicity using Ang II type 1a receptor (AT1) knockout (KO) mice. To examine the role of AT1 in the acute effects of DOX, we injected a single 20 mg/kg dose of DOX into AT1KO mice, wild type (WT) mice and WT mice treated with an AT1 antagonist, RNH-6270; to examine the role of AT1 in the chronic effects of DOX, we injected mice of the same groups with 1 mg/kg DOX once a week for 12 weeks. Echocardiography revealed that cardiac function was significantly impaired in WT mice, but not in AT1KO mice or WT mice administered RNH-6270, by both acute and chronic DOX treatment. Histological analysis showed that DOX induced myofibrillar loss and increased the number of apoptotic cells in WT mice, but not in AT1KO mice or WT mice administered RNH-6270. Expression of the ANP gene was downregulated by DOX treatment in WT mice, and this alteration was attenuated in AT1KO mice and in RNH-6270-treated mice. We conclude that the AT1-mediated Ang II signaling pathway plays an important role in DOX-induced cardiac impairment, suggesting that an AT1 antagonist can be used to prevent DOX-induced cardiomyopathy. (Hypertens Res 2002; 25: 597-603)
104 citations
TL;DR: It is suggested that leptin per se directly causes vasodilation and that leptin-induced vasodilatation is nitric oxide-independent in healthy men.
Abstract: Leptin, a product of the ob gene, plays an important role in the regulation of body fat and has been suggested to cause vasodilation in rats. The purpose of this study was to evaluate whether leptin also has a vasodilating effect in humans. Using a strain-gauge plethysmography, we evaluated forearm blood flow (FBF) during intra-arterial infusion of leptin (1, 10 or 100 ng/kg/min for 5 min) in the absence and presence of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 8 micromol/min for 5 min) in ten healthy men (mean age, 23.0+/-1.2 years). Leptin infusion significantly increased the FBF (8.5+/-3.8, 20.3+/-7.0 and 17.7+/-5.4% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05) and the forearm vascular resistance (FVR; -6.9+/-3.1, -14.6+/-4.3 and -13.4+/-3.9% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05). No significant changes in blood pressure or heart rate were detected during infusion of leptin. The intra-arterial infusion of L-NMMA did not alter the FBF response (6.6+/-4.9, 22.1+/-7.5, 13.3+/-3.2% at 1, 10 and 100 ng/kg/min of leptin, respectively) or the FVR response (-4.3+/-4.6, -15.2+/-5.4, -11.1+/-2.5% at 1, 10 and 100 ng/kg/min of leptin, respectively) to leptin. These findings suggest that leptin per se directly causes vasodilation and that leptin-induced vasodilatation is nitric oxide-independent in healthy men.
93 citations
TL;DR: Home BP was more effective than clinic BP as a predictor of changes in left ventricular hypertrophy in treated hypertensive patients and should be controlled to below 135/85 mmHg to prevent cardiachypertrophy.
Abstract: Cross-sectional studies have shown that home blood pressure (BP) correlates with hypertensive target organ damage better than clinic BP. However, there have been few longitudinal studies regarding the predictive value of home BP on the changes in organ damage in treated hypertensive patients. Clinic and home BP over a 12-month period, antihypertensive medication use, echocardiographic and electrocardiographic results, and serum creatinine and urinary protein levels were examined in 209 treated hypertensive patients in 1993. These patients were prospectively followed for 5 years. The patients were divided into 4 subgroups according to hypertension control as follows: good control (<140/90 mmHg for clinic BP, <135/85 mmHg for home BP), improved, worsened, and poor control. The average clinic BP was 147.0+/-14.9/87.0+/-7.6 mmHg (mean+/-SD) in 1993 and 146.0+/-13.7/84.1+/-7.5 mmHg in 1998. The average home BP was 136.8+/-10.4/84.3+/-7.6 mmHg in 1993 and 136.1+/-9.7/81.2+/-7.7 mmHg in 1998. The left ventricular mass index (LVMI) positively correlated with both home systolic BP and clinic systolic BP in 1998 but not in 1993. The correlation tended to be closer for home BP than for clinic BP. LVMI did not change in patients with good or improved home systolic BP, while it increased in those with poor or worsened home systolic BP. The relationship between changes in LVMI and clinic BP was not significant. In conclusion, Home BP was more effective than clinic BP as a predictor of changes in left ventricular hypertrophy in treated hypertensive patients. Home BP should be controlled to below 135/85 mmHg to prevent cardiac hypertrophy.
89 citations
TL;DR: The plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANPand BNP increased in associations with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system.
Abstract: Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert vasodilator and natriuretic actions and are thought to share roles in counteracting the progression of hypertension or heart failure as circulating or locally-acting hormones. However, little data is available with regard to their roles in subjects who have no apparent cardiovascular diseases. The present study was carried out to identify the factors that affect plasma levels of AM, ANP and BNP in the general population. We measured the plasma levels of AM, ANP and BNP in 184 local residents who had a scheduled regular health checkup, and compared the findings with those for other clinical parameters. Univariate analyses showed that the plasma levels of AM, ANP and BNP were significantly correlated with age. The plasma levels of ANP and BNP were also significantly correlated with systolic blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness of the great vessels. Multivariate analyses conducted using a stepwise method revealed that age was a significant, independent variable for the plasma levels of AM, ANP and BNP. In addition, PP was a significant factor for the plasma levels of ANP and BNP, while the plasma AM was significantly associated with body mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANP and BNP increased in association with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system. (Hypertens Res 2002; 25: 887-892)
82 citations
TL;DR: The poor blood pressure control in treated hypertensive subjects was attributable not only to the white coat effect but also to inadequate control of blood pressure.
Abstract: To assess blood pressure control in the Japanese population, we analyzed previously obtained measurements of conventional, home and ambulatory blood pressures in 1,174 subjects aged > or =40 in a Japanese community. On the basis of conventional blood pressure values and the use of antihypertensive medication, participants were classified as normotensive, untreated hypertensive and treated hypertensive subjects. When 140/90, 135/85 and 135/85 mmHg were used as the hypertension criteria for conventional, home and ambulatory blood pressure measurements, respectively, all three blood pressure values were higher in untreated and treated hypertensive subjects than in normotensive subjects. Among the treated hypertensive subjects, approximately half were classified as hypertensive not only by conventional blood pressure, but also by home or ambulatory measurements. Approximately 10% of the subjects defined as normotensive by conventional blood pressure measurement were classified as hypertensive by home or ambulatory measurements, whereas 60% of the untreated hypertensive subjects as defined by conventional blood pressure measurement had normal home or ambulatory blood pressure values. Therefore, we concluded that 1) the poor blood pressure control in treated hypertensive subjects was attributable not only to the white coat effect but also to inadequate control of blood pressure; and 2) a certain percentage of subjects were misclassified as hypertensive or normotensive by conventional blood pressure measurement.
82 citations
TL;DR: Results indicate that AT1 receptor blockade with olmesartan retards the progression of nephropathy associated with type 2 diabetes without affecting glucose metabolism, and that this renal protective effect is at least partly independent of the antihypertensive effect of the drug.
Abstract: To evaluate the efficacy of angiotensin II receptor blockers (ARBs) for use in the treatment of diabetic nephropathy, we examined the effects of olmesartan medoxomil (olmesartan), an angiotensin II type 1 (AT1) specific ARB, on the progression of nephropathy in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes. We used 2 doses of olmesartan, a sub-antihypertensive dose and an antihypertensive dose, to specifically examine whether the drug exerts beneficial effects on the kidney without lowering blood pressure. Olmesartan mixed in the diet at a concentration of 0.001% (approximately 0.6 mg/kg/day) or 0.01% (approximately 6 mg/kg/day) was administered for 19 weeks starting from 12 weeks of age, when the animals developed microalbuminuria. Lean non-diabetic rats served as controls. ZDF rats had hyperglycemia, hyperinsulinemia, and moderate hypertension as compared to lean control rats. Plasma glucose and insulin concentrations were not affected by olmesartan, and blood pressure was lowered only by the high dose of olmesartan. Progressive proteinuria in ZDF rats was greatly (about 70%) suppressed by the high dose of olmesartan and moderately (about 30%) suppressed by the low dose that did not significantly lower blood pressure. ZDF rats exhibited hyperlipidemia and hypoalbuminemia, both of which were substantially corrected by treatment with olmesartan. The histological evidence of glomerular and tubular damage in the ZDF rats was also reduced by the drug. These results indicate that AT1 receptor blockade with olmesartan retards the progression of nephropathy associated with type 2 diabetes without affecting glucose metabolism, and that this renal protective effect is at least partly independent of the antihypertensive effect of the drug.
TL;DR: The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.
Abstract: In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians. The aim of this study was to elucidate the relation between ALDH2 genotypes and blood pressure levels or hypertension in Japanese. After obtaining informed consent for genetic analysis from 917 men and 1,478 women who lived in a mountainous farming region near Kyoto and who were free from cardiovascular disease and liver dysfunction, the authors identified the ALDH2 genotype in all subjects. Differences in blood pressure level among genotypes were then compared by analysis of covariance, and the relation between genotypes and hypertension was also analyzed by logistic regression analysis. The frequencies of genotypes *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and 6.8% in women, respectively. In men, systolic and diastolic blood pressures tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for confounding factors including alcohol consumption resulted in the disappearance of significance. Logistic regression analysis adjusted for the same confounding factors for men showed that the odds ratios (OR) of being hypertensive in the *2 allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47-0.96). However, in the subgroup analyses, this relation was not observed in the group having a below-median level of alcohol consumption (OR = 0.92; 95% CI: 0.53-1.62) or in the group not taking antihypertensive agents (OR = 0.77; 95% CI: 0.52-1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele and hypertension in women (OR = 1.07; 95% CI: 0.80-1.42). The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.
TL;DR: High blood pressure alone is a high risk for early atherosclerosis, but persistent endothelial damage and moderate inflammation may increase the risk of early Atherosclerosis synergistically under the presence of hypertension in Japanese.
Abstract: 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.
TL;DR: Leptin may play a role in the pathophysiology of obese hypertension even after adjusting for the total abdominal fat, 24hU-NE and either sigmaIRI or HOMA in a multiple regression analysis only in the HT group.
Abstract: Insulin resistance is thought to raise blood pressure. Recently, a significant positive relationship between mean blood pressure and plasma leptin levels, but there have been no reports dealing with the relationship between blood pressure and either insulin resistance or serum leptin levels after weight loss. In the present work, we attempted to clarify the relationship between changes in blood pressure and either the serum leptin level or the insulin level in 102 moderately obese females (mean body mass index (BMI), 29.5 +/- 0.5 kg/m2; age, 47.0 +/- 0.9) during a 3 month period. No differences in age, fat-mass, homeostasis model assessment (HOMA), the summation of insulin (sigmaIRI), plasma renin activity (PRA) or 24 h norepinephrine excretion (24hU-NE) were observed between the hypertensive (HT) group (n = 31) and normotensive (NT) group (n = 71) before weight loss, but the basal serum leptin was significantly higher in the HT (16.8 +/- 1.1 ng/ml) than in the NT group (15.2 +/- 0.8 ng/ml), after adjusting for abdominal total fat. After a 3 month weight reduction program, the total abdominal fat, serum leptin and sigmaIRI significantly decreased in both groups. The systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 144/84 to 130/77 mmHg only in the HT but not in the NT group. The PRA decreased in both groups, while the 24hU-NE significantly decreased only in the HT group. The changes in the leptin level were significantly correlated with the changes in both sigmaIRI and HOMA after weight loss in the two groups, respectively. Finally, a statistically significant positive correlation was observed between the changes in the leptin and the changes in the mean blood pressure (MBP) (r = 0.412, p < 0.05) only in the HT group. Multiple regression analysis revealed that the changes in MBP were independently associated with the changes in 24hU-NE and the changes in either sigmaIRI or HOMA in all subjects. However, a statistically significant positive correlation was observed between the changes in MBP and the changes in leptin levels even after adjusting for the total abdominal fat, 24hU-NE and either sigmaIRI or HOMA (both expressed as a percentage of the baseline value) in a multiple regression analysis only in the HT group. These results suggest that leptin may play a role in the pathophysiology of obese hypertension.
TL;DR: It is concluded that more attention should be paid to RAS in Japanese patients with hypertension and cardiovascular disease, and particularly in those with 3-vessel disease.
Abstract: Renal artery stenosis (RAS) is recognized as a major co-morbid condition for patients with cardiovascular disease. Although the prevalence of RAS in Western countries has been reported as 13.5-18% in patients with suspected coronary artery disease (CAD) undergoing coronary angiography, there is little information available about the prevalence of RAS in Asian populations, which are less susceptible to atherosclerosis. To evaluate the prevalence of RAS in Japanese patients suspected of cardiovascular disease and the relationships among RAS and vascular risk factors, especially hypertension, renal artery angiography was performed in a total of 289 consecutive patients receiving diagnostic cardiac catheterization. RAS with a stenosis diameter greater than 50% was considered significant. The prevalence of RAS was 21/289 (7%) including 18 (6%) cases of unilateral stenosis and 3 (1%) of bilateral stenosis. RAS accompanied 14/220 (6%) cases of CAD, 4/34 (12%) cases of valvular heart disease and 1/14 (7%) cases of cardiomyopathy. In the subgroups of CAD, the prevalence of RAS was 5%, 10%, 9%, and 19% in cases of 0, 1, 2 and 3-vessel disease, respectively. Hypertension was more frequent among patients with than among those without RAS (86% vs. 45%, p=0.0003). The prevalence of RAS was 13% in hypertensives and 2% in normotensives (p = 0.004). Thus RAS was frequent in patients with established CAD, and particularly in those with 3-vessel disease. Together, the results showed that hypertension was closely associated with RAS, appearing as both a risk factor and a possible clinical manifestation of the disease. We conclude that more attention should be paid to RAS in Japanese patients with hypertension and cardiovascular disease.
TL;DR: The study strongly suggests the possibility that attenuation of the effects of cardiac aldosterone in patients with EH by treatment with spironolactone and an ACE inhibitor may become a new goal for the prevention and regression of cardiac hypertrophy.
Abstract: It has been reported that treatment with an angiotensin-converting enzyme (ACE) inhibitor is not adequate to suppress aldosterone, and we previously demonstrated that adding spironolactone to an ACE inhibitor may have beneficial effects on left ventricular hypertrophy (LVH) in selected patients with essential hypertension (EH). We have extended our previous short-term study, and addressed the relative long-term clinical effects of spironolactone and an ACE inhibitor in patients with EH who have LVH. Twenty patients with EH and concomitant LVH participated in this study. Subjects were treated with either an ACE inhibitor alone (group 1: 10 patients) or an ACE inhibitor plus spironolactone at the dose of 25 mg (group 2: 10 patients) for 60 weeks. The baseline clinical and echocardiographic characteristics of the two groups were similar. Final values of blood pressure were also similar between the two groups. The LV mass index (LVMI) decreased significantly in both groups, but the extent of reduction was significantly greater in group 2 at 60 weeks. The early peak to atrial peak filling velosities ratio (E/A ratio) was significantly increased to a similar extent in both groups. Serum procollagen type III amino-terminal peptide (PIIINP) was significantly decreased in group 2, but not in group 1. In group 2, there was a statistically significant correlation between the changes in LVMI and PIIINP. In conclusion, adding spironolactone to therapy with an ACE inhibitor for 60 weeks may have beneficial effects in patients with EH and concomitant LVH. Our study strongly suggests the possibility that attenuation of the effects of cardiac aldosterone in patients with EH by treatment with spironolactone and an ACE inhibitor may become a new goal for the prevention and regression of cardiac hypertrophy. (Hypertens Res 2002; 25: 837-842)
TL;DR: Cardiovascular reactivity triggered by psychological and physical stress in the laboratory may be a weak, but significant, determinant of diurnal BP variation; in addition, work shift appears to moderate the relationship between these two pressor mechanisms.
Abstract: There is increasing evidence that diurnal blood pressure (BP) variation, in addition to high BP per se, is related to target organ damage and the incidence of cardiovascular events However, the determinants of diurnal BP variation are not adequately understood This paper tests the hypothesis that cardiovascular reactivity to acute stress and/or delayed recovery predicts greater diurnal BP variation (ie, a lower sleep/awake BP ratio) We studied the relationship of diurnal BP variation (assessed by ambulatory BP monitoring) to mental stress (mental arithmetic and anger recall tasks) and physical stress (treadmill)-induced cardiovascular reactivity and recovery in 87 female nurses who worked different shifts The sleep/awake systolic BP (SBP) ratio was negatively correlated with relative SBP reactivity (maximum SBP increase/baseline SBP: r = -021, p = 006) and relative stress response (average of SBP during stress/baseline SBP:r = -023, p = 004) induced by anger recall, while the correlations of the sleep/awake SBP ratio with other parameters of reactivity or recovery in the anger recall or mental arithmetic task were not significant When subjects were divided into day-shift workers (n=54) and night-shift workers (n = 33), the sleep/awake SBP ratio was negatively correlated with relative SBP reactivity (r = -041, p = 002) and relative stress response of SBP (r = -048, p = 0006) induced by anger recall, and positively correlated with recovery rate (r = 034, p = 006) in the latter group, while these correlations were not significant in the former group The sleep/awake SBP ratio was inversely correlated with the exercise-induced SBP increase in the day-shift workers (r = -030, p = 003), while this association was not found in the night-shift workers In conclusion, cardiovascular reactivity triggered by psychological and physical stress in the laboratory may be a weak, but significant, determinant of diurnal BP variation; in addition, work shift (day or night) appears to moderate the relationship between these two pressor mechanisms
TL;DR: A significant association between the D allele of the ACE gene and hypertension in Tibetan women but not in Tibetan men is shown.
Abstract: There is strong evidence to support the idea that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of essential hypertension (EH) and its complications. However, existing data about the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with blood pressure is conflicting, mainly due to racial differences and environmental exposure status. We therefore conducted a case control study to observe the relationship between ACE I/D polymorphism and EH in a Tibetan population who live in relatively isolated areas and are genetically homogeneous. The study was conducted at stable residential communities in the urban district of Lhasa, the capital of the Tibet autonomous region, China, and 106 unrelated EH patients and 135 normotensive subjects were recruited. PCR, PCR/RFLP and PCR-SSCP were carried out to study the association between RAS genes and EH. Frequencies for the DD, ID and II genotypes were 27, 47 and 29 in hypertensive subjects, and 15, 60 and 48 in normotensive subjects, respectively. Derived allele frequencies for the I and D alleles were 0.51 and 0.49 in hypertensive subjects and 0.64 and 0.36 in normotensive subjects. There were significant differences in genotype distribution and derived allele frequency between these two groups. The genotype and allele frequencies of the ACE gene differed significantly between hypertensive and normotensive females (p>0.05), but there were no differences in males. In females, the DBP and MAP level were significantly higher for the DD than for the ID and II genotype, and SBP was significantly higher for the DD than for the II genotype. But in males, there were no significant differences in blood pressure among ACE genotypes. The results showed a significant association between the D allele of the ACE gene and hypertension in Tibetan women but not in Tibetan men. (Hypertens Res 2002; 25: 481-485)
TL;DR: Treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity, and the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated.
Abstract: The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(NG-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity. (Hypertens Res 2002; 25: 365-371)
TL;DR: A convincing cross-sectional inverse association between dietary protein intake and BP was demonstrated by the meta-analysis of nine population-based studies, and the evidence from longitudinal epidemiological studies was limited.
Abstract: The purpose of this study was to address the association between dietary protein intake and blood pressure (BP) by combining information from all epidemiological studies that presented quantitative estimates of dietary protein intake and BP assessment. A literature search of MEDLINE, restricted to human studies on dietary protein intake and BP, was conducted. References cited in related studies were also reviewed. The results were as follows. 1) Of eleven cross-sectional studies identified, nine were suitable for quantitative pooled analysis. In men (total sample, n=19,954 for SBP, and 19,982 for DBP), the pooled regression coefficients (betas) of SBP and DBP on dietary protein intake were -0.03 (0.001) and -0.025 (0.01) (both, p<0.01). In women (n=950), the pooled betas were -0.014 (0.01) for SBP (p<0.05) and -0.021 (0.00) for DBP (p<0.01). In the studies that reported data for both sexes (n=12,716 for SBP and 12,508 for DBP), the pooled betas were -0.029 (0.01) and -0.0156 (0.00) for SBP and DBP (both p<0.01). 2) Twenty-four-hour dietary recall and 24-h urine collection were the main methods used for diet assessment, and their pooled results were consistent with the combined results for both sexes. 3) Results from two longitudinal studies showed inverse associations between dietary protein intake and BP after 3 and 7 years' follow-up. In conclusion, a convincing cross-sectional inverse association between dietary protein intake and BP was demonstrated by the meta-analysis of nine population-based studies. The evidence from longitudinal epidemiological studies was limited. Further studies will be needed to confirm the hypothesis of the inverse dietary protein-BP association.
TL;DR: The findings indicate that renal artery stenosis is common in patients with renal dysfunction and concomitant cardiovascular disease, especially in those with carotid arteries stenosis, and that a substantial difference in the length of kidneys may be a predictor of renovascular disease.
Abstract: We investigated the prevalence of renal artery disease and outcome in a cohort of atherosclerotic patients with renal dysfunction. We studied 44 consecutive patients who were older than 50 years of age, who had renal dysfunction and in whom one or more of the following atherosclerotic diseases was confirmed: cerebral infarction, coronary artery disease or peripheral vascular disease. Renal artery stenosis was assessed by gadolinium-enhanced magnetic-resonance angiography. Patients who were treated medically were prospectively followed up in our outpatient clinic and the impact of renal artery stenosis on survival was evaluated. Renal artery stenosis was found in 22 (50%) of the 44 patients. Difference in kidney length and carotid artery stenosis were identified as independent predictors of renal artery stenosis. Among the patients who were treated medically (n=42), rates of mortality were 4.4, 12.7 and 18.1 per 100 patient-years in those without renal artery stenosis, those with unilateral renal artery stenosis and those with bilateral renal artery stenosis, respectively. The mortality and renal survival curves were significantly different among these three groups. These findings indicate that renal artery stenosis is common in patients with renal dysfunction and concomitant cardiovascular disease, especially in those with carotid artery stenosis, and that a substantial difference in the length of kidneys may be a predictor of renovascular disease. Patients with renal dysfunction resulting from renal artery stenosis are at risk of death from cardiovascular disease and end-stage renal failure.
TL;DR: A patient with high arterial blood pressure of over 300/160 mmHg on admission, who had extensive MRI-documented reversible lesions throughout the whole brain, including the brainstem, thalami, basal ganglia, and cerebellum, is reported.
Abstract: In patients with hypertensive encephalopathy, brain edema is frequently distributed in the parieto-occipital white matter. We report a patient with high arterial blood pressure of over 300/160 mmHg on admission, who had extensive MRI-documented reversible lesions throughout the whole brain, including the brainstem, thalami, basal ganglia, and cerebellum. Extraordinarily severe acceleration of hypertension may be essential for the breakdown of autoregulation in the deep structures, especially in the brainstem including medulla.
TL;DR: The results suggest that increases in local Ang II formation induced by chymase-like enzymes may play important roles in the pathogenesis of aneurysmal formation.
Abstract: Aortic aneurysm is a chronic degenerative condition associated with atherosclerosis. Recent studies have revealed that angiotensin (Ang) II plays important roles in atherosclerosis. In this study, to investigate the relationship between aortic aneurysm and Ang II, we measured the activities of the angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase-like enzyme, in human aneurysmal and control aortae. Aneurysmal aortic specimens were obtained from 16 aneurysm patients and control aortic specimens were obtained from 16 patients who underwent coronary artery bypass surgery (8 patients in each group were administered ACE inhibitors). The ACE and chymase-like enzyme activities were determined using extracts from vascular tissues. Both the ACE and chymase-like enzyme activities in the aneurysmal aortae were significantly higher than those in the control aortae (p <0.01). In the patients treated with ACE inhibitors, the ACE activity in the aneurysmal aortae tended to be low, but the chymase-like enzyme activity tended to be high. In the aneurysmal aortae, the chymase-like enzyme activity in the adventitia was significantly higher than that in the intimal or medial layers (p <0.01), while differences in ACE activity were not observed. Our results suggest that increases in local Ang II formation induced by chymase-like enzymes may play important roles in the pathogenesis of aneurysmal formation. (Hypertens Res 2002; 25: 817-822)
TL;DR: It is believed that a precise understanding of the manner in which genetic variations affect hypertension can be achieved, and that clarification of the associated phenotypes will lead to the development of effective preventive and treatment strategies.
Abstract: Hypertension is considered to be a complex trait to which genetic, environmental, and demographic factors contribute interactively. Recently, molecular genetic studies have achieved remarkable success in the elucidation of causative mutations in several Mendelian hypertensive disorders in which single nucleotide polymorphisms (SNPs) disrupt the function of single genes, thereby leading to unambiguous phenotypes. It seems unlikely, however, that such a simple base-substitution is the primary mechanism in cases of essential hypertension, even if SNPs modify the relevant gene function to some extent. Despite the enormous efforts made to date, no consistent association between any of the candidate genes and essential hypertension has been established. One plausible explanation is that because individual genes play a modest role in the pathogenesis of hypertension, confounding variables, whether individual (sex, ethnic origin, etc.) or environmental, may decrease the chance of identifying a causative relation between the genes and hypertension, depending on the populations studied. Several approaches can be proposed to overcome this problem, including long-term follow-up of clinical events collected to attain sufficient phenotypic information and statistical power. With the recent advances in high-throughput genotyping techniques and bioinformatic strategies, it has become possible to perform even SNP-based genome-wide screening. At present, however, the need for identification of susceptibility genes for hypertension still poses a great and unanswered challenge. Nonetheless, we believe that a precise understanding of the manner in which genetic variations affect hypertension can be achieved, and that clarification of the associated phenotypes will lead to the development of effective preventive and treatment strategies.
TL;DR: Among employed women, work stress may increase ambulatory BP levels throughout the day, while home stress may induce additional sympathetic activation at home, and among employed women who perceive greater stress at home than at work, higher home stress levels may also elevate sleep BP levels.
Abstract: The purpose of this study was to examine the effects of self-reported perceived stress at work and home on the levels, variation and co-variation of ambulatory blood pressure (BP), pulse rate (PR) and urinary catecholamine, cortisol, and aldosterone excretion measured at work, home and during sleep in women employed outside the home. The subjects of the study were 134 women (mean age 34.4 +/- 9.6 years, range 18 to 64 years) who were employed in managerial, technical or clerical positions at the same work place. Perceived stress at work and home was self-reported on a scale from 0 (low) to 10 (high). BP, PR and the urinary rates of excretion of epinephrine, norepinephrine, cortisol and aldosterone were averaged in the daily work environment from 11 AM to 3 PM, in the daily home environment from approximately 6 PM to 10 PM, and during sleep from approximately 10 PM to 6 AM the following morning. The results showed that systolic and diastolic BP (SBP and DBP) and the rates of urinary catecholamine, cortisol, and aldosterone excretion measured in the work environment were significantly higher than corresponding measurements taken in the home environment. SBP measured at work was also positively correlated with the difference in perceived stress between work and home (p < 0.05). PR (p < 0.001) and the rate of urinary norepinephrine excretion (p < 0.05) measured in the home environment were positively correlated with stress at home. When the subjects were divided into groups based on whether the work or home environment was perceived to be most stressful, women reporting greater stress at work (n=85) had higher work SBP (p < 0.005), work DBP (p < 0.05), and sleep SBP (p < 0.005) than women who perceived the home environment to be more stressful (n=34). There were no differences in the urinary hormonal excretion rates between these perceived-stress groups. Among women with greater perceived stress at home, the home-stress score was positively correlated with sleep SBP level (r = 0.310, p < 0.05), its variation (SD of sleep SBP: r = 0.402, p < 0.01) and home pulse rate ( r= 0.414, p < 0.01). These findings suggest that among employed women, work stress may increase ambulatory BP levels throughout the day, while home stress may induce additional sympathetic activation at home. In addition, they also show that among employed women who perceive greater stress at home than at work, higher home stress levels may also elevate sleep BP levels.
TL;DR: BNP, which is synergistically increased with aging and left ventricular hypertrophy, may be an important risk marker for hypertensive cardiovascular events.
Abstract: We examined the effects of aging and hypertensive left ventricular hypertrophy on the plasma level of brain natriuretic peptide (BNP), and assessed BNP as a risk marker for incident hypertensive cardiovascular events. One hundred and eighty-five hypertensive patients were echocardiographically divided into a hypertensive group with normal left ventricular mass (n =96; age range, 37-86 years; left ventricular mass, 97±14 g/m2) and a hypertensive group with left ventricular hypertrophy (n =89; 37-90 years; 140±20 g/m2). Forty-four normotensive subjects served as the normotensive group (32-84 years; 91±15 g/m2). We examined the association of age with BNP in the three groups and also evaluated BNP as a risk marker for incident cardiovascular events by following up all patients for 40 months. All three groups demonstrated a significant positive relationship between age and BNP. The slope of the relation between age and BNP was steepest in the hypertensive group with left ventricular hypertrophy (p <0.0001 vs. the other two groups). Multiple regression analysis revealed that age, pulse pressure and left ventricular mass index were significantly associated with the increase in BNP. Multivariate Cox proportional hazards regression analysis, which was used to assess the potential association of age, pulse pressure, left ventricular mass index and BNP with the cardiovascular events during follow-up, revealed the highest correlation between BNP and incident cardiovascular events (risk ratio=1.011; p =0.0011). BNP, which is synergistically increased with aging and left ventricular hypertrophy, may be an important risk marker for hypertensive cardiovascular events. (Hypertens Res 2002; 25: 669-676)
TL;DR: The clustering characteristics and the significance of heritability estimation for these metabolic variables indicate that IRS is familial in nature and heritable in Chinese and Japanese hypertensive families.
Abstract: The clustering between hypertension and other metabolic abnormalities related to insulin resistance syndrome (IRS) has been investigated in cross-sectional and prospective studies. Offspring studies have revealed that the clustering characteristics of IRS have familial components. However, it is not known whether the clustering also occurs in siblings (sibs) with different levels of blood pressure (BP). In addition, the genetic susceptibility accounting for the clustering in hypertensive families has not been determined. Siblings with Japanese or Chinese ancestry and having either similar BP levels (concordant sibs) or different BP levels (discordant sibs) were recruited. The delta method and variance component model were applied to analyze the differences in metabolic variables between hypertension (HTN) and low BP (LBP) sibs, and to compute the polygenic heritabilities for these metabolic variables and insulin sensitivity. After adjustment for age, gender and body mass index (BMI), HTN (n=393) sibs had higher levels of triglyceride (p < 0.0001), VLDL-cholesterol (p<0.0001), fasting insulin (p < 0.05), and homeostasis model assessment of insulin resistance (HOMAir) (p < 0.05) than LBP sibs (n = 389), but there were no differences in fasting glucose or high density lipoprotein (HDL)-cholesterol. The HTN sibs also had higher plasma glucose and insulin levels at 2 h after 75 g oral glucose loading (p<0.001 and p<0.01, respectively). The heritability estimates for fasting glucose, fasting insulin and HOMAir were 0.58, 0.43 and 0.46, respectively; for triglyceride, HDL-cholesterol, and BMI they were 0.60, 0.63 and 0.54, respectively. In hypertensive families, sibs with extreme levels of BP have significant differences in IRS-associated metabolic variables. The clustering characteristics and the significance of heritability estimation for these metabolic variables indicate that IRS is familial in nature and heritable in Chinese and Japanese hypertensive families.
TL;DR: The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity.
Abstract: We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg⁄kg⁄day) from 12 to 24 weeks of age. Systolic blood pressure (BP) and heart rate were measured every week after the treatment using the tail-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BP, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity. (Hypertens Res 2002; 25: 117-124)
TL;DR: The identification of differentially expressed genes may not be an efficient method for selecting candidate genes for hypertension in the SHR-WKY system because of the weak correlation between these genes and hypertension.
Abstract: We identified genes that were differentially expressed between spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using cDNA microarray analysis, and analyzed the correlation between these genes and hypertension. Twenty four genes were found to be up-regulated and 20 were down-regulated in SHR. We selected 11 genes (6 up-regulated genes: SAH, Hsp70, MCT1, RBP, IDI1, Prion; and 5 down-regulated genes: Thrombin, Dyn, SOD3, Ela1, Gst Y(b)) and subjected them to an F2 cosegregation analysis. One hundred five F2 rats were obtained from the same strains used for microarray analysis, and blood pressure was measured directly with a catheter implanted in the femoral artery. The genotypes of monocarboxylate transporter 1 and glutathione S-transferase Y(b) subunit significantly affected diastolic blood pressure in F2 rats, and these two genes are located near each other on chromosome 2. However, quantitative trait loci (QTL) analysis in this region revealed that the QTL for diastolic blood pressure were from these two genes. Antihypertensive treatment with either enalapril or hydralazine only affected the expression level of Hsp70, which was up-regulated by hydralazine, probably through compensatory sympathetic activation. We were unable to associate the other 10 genes with hypertension in SHR. Based on these results, the identification of differentially expressed genes may not be an efficient method for selecting candidate genes for hypertension in the SHR-WKY system.
TL;DR: It is suggested that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus anARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function.
Abstract: Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection. We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker (CCB) plus an angiotensin II receptor blocker (ARB) or an angiotensin converting enzyme inhibitor (ACE-I) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension. After a 12-week dietary control period, diabetic patients with mildly to moderately impaired renal function were randomly assigned to either a CCB (amlodipine 5 mg once daily) or an ACE-I (temocapril 2 mg once daily) for 12 weeks (monotherapy period). Both groups then received add-on therapy with an ARB (candesartan 4 mg once daily) for an additional 12 weeks. During the monotherapy period, blood pressure was decreased equally well in both groups. Daily urinary protein excretion remained unchanged in the CCB-treated group (control period, 4.0 +/- 1.8 g/day vs. CCB period, 4.1 +/- 1.9 g/day; ns; n = 8), but decreased in the ACE-I-treated group (control period, 4.3 +/- 1.8 g/day vs. ACE-I period, 3.5 +/- 1.7 g/day; p < 0.05; n = 9). After the combined therapy period, blood pressure was decreased to the same degree in both groups. Although ARB plus CCB significantly reduced urinary protein excretion (to 3.5 +/- 1.5 g/day; p < 0.05 vs. control period; n = 8), a more profound reduction was achieved with ARB plus ACE-I (to 2.6 +/- 1.3 g/day; p < 0.01 vs. control period; n = 9). Monotherapy with the ACE-I increased the serum potassium concentration, and this elevation was sustained after addition of the ARB. In contrast, the serum potassium concentration was not influenced by monotherapy with the CCB, but was significantly increased after addition of the ARB. A decreased hematocrit was observed in the ARB plus ACE-I group. The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function. Although the latter combination had a more profound effect, it was associated with an increased serum potassium concentration and worsening of renal anemia. Thus, the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy. The long-term efficacy of these combined antihypertensive therapies will need to be further addressed in a future study.