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Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

Objective:The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial.Methods:Japanese hypertensive patients age

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (P =0.38). In summary, blood pressure targets of

High heart rate and chronic kidney disease (CKD) are both risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and the risk of developing CKD, however, has not been studied in a large screened cohort.We examined the relationship between heart rate and the risk of developing CKD in participants in a health evaluation program. CKD was diagnosed as glomerular filtration rate of less than 60 mL/min/1.73 m(2), calculated using the Modification of Diet in Renal Disease (MDRD) study equation or dipstick proteinuria. Among 7,958 subjects, 1,199 subjects diagnosed with CKD or with arrhythmia at baseline examination were excluded. A total of 6,759 subjects (4,268 men, 2,491 women, 20-84 years of age) were evaluated. The subjects were quadrisected according to baseline heart rate. The subjects were followed up for a mean of 47 +/- 16 months (range 7-71 months). Seven hundred and thirty-four subjects developed CKD over the 5-year follow-up period. Subjects with a high heart rate had greater magnitude of decreasing glomerular filtration rate (eGFR) and higher odds ratio of developing proteinuria. Cox analysis indicated that each heart rate category increment led to approximately 1.1 times increase in the risk of developing CKD, eGFR less than 60 mL/min/1.73 m(2), and 1.2 times increase of the risk of developing proteinuria in middle-aged or older subjects.High heart rate is a risk factor for developing CKD in middle-aged or older subjects.

High heart rate and metabolic syndrome are risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and risk of developing metabolic syndrome has not been studied in a large cohort. We examined the relationship between heart rate and the risk of developing metabolic syndrome in individuals who participated in a health evaluation program from 1997 to 2002. Among the 7958 individuals who participated in the program, 1677 were excluded from our study because they were being treated for heart disease or had been diagnosed with metabolic syndrome at baseline examination. A total of 6281 individuals (3789 men and 2492 women, 20-89 years of age) were evaluated. They were categorized according to their baseline heart rate and were followed up for a mean of 47+/-16 months (range: 7-71 months). Over the 5-year period, 619 individuals (9.9%) developed metabolic syndrome. Men with elevated baseline heart rates were more likely to experience metabolic syndrome than were those with normal heart rates. This was not true for female patients. The odds ratio (95% confidence interval) of developing metabolic syndrome among men in the highest quartile for heart rate was 1.725 (1.282-2.320) compared with those in the lowest quartile. Each increase in the heart rate category led to an approximately 1.2-fold increase in the risk of developing metabolic syndrome for men only, even after adjusting for age and lifestyle. Elevated heart rate is a risk factor for developing metabolic syndrome in men.

Obesity and metabolic syndrome are risk factors for the development of chronic kidney disease (CKD). Few studies have examined the effect of change in body mass index (DeltaBMI) on CKD incidence in a general screening setting.Subjects of this study were screenees that participated in the screening program of the Okinawa General Health Maintenance Association in 1993 and 2003 in Okinawa, Japan. Using identification number, birth date, sex, and other recorded identifiers, we identified 33,389 subjects among the 1993 screening participants (N = 143,948) who also participated in the 2003 screening. CKD was defined as estimated glomerular filtration rate60 ml/min/1.73 m(2), according to the modification of diet in renal disease study equation. Obesity was defined as BMIor = 25 kg/m(2).CKD prevalence was 13.8% in 1993 and 22.4% in 2003. The incidence of developing CKD in 10 years was 15.5%. The effect of DeltaBMI on CKD incidence was evaluated after considering other confounding factors such as age, sex, blood pressure, BMI, fasting plasma glucose, and proteinuria. Median DeltaBMI was 1.0%. The adjusted odds ratio (95% CI) for the effect of DeltaBMI on CKD incidence was 1.111 (1.026-1.204, P0.01; entire study population), 1.271 (1.116-1.448, P = 0.0030; men), and 1.030 (0.931-1.139, NS; women), when DeltaBMIor = 1% was taken as a reference. DeltaBMI was an independent predictor of CKD incidence.The present results suggest that there was an inverse relationship between DeltaBMI and CKD incidence among screened subjects. The reasons for this observation are not clear, but careful follow-up for DeltaBMI is necessary, particularly in obese men with proteinuria.

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being

Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of I(f) channel produced by HCN4 in a computer simulation model and found that the I(f) channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the I(f) channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.

Cardiac involvement is a rare complication with thromboangiitis obliterans (TAO). We report a 29-year-old man with TAO accompanied with non-ischemic dilated cardiomyopathy. He had no history of heart disease, but echocardiogram demonstrated diffuse hypokinesis and dilated left ventricle. Coronary angiography revealed no organic stenotic lesion. For limb salvage, he was treated with granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cell (PBMNC) implantation on his right leg. Not only ischemic leg symptoms, but also plasma level of BNP and ^I-metaiodobenzylguanidine scintigraphic parameters improved after 24 weeks. G-CSF-mobilized PBMNC implantation could be an effective approach to treating non-ischemic cardiomyopathy., 論文

Background Increased heart rate (HR) and metabolic syndrome are risk factors for cardiovascular morbidity and mortality, but their relationship has not been studied in a large, screened cohort. Methods and Results The association between HR and multiple risk factor syndrome, resembling metabolic syndrome, was examined in participants of a health evaluation program in 1997. Of the 8,432 subjects (5,223 males, 3,209 females, 18‐89 years of age), 1,502 (1,185 males, 317 females) were diagnosed with multiple risk factor syndrome and these subjects had higher HR than those without the syndrome (p

Buckground A higher heart rate (HR) is associated with cardiovascular morbidity and mortality. Hypertension is an important cardiovascular risk factor. The present study evaluated whether a higher HR was associated with the development of hypertension in normotensive, screened subjects. Methods and Results Among normotensive participants of a 1-day health evaluation in 1997, we studied those who also participated in the program in 2000 (n=4,331; 2,823 men (65%), 1,508 women; mean age 47±9 years). Subjects were divided into 4 groups based on their HR in 1997: quartile 1 (HR ≤58, n=1,033), quartile 2 (59≤HR ≤64, n=1,162), quartile 3 (65≤HR ≤70, n=1,012), and quartile 4 (HR ≥71, n=1,124). The 3-year frequency of developing hypertension in 2000 was 4.5% for quartile 1, 6.8% for quartile 2, 6.0% for quartile 3, and 7.2% for quartile 4 (p=0.0424). Subjects with a higher HR were likely to have a greater number of metabolic syndrome components and a higher incidence of proteinuria. In a logistic regression analysis adjusted for gender, age, alcohol consumption, exercise, atherosclerotic risk factors, and lifestyle, the odds ratios (95% confidence intervals) for the development of hypertension were 1.53 (1.04-2.24) for quartile 2, 1.35 (0.90-2.02) for quartile 3, and 1.61 (1.10-2.37) for quartile 4, compared with quartile 1 as a reference. Conclusion A higher HR was associated with the development of hypertension. Subjects with a higher HR should be followed carefully, even if they are normotensive. (Circ J 2007; 71: 1755 - 1760)

There are no known predictors of renal dysfunction, particularly for a community-based screening. We evaluated the changes in serum creatinine (SCr) and glomerular filtration rate (GFR) among screenees who participated in the screening program of the Okinawa General Health Maintenance Association both in 1983 and 1993. A total of 4,662 screenees at least 30 years of age at the 1983 screening were analyzed to examine whether they developed high SCr (>or=1.4 mg/dl for men, >or=1.2 mg/dl for women) or low GFR (

To compare the risk factor demographics and the prevalence of chronic kidney disease (CKD), we analyzed two databases from the 1993 (N=143,948) and 2003 (N=154,019) mass screenings in Okinawa, Japan (Okinawa General Health Maintenance Association registry). We estimated the glomerular filtration rate (GFR) using serum creatinine (SCr) levels. SCr was measured by the modified Jaffe method in 1993 and by enzyme assay in 2003; the relation between the two methods was: SCr (Jaffe) = 0.194 + 1.079 x SCr (enzyme). CKD prevalence was compared using the estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. SCr was measured in 66.2% (1993) and 69.8% (2003) of the total screenees. Proteinuria was present in 3.4% (1993) and 4.3% (2003) of the total screened population, respectively. The prevalence of CKD (GFR60 ml/min/1.73 m(2)) was similar between the two databases, being 15.7% in 1993 and 15.1% in 2003. However, the demographics of the CKD risk factors changed during the study period. The mean level of systolic blood pressure decreased, whereas the prevalence of obesity and the mean levels of serum cholesterol and fasting plasma glucose increased. In 2003, the estimated prevalence of metabolic syndrome in the general population of Japan calculated using the modified National Cholesterol Education Program (NCEP) criteria was 19.1%. The prevalence of CKD was significantly associated with that of metabolic syndrome: the age- and sex-adjusted odds ratio was 1.332 (95% confidence interval [CI], 1.277-1.389; p0.0001). In conclusion, the demographics of the participants of the general screenings in Okinawa, Japan differed between the 1993 and 2003 screenings, but the prevalence of CKD seemed to be similar, or at least did not increase substantially, between the two databases.

A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain renin-angiotensin system (RAS) in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WKY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least partly mediated by the brain RAS.

A high plasma aldosterone concentration (PAC) is known to be associated with poor outcome in patients with cardiac disease. However, the prognostic value of PAC in chronic hemodialysis (HD) patients is unknown. In 1996 we examined 128 hypertensive patients treated with antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, who were undergoing chronic HD (ages 61.8+/-13.8 years, 62% male), and for whom PAC (ng/dl) data were obtained. We followed up these patients until November 2003. During the follow-up period, 30 patients died. About half of all patients (48%) had PAC values above the normal range. We assigned the 128 patients to a lower (22.9) or higher (or = 22.9) PAC group according to the median baseline PAC. The survival rate as calculated by the Kaplan-Meier method was 90.6% in the higher PAC group and 62.5% in the lower PAC group (p=0.003). In multivariate analysis, serum potassium and plasma renin activity were independent determinants of PAC. Cox proportional hazards analysis, with adjustment for other variables including diabetes, showed that lower PAC was independently predictive of death. The adjusted hazard ratio (95% confidence interval) of the lower PAC group was 2.905 (1.187-7.112, p=0.020). The significance of PAC became marginal by adjustment with albumin or potassium. These results indicate that higher PAC is common, but not associated with an increase in total and cardiovascular deaths among hypertensive patients undergoing chronic HD. The association between lower PAC and poor survival may be driven by volume retention and/or lower potassium.

We evaluated the relationship between admission blood pressure (BP) and early prognosis in patients with acute stroke in a single cohort.The subjects comprised 1004 cases of brain infarction and 1097 cases of brain hemorrhage, who were admitted to hospitals on the day of stroke onset. Death within 30 days after onset was evaluated in relation to admission BP levels.In brain infarction, a U-shaped relationship was found between BP levels and mortality rate, with a nadir at systolic blood pressure (SBP) of 150-169 mmHg and at diastolic blood pressure (DBP) of 100-110 mmHg. After adjustments for age and sex, the highest relative risks (RR) was observed in the lowest BP levels compared with nadir groups, and were 2.69 [95% confidence interval (CI), 1.43-5.07] in SBP and 3.49 (95% CI, 1.58-7.74) in DBP. In subjects with previous hypertension, the relationship between prognosis and SBP level shifted significantly toward higher pressure by about 10 mmHg compared with those without previous hypertension. In subjects with brain hemorrhage, the relationship between BP levels and mortality rate showed a J-shape in SBP and a U-shape in DBP. Highest BP levels had the poorest prognoses (/= 230 mmHg in SBP, RR = 4.13, 95% CI = 2.45-6.94;/= 120 mmHg in DBP, RR = 1.83, 95% CI = 1.11-3.04).Lower and higher BP after brain infarction and higher BP after brain hemorrhage were predictors for poor early prognosis. In subjects with brain infarction, patients with previous hypertension had better outcomes at higher admission BP level than did normotensive patients.

Aims Left ventricular (LV) hypertrophy and LV diastolic dysfunction are cardiac changes commonly observed in patients with chronic renal failure (CRF) as well as hypertension. Although the impairment of LV diastolic function in patients with diabetes mellitus has been shown, little is known about the specific effect of diabetes on LV diastolic function in patients with CRF. The present study was designed to investigate the impact of diabetic nephropathy on LV diastolic dysfunction, independent of LV hypertrophy, in CRF patients. Methods In 67 patients with non-dialysis CRF as a result of chronic glomerulonephritis (n = 33) or diabetic nephropathy (n = 34), and 134 hypertensive patients with normal renal function, two-dimensional and Doppler echocardiographic examinations were performed, and LV dimension, mass, systolic function, and diastolic function were evaluated. Results LV mass was increased and LV diastolic dysfunction was advanced in subjects with CRF compared with hypertensive controls. In the comparison of echocardiographic parameters between the two groups of CRF patients, i.e. chronic glomerulonephritis and diabetic nephropathy groups, all indices of LV diastolic function were more deteriorated in the diabetic nephropathy group than in the chronic glomerulonephritis group, although LV structure including hypertrophy and systolic function did not differ between the groups. In a multiple regression analysis, the presence of diabetes (i.e. diabetic nephropathy group) was a significant predictor of LV diastolic dysfunction in CRF subjects, independent of other influencing factors such as age, blood pressure, renal function, anaemia and LV hypertrophy. Conclusion The present findings suggest that LV diastolic dysfunction, independent of LV hypertrophy, is specifically and markedly progressed in patients with CRF as a result of diabetic nephropathy.

Disturbances in lipid metabolism are often observed in patients with renal failure and could be a risk factor for end-stage renal disease (ESRD). However, few studies have examined abnormal lipid metabolism as a risk factor for the development of ESRD in the general population.We examined the cumulative incidence of ESRD based on the results of a community-based mass screening in Okinawa, Japan, which was conducted in 1993 by the Okinawa General Health Maintenance Association. Screenees who developed ESRD by the end of 2000 were identified through the Okinawa Dialysis Study registry.Total cholesterol (TC) data were available for 133,338 (92.6%) of the total 143,948 screenees) and triglyceride (TG) data were available for 132,094 (91.8%). Dyslipidemia was defined as TCor = 220 mg/dl or TGor = 150 mg/dl. The cumulative incidences of ESRD, per 1000 screenees, were 1.12 for those without dyslipidemia and 2.53 for those with dyslipidemia. The adjusted hazard ratio (95% confidence interval) for dyslipidemia was 0.856 (0.484-1.516) for men and 1.260 (0.661-2.400) for women; neither was significant when adjustment was made for age, systolic blood pressure, diastolic blood pressure, body mass index, creatinine clearance, diabetes mellitus, and proteinuria.The present study showed dyslipidemia to be an insignificant predictor of development of ESRD in the general Okinawa population.

The number of diabetic dialysis patients is increasing worldwide. Only a few studies, however, have examined the effect of diabetes mellitus (DM) as a risk factor for the development of end-stage renal disease (ESRD) in the general population. We examined the cumulative incidence of ESRD based on the results of community-based mass screening in Okinawa, Japan, performed in 1993 by the Okinawa General Health Maintenance Association. Fasting plasma glucose (FPG) data were available for 78 529 screenees (37 197 men and 41 332 women). DM was diagnosed when the FPG was 126 mg/dl or more. Screenees who developed ESRD by the end of 2000 were identified through the Dialysis Registry, Okinawa Dialysis Study. The mean (SD) FPG was 96.5 (22.8) mg/dl, ranging from 45 to 577 mg/dl. The prevalence of DM among the screenees was 4089 (5.2%). A total of 133 screenees (82 men and 51 women) developed ESRD during the 7.75-year study period. The adjusted odds ratio (95% confidence interval [CI]) in the high-FPG group for the risk of developing ESRD was 3.098 (95% CI, 1.738–5.525; P = 0.0001), when adjusted for age, sex, systolic blood pressure, diastolic blood pressure, body mass index, total cholesterol, triglyceride, hematocrit, serum creatinine, hematuria, and proteinuria. The results of the present study indicated that FPG is a significant, independent predictor of ESRD. FPG and proteinuria measurements are euqally important in detecting individuals at high risk for developing ESRD.

Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.

Electron-beam computed tomography (EBCT) is a noninvasive measure of coronary artery calcification and, therefore, could be a marker of developing cardiovascular disease. Whether the coronary artery calcification score (CACS) is a prognostic marker in chronic dialysis patients is not known.In the present study, the mortality rate was observed in relation to the baseline CACS. EBCT was performed in 104 chronic hemodialysis patients (62 men and 42 women) in one dialysis unit. The mean (SD) duration of hemodialysis was 48.7 (62.6) months at the time of EBCT. The mean (SD) age at EBCT was 55.9 (13.6) years, ranging from 23 to 88 years. The duration of follow-up was 43.8 (19.3) months after the EBCT. Cox proportional hazard analysis was performed to examine the impact of CACS on survival after adjusting for age, sex, duration of dialysis, diabetes mellitus, hypertension, serum albumin, and dyslipidemia.The CACS was distributed from zero to 5896, with a median of 200. During the study period, 24 patients (15 men and 9 women) died, 7 in the low CACS group (200) and 17 in the high CACS group (or =200). The 5-year cumulative survival rate was 84.2% in the low CACS group and 67.9% in the high CACS group. The adjusted relative risk (95% confidence interval) of death was 1.001 (1.000-1.002); P = 0.0003, for the absolute value of CACS.The present study suggested that CACS was an independent predictor of death in patients on chronic hemodialysis. Patients with a high CACS should be carefully monitored and evaluated for reversible prognostic factors such as dyslipidemia and, probably, hyperphosphatemia and a high value for the calcium x phosphate product.Electron-beam computed tomography (EBCT) is a noninvasive measure of coronary artery calcification and, therefore, could be a marker of developing cardiovascular disease. Whether the coronary artery calcification score (CACS) is a prognostic marker in chronic dialysis patients is not known.

Several epidemiological studies have shown a positive association between serum uric acid levels and the risk of hypertension. However, subjects in these studies were mostly men, or were incompletely examined for lifestyle-related variables. We prospectively examined the relation between hyperuricemia and the risk of developing hypertension with consideration for alcohol consumption and smoking habits in a large screened cohort of men and women. A total of 4,489 individuals (2,927 men and 1,562 women) who did not have hypertension and were not currently using antihypertensive medication were examined at the Okinawa General Health Maintenance Association in 1977. Subjects were re-examined in 2000. Hyperuricemia was defined as a serum uric acid level >or=7.0 mg/dl in men and >or=6.0 mg/dl in women. Hypertension was defined as systolic blood pressure (SBP) >or=140 mmHg, and/or diastolic blood pressure (DBP) >or=90 mmHg. A total of 289 subjects (201 men and 88 women) were hypertensive (SBP >or=140 mmHg, and/or DBP >or=90 mmHg) in 2000. Multivariate analysis was performed for development of hypertension in hyperuricemic subjects, adjusted for age, family history of hypertension, alcohol consumption, cigarette smoking, obesity, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein cholesterol, and diabetes mellitus. The adjusted odds ratio (95% confidence interval) in men was 1.48 (1.08-2.02) and in women was 1.90 (1.03-3.51) (p

The Determinants of the prescribed dialysis dose have not been well studied in a large patient population. Few studies have examined survival rates after adjusting for dose determinants.Data were obtained from a cohort of chronic hemodialysis patients for the period January 1991 through December 2000. The prescribed dialysis dose was calculated as the dialyzer membrane area (m2) times session hours, and was expressed as m2h per week. Determinants of the prescribed dialysis dose were examined by multivariate logistic regression analysis of baseline clinical and laboratory variables. Survival curves for each prescribed dose were calculated by the Kaplan-Meier method. Cox proportional hazards analysis was used to evaluate differences in the survival curves after adjusting for confounding variables. The delivered dose of dialysis, Kt/V, was calculated in a subgroup of the cohort.For 1041 patients receiving thrice-weekly dialysis, the mean (SD) dialysis dose was 19.8 (5.8) m2h/week (range, 6.3 to 33.0 m2h/week). The significant and independent determinants of prescribed dialysis dose were sex, age, diabetes mellitus (DM), body mass index (BMI), serum albumin, diastolic blood pressure, serum creatinine, duration of dialysis, and comorbidity. The dialysis dose received by women and patients with DM was relatively low, even when adjusted for BMI ( P0.01 for both). During the follow-up period, 463 patients died, 60 underwent renal transplant, and 10 were transferred away from Okinawa. The hazard ratio (95% confidence interval) for death was 1.016 (0.995-1.037; not significant) for the dialysis dose (m2h/week) after adjustment for multiple confounding factors. The mean (SD) Kt/V was 1.31 (0.28). The hazard ratio (95% confidence interval) for Kt/Vor = 1.31 vs Kt/Vor = 1.30 was 0.706 (0.553-0.900; P = 0.0049).The prescribed dialysis dose did not significantly influence mortality in our cohort. Empirically based prescription practice, such as increasing the prescribed dialysis dose in male patients, when the BMI is large, or when serum creatinine or diastolic blood pressure is high may explain the relatively good prognosis of chronic hemodialysis patients in Japan.

Blood pressure as a risk factor for development of end-stage renal disease has not been fully studied, particularly in women. We studied the development of end-stage renal disease from 1983 through 2000 in 98 759 subjects, 46 881 men and 51 878 women, 20 to 98 years of age, who were screened in 1983 in Okinawa, Japan. Data for all dialysis patients registered from 1983 to 2000 in Okinawa were used to identify the screened subjects in whom end-stage renal disease developed. In follow-up, 400 subjects, 231 men and 169 women, had end-stage renal disease. Age, body mass index, and adjusted relative risk for systolic and diastolic blood pressure for both men and women were measured. When these results were compared with an optimal blood pressure, the relative risk of development of end-stage renal disease for those with high-normal blood pressure and hypertension were significant in both men and women. Hypertension is a significant risk factor for development of end-stage renal disease not only in men but also in women. Control of blood pressure within normal levels should be stressed as a strategy to prevent end-stage renal disease in both men and women.

Background. Atherosclerosis and vascular calcification are common in chronic haemodialysis (HD) patients, and usually progress with time. Whether the length of dialysis treatment in chronic HD patients is a significant independent risk factor of death is not clear. Methods. A cohort of chronic HD patients from the Okinawa Dialysis Study, ii = 1243(720 men. 523 women), was followed from January 1991 to December 2000, and their survival rates were compared against the duration of HD, which was calculated in months from the start of dialysis therapy to January 1991. A Cox proportional hazards regression analysis was done to examine the influence of the duration of dialysis on survival, after adjusting for other factors such as age, sex. serum albumin concentration and diastolic blood pressure. The hazards ratio and 95% confidence interval (CI) were calculated in both diabetic and non-diabetic patients. Results. The mean duration of dialysis was 61.9 months and ranged from 1 to 233 months. The numbers of patients who died, underwent renal transplantation or were transferred outside Okinawa were 568 (45.7%). 61 (4.9%) and 14 (1.1%), respectively. during the study. The hazards ratio (95% Cl) was 1.002 (1.000. 1.004, P=0.0245) for non-diabetic patients and 1.006 (1.001 1.011, P=0.0214 for diabetic patients, suggesting that the longer the duration of dialysis, the greater the risk of death. Conclusions. This study shows that prolonged dialysis is a significant predictor of death in chronic HD patients, in particular diabetic patients. Whether this is related to the progression of the atherosclerotic process or to uraemic conditions remains to be shown.

Evidence for elevated pulse pressure in patients on chronic hemodialysis: A case-control study.BackgroundFew analyses have compared pulse pressure (PP) values in hemodialysis patients with healthy individuals, and they have provided only limited data. We retrospectively examined PP in a large cohort of hemodialysis patients and healthy control subjects.MethodsThe relationships of systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP to mean arterial pressure (MAP) levels were investigated in 234 chronic hemodialysis patients and in 682 control subjects matched for age, sex, diabetes mellitus, and body mass index.ResultsIn both control and patients, PP was positively correlated with MAP, and the two regression lines were parallel (beta of control subjects = 0.52; beta of hemodialysis patients = 0.57, P = 0.48). According to the regression line, at any MAP level, the PP in hemodialysis patients was significantly higher than that in control subjects: the mean PP difference between control and patients was 19.2mm Hg (95% CI, 17.2 to 21.1mm Hg, P < 0.0001). When the relationships between MAP and SBP and that between MAP and DBP were analyzed, the regression lines were also parallel. However, at any MAP level, SBP was higher and DBP was lower in hemodialysis patients than control subjects; the mean SBP difference was 12.8mm Hg (95% CI, 11.5 to 14.1mm Hg, P < 0.0001) and mean DBP difference was 6.4mm Hg (95% CI, 5.7 to 7.0mm Hg, P < 0.0001).ConclusionsAt any MAP level, hemodialysis patients had a higher SBP, lower DBP, and higher PP values than those control subjects with a normal renal function who were matched for age, sex, diabetes mellitus, and body mass index. Further study is needed to determine whether preventing or reducing an elevated PP improves the prognosis for hemodialysis patients.

Triglyceride, but not total cholesterol or low-density lipoprotein cholesterol levels, predict development of proteinuria. Background Epidemiological data about the relationship between dyslipidemia and proteinuria are sparse. We conducted a retrospective and longitudinal study in a large screened cohort to evaluate whether triglyceride, high-density lipoprotein (HDL) cholesterol, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels increase the risk of development of proteinuria and loss of renal function. Methods Post hoc analysis was performed for 4326 subjects who were free from proteinuria (dipstick 1+ or higher) at baseline (1997) with a follow-up period through 2000. Outcome measures were the development of proteinuria (1+ or higher) and change in glomerular filtration rate (GFR). Multiple logistic analysis and multiple regression analysis were used to analyze baseline characteristics related to the outcome measures. Results During the observational period, 505 (11.7%) of subjects had one or more episodes of proteinuria (≥1+). Adjusted relative risk of triglycerides for one or more incidences of proteinuria was 1.007 (95% CI 1.000 to 1.105, P = 0.04) in men and 1.032 (95% CI 1.004 to 1.061, P = 0.02) in women. Total cholesterol, HDL cholesterol, and LDL cholesterol were not significant predictors of proteinuria. The mean change in GFR between 1997 and 2000 was -6.3 (SD = 9.0) mL/min/1.73 m 2 in men, and -7.8 (SD = 10.7) mL/min/1.73 m 2 in women. HDL cholesterol (β = 0.04, t=3.7, P = 0.0002) in men and triglycerides (per 10 mg/dL, β = -0.09, t=-2.2, P = 0.02) in women were correlated with the change in GFR. Conclusions High triglyceride levels predicted a risk of developing proteinuria in both men and women, but not total cholesterol nor LDL cholesterol. High triglyceride in women and low HDL cholesterol in men predicted the decline of renal function. It remains to be determined whether prospective treatment of dyslipidemia will protect against renal injury.

Background. Information concerning medication use in Asian haemodialysis patients is sparse. We surveyed prescribed medications and examined the relation between the number of medications and mortality and clinical characteristics in chronic haemodialysis patients, in Okinawa, Japan. Methods. We conducted a cross-sectional multicentre survey in August 1999 and patients were observed during 13 months of follow up. Results. The clinical demographics of 850 chronic haemodialysis patients in seven dialysis units were obtained. Compared with the mean number of medications prescribed in ambulatory patients treated in general practice reported from Ministry of Health and Welfare of Japan (2.7 (n=20716)), the mean number medications in haemodialysis patients was larger (7.2 (n = 850)). The three most prescribed drug types in haemodialysis patients were those related to calcium and phosphate metabolism (88%), antihypertensive agents (71%), and erythropoietin (60%). Among the 850 patients, 38 died during the 13-month follow-up period. The number of medications was positively associated with mortality after adjusting for age, sex, and other clinical factors: the hazard ratio was 1.14 (95% confidence interval 1.03-1.26, P=0.007). A multiple linear regression analysis using the number of medications as a dependent factor and sex and other clinical characteristics as independent factors revealed that male sex (P=0.04), diabetes mellitus (P

Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis. Background Pulse pressure (PP) has been shown as a risk factor for mortality or cardiovascular events in several studies. However, the impact of PP on prognosis in a cohort of chronic hemodialysis patients has not been sufficiently studied. We examined the effect of PP on total mortality and cardiovascular events in chronic hemodialysis patients, and whether PP adds useful value to systolic blood pressure (SBP) or diastolic blood pressure (DBP) for predicting total mortality and cardiovascular events in chronic hemodialysis patients. Methods Chronic hemodialysis patients ( N = 1243, 720 men, 523 women) alive on January 1, 1991 at baseline were involved in this study. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relation between blood pressure components and risk of death and cardiovascular events over a nine-year follow-up. Results The association with the risk of total mortality was positive for PP ( P = 0.002) and SBP ( P = 0.04), but not significant for DBP ( P = 0.4), considering each pressure individually (single blood pressure component model, SPM); of the three measurements, PP yielded the highest X 2 value. When SBP and DBP were jointly entered into the Cox regression model (dual blood pressure component model, DPM), the association with the risk of total mortality was positive for SBP (HR, 1.083; 95% CI, 1.030 to 1.137) and negative for DBP (HR, 0.886; 0.808 to 0.970). After the addition of diabetes mellitus as an adjusted variable to the model, PP was not a significant predictor for total mortality; PP was a significant predictor for total mortality in non-diabetic patients, but not in diabetic patients. PP was positively associated with the risk of stroke, and stroke and AMI; however, predictive value of PP for each endpoint was not superior to SBP and DBP in SPM. In DPM with SBP and DBP, the association with the risk of stroke and acute myocardial infarction (AMI) was positive for SBP ( P = 0.02) but not significant for DBP ( P = 0.5). In DPM with SBP and PP, the association with the risk of stroke and AMI was positive for SBP ( P = 0.01) but not significant for PP ( P = 0.5). Conclusions In non-diabetic patients on chronic hemodialysis, PP was an independent predictor of total mortality. PP was more potent predictor of total mortality than SBP or DBP. For predicting cardiovascular events, SBP was superior to PP or DBP.

The incidence of end-stage renal disease due to diabetes mellitus (DM) is increasing. There have been too few epidemiological studies of the predictors of DM nephropathy, particularly type 2 DM, among a statistically significant population. We studied the prevalence and correlates of DM in a screened cohort in Okinawa, Japan. A total of 9,914 screenees (6,163 men and 3,751 women) over 18 years of age underwent a 1-day health check at the Okinawa General Health Maintenance Association between April 1997 and March 1998. Subjects were considered to have DM if they showed a fasting plasma glucose > or = 126 mg/dl and hemoglobin A1c > or = 7.0%, or if they were receiving treatment for DM. Non-DM subjects were followed-up until March 2000 to see whether or not they developed DM. Relative risk for developing DM was evaluated by Cox proportional hazard analysis after adjusting for confounding variables. A total of 673 screenees (520 men and 153 women) were diagnosed with DM. The prevalence of DM was 67.9 per 1,000 screenees (84.4 for men and 40.8 for women). A total of 7,125 non-DM screenees were examined a second time. Among them, 164 screenees (130 men and 34 women) had developed DM during the follow-up period. Over 2 years, the cumulative incidence of DM was 2.3% (2.9% in men and 1.3% in women). The adjusted relative risk (95% confidence interval) for developing DM was highest for proteinuria, or 1.90 (1.14-3.17). The results indicated that the prevalence and incidence of DM were high among this screened cohort in Okinawa, Japan. Subjects with proteinuria may thus be at high risk for developing DM.

A family history of hypertension, obesity, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia have all been associated with risk of hypertension. We retrospectively conducted a longitudinal study in a large screened cohort to explore the effect of the clustering of these five risk factors on the elevation of blood pressure (BP) in normotensive subjects at baseline. The study group comprised 4,857 normotensive subjects not treated with antihypertensive drugs (systolic BP140 mmHg, diastolic BP90 mmHg, 3,111 men and 1,746 women) who were followed up from 1997 to 1999. By 1999, 360 subjects had BP at the hypertensive level (systolic BPor = 140 mmHg or diastolic BPor = 90 mmHg). The incidence of subjects whose BP became hypertensive was 37 per 1,000 person-years. After adjusting for age, sex, systolic BP and other clinical factors, multiple logistic analysis showed that the relative risk of BP elevation was 1.49 (95% Cl: 1.09 to 2.05) in subjects with one risk factor; 1.65 (95% Cl: 1.15 to 2.27) in those with two risk factors; 1.42 (95% Cl: 0.91 to 2.32) in those with three; and 4.86 (95% Cl: 2.58 to 9.16) in those with four or more when compared with subjects with no risk factors. Multiple regression analysis showed that the number of risk factors was positively correlated with an increase in BP from 1997 to 1999; the regression coefficient was 0.51 (p = 0.001) for increase in systolic BP, and 0.31 (p = 0.008) for increase in diastolic BP after adjusting for age and sex. In conclusion, clustering of risk factors significantly predicted the development of hypertension.

A 39-year-old man had been suffering from periodic fever since childhood. He was started on hemodialysis due to secondary amyloidosis on December 2000. The patient was believed to have Familial Mediterranean fever (FMF) because of recurrent fever with peritonitis, arthritis and inflammatory changes and secondary amyloidosis in his kidneys, heart and colon. No other family member had recurrent fever. IL-6, TNF, and dopamine β-hydroxylase were not increased in the febril phase. The patient was homozygous for the M694I mutation. We report the first Japanese case of FMF associated with amyloidosis and confirmed by a gene mutation.(Internal Medicine 41: 221-224, 2002)

We report a case of IgA nephropathy with renal failure in which the deterioration of renal function was inhibited by the addition of angiotensin II receptor blocker (ARB) losartan. Before administration of losartan, the mean decline in the patient's glomerular filtration rate (GFR) was 0.64 ml/min/1.73 m2/month. Losartan treatment was started when serum creatinine rose above 4.0 mg/dl. With this treatment the serum creatinine level has remained stable for 3.5 years, and the mean decline in GFR was 0.06 ml/min/1.73 m2/month. We document successful retardation of renal failure with the use of losartan. Our experience suggests that dialysis therapy can be delayed significantly in patients using this drug.(Internal Medicine 41: 1167-1170, 2002)

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 (

A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines. (Hypertens Res 2002; 25: 69-75)

A 40-year-old woman was referred for several episodes of coma lasting from 2 hours to 2 days. She had been on maintenance hemodialysis for polycystic kidney disease for 9 months. Laboratory findings showed high serum levels of ammonia and citrulline, and a diagnosis of adult-onset type II citrullinemia was made. Multiple areas of focal brain edema were shown by magnetic resonance imaging. The clinical manifestations of coma and abnormal behavior were resolved with intensified dialysis (ie, four 5-hour sessions per week with glycerol and continuous ambulatory peritoneal dialysis). No abnormal shadow was present on follow-up magnetic resonance imaging. Such intensified dialysis therapy may be effective for adult-onset type II citrullinemia and may be applicable even in patients who do not have end-stage renal disease if liver transplant is not an option.

Calcitonin receptor–like receptor/receptor activity–modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.

Increased heart rate (HR) is a predictor of cardiovascular mortality, so the present study used a screened cohort to investigate whether the clustering of cardiovascular risk factors is associated with increased HR. Individuals who were receiving medication for hypertension or heart disease and those who did not have an ECG record or who had a record of arrhythmia were excluded. In total, 8,508 subjects (5,299 men, 3,209 women; age range, 18-89 years) were studied. Subjects were divided into 2 HR classes using the value of mean HR+ 1 SD as the cut-off point: low HR (HR77 beats/min, n=7,320) and high HR (HRor = 77 beats/min, n=1,188). For logistic regression analysis, the dependent variable was HR class and the independent variables were the number of risk factors (ie, hypertension, diabetes mellitus, and hypertriglyceridemia each of which was associated positively with HR class by multivariate analysis). The odds ratios and 95% confidence intervals for the number of risk factors were 1.412 (1.216-1.640) for 1 risk factor, 2.800 (2.269-3.455) for 2, and 4.582 (2.815-7.459) for 3. Multivariate regression analyses showed that the number of risk factors from 0 to 3 correlated positively with high HR. HR increased significantly with clustering of risk factors even with low HR (regression coefficient was 1.147, p0.0001). Modifying the risk factors may lower HR and reduce cardiovascular mortality.

Aims The aim of the present study was to evaluate the effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension.

OBJECTIVE To clarify the role of insulin resistance and hyperinsulinaemia in the pathogenesis of obesity-related hypertension. DESIGN An open study comparing the effects of weight reduction by low-energy diet and treatment with troglitazone, an insulin-sensitizing agent. SETTING A tertiary teaching hospital. PATIENTS Thirty overweight hypertensive patients (15 men and 15 women, mean age 61 years, mean body mass index 29.1 kg/m2). INTERVENTIONS Fifteen patients were assigned to a weight-reduction programme by low-energy diet (3360 kJ/day) for 3 weeks; the remaining 15 patients were treated with troglitazone (400 mg/day) for 8 weeks. MAIN OUTCOME MEASURES Casual and ambulatory blood pressures, glucose and lipid metabolism, and insulin sensitivity. RESULTS The baseline values of body mass index, fasting and post-glucose plasma insulin, and casual and ambulatory blood pressures were comparable between the two groups. Weight reduction (4.1 +/- 0.3 kg, mean +/- SEM) was associated with significant decreases in plasma insulin, blood glucose, homeostasis model assessment (HOMA) insulin resistance index, serum triglyceride, casual blood pressure (7.7 +/- 2.3/ 3.9 +/- 1.4 mmHg) and 24 h blood pressure (8.3 +/- 1.9/ 4.3 +/- 1.1 mmHg). Treatment with troglitazone caused comparable decreases in the metabolic parameters and HOMA index, but did not change casual or 24 h blood pressure (0.8 +/- 3.4/0.8 +/- 2.1 and 1.5 +/- 2.4/ 1.0 +/- 1.9 mmHg, respectively). CONCLUSIONS Insulin resistance/hyperinsulinaemia may not have an important role in the pathogenesis of obesity-related hypertension. The antihypertensive effect of weight reduction seems to be mediated mainly by other mechanisms.

Background Dihydropyridine calcium antagonists increase heart rate due to reflex activation of the sympathetic nervous system, although these effects are less obvious for long-acting agents. Objective To study the effects of diltiazem retard, a long-acting nondihydropyridine calcium antagonist, on 24h blood pressure, heart rate and autonomic nerve activity in patients with essential hypertension. Design Randomized crossover design. Methods Thirteen patients [five men and eight women, aged 64+/-2 years (mean+/-SEM)] were administered placebo or diltiazem retard (100-200mg once daily) for 4 weeks each. Ambulatory monitoring of blood pressure and heart rate, and electrocardiography were carried out at the end of each period using a multibiomedical recorder (TM-2425). Autonomic nerve activity was evaluated by power spectral analysis of variability of heart rate using the high-frequency component as an index of parasympathetic nerve activity and the ratio of the low-frequency component and the high-frequency component as an index of sympathovagal balance. Results Treatment with diltiazem retard significantly decreased 24h average blood pressure and heart rate by 11.6+/-3.6/5.7+/-1.8mmHg and 5.0+/-1.1 beats/min, respectively. The changes in daytime and night-time values were comparable. Diltiazem retard also significantly decreased daytime and 24h low:high-frequency-component ratio (2.0+/-0.2 versus 1.7+/-0.2 and 1. 8+/-0.2 versus 1.6+/-0.2, respectively). Conclusions These results indicate that diltiazem retard is effective as a once-daily antihypertensive agent and has favorable effects on heart rate and the autonomic nervous system.

Ingestion of alcohol acutely decreases vascular resistance and blood pressure (BP) with activation of the sympathetic nervous system in Orientals. Although alpha1-blockers are widely used in the treatment of hypertension, the possible interaction between alcohol and alpha1-blockers has not been clarified. We examined the effects of prazosin on the alcohol-induced BP changes in Japanese men with mild hypertension. Ten hypertensive patients (54 +/- 3 years, mean +/- SE) were given 1 mL/kg of alcohol or isocaloric control drink with a light meal in the evening before and 5 to 7 days after treatment with prazosin (1 mg three times daily). Ambulatory BP monitoring was carried out every 30 min for 24 h in each period using Colin ABPM-630. Blood samples were obtained before and 2 h after intake of alcohol or control drink. Before prazosin treatment, alcohol ingestion decreased BP for several hours with a significant reduction in average 24-h BP, whereas it increased heart rate, plasma norepinephrine, and plasma renin activity. Treatment with prazosin caused a significant decrease in 24-h BP (136.3 +/- 4.0/82.8 +/- 2.5 v 131.6 +/- 3.2/80.0 +/- 2.3 mm Hg). The alcohol-induced hypotension at 2-4 h after ingestion was enhanced by prazosin (-18.0 +/- 3.7/-11.8 +/- 2.7 v -24.4 +/- 4.9/-17.8 +/- 2.8 mm Hg, P < .05 for diastolic BP). These results suggested that inhibition of the sympathetic nervous system with alpha1-blockers accentuates alcohol-induced hypotension. Ingestion of alcohol may cause a marked BP reduction in hypertensive Orientals treated with alpha1-blockers.

Alcohol ingestion acutely lowers blood pressure (BP) with vasodilation and sympathetic activation in Oriental subjects. We examined the effects of beta blockade on cardiovascular and neurohumoral actions of alcohol in Japanese men with mild-to-moderate essential hypertension. Ten hypertensive patients (54+/-5 years, mean+/-SE) were given 1 ml/kg of alcohol or isocaloric control drink with a light meal in the evening before and 5-7 days after treatment with propranolol (20 mg three times daily). BP and heart rate (HR) were measured every 30 min for 24 h in each period. Blood sampling and echocardiographic examination were carried out before (17.00 h) and after (19.00 h) intake of alcohol or control drink, Before treatment, alcohol ingestion caused significant decreases in BP, total peripheral resistance and serum potassium concentration, while it increased heart rate (HR), cardiac output (CO), plasma norepinephrine and plasma renin activity (PRA). Treatment with propranolol significantly decreased BP and HR for 24 h. Propranolol and alcohol showed an additive depressor effect on night-time BP, and the alcohol-induced hypotension was similar before and after propranolol treatment. The alcohol-induced changes in HR, CO, PRA and serum potassium were significantly attenuated by propranolol. These results suggest that activation of the sympathetic nervous system plays a role in alcohol-induced cardiac stimulation, renin release and hypokalemia through beta receptors. Moderate doses of beta-blockers may not modify alcohol-induced BP reduction in Oriental subjects with hypertension.

Adrenomedullin, a potent hypotensive peptide, reduces blood pressure and pulmonary vascular resistance, and increases pulmonary blood flow. The mRNA for adrenomedullin and its receptor is highly expressed in the lung, suggesting a regulatory role for adrenomedullin in the pulmonary circulation. To investigate the clinical significance of adrenomedullin in patients with pulmonary hypertension, we studied the relationship between plasma levels of adrenomedullin and pulmonary haemodynamics. Venous, arterial and pulmonary arterial blood samples were obtained during cardiac catheterization and plasma levels of adrenomedullin were measured by specific radioimmunoassay in 33 consecutive patients with severe pulmonary hypertension (12 cases of primary pulmonary hypertension, 21 with chronic thromboembolic pulmonary hypertension; age 49±16 years, mean pulmonary arterial pressure 50±15 mmHg). In addition, plasma levels of adrenomedullin were measured before and after acute nitric oxide inhalation. The changes in plasma adrenomedullin during the follow-up period of 10.3±4.3 months were also evaluated (n ;= ;5). Sixty-two healthy subjects served as the control group. Adrenomedullin was measured in an antecubital vein in the controls. Plasma levels of adrenomedullin were significantly higher in the patients with pulmonary hypertension than in the control subjects (10.1±8.7 versus 4.9±1.1 pmol/l, P< 0.01). Plasma levels of adrenomedullin, expressed as their natural logarithm, were significantly correlated with mean right atrial pressure (r ;= ;0.71, P< 0.01), stroke volume (r ;=-0.63, P< 0.01), total pulmonary resistance (r ;= ;0.60, P< 0.01), mean pulmonary arterial pressure (r ;= ;0.37, P< 0.05), and the natural logarithm of plasma atrial natriuretic peptide (r ;= ;0.63, P< 0.01). Plasma levels of adrenomedullin did not change significantly after nitric oxide inhalation, but significantly increased in association with the elevation of the total pulmonary resistance during the long-term follow-up period. These results suggest that plasma levels of adrenomedullin increase in proportion to the extent of pulmonary hypertension.

The present study investigated the secretion level and gene expression of adrenomedullin (AM), a novel vasorelaxant peptide, in cultured neonatal rat cardiac myocytes and nonmyocytes, and the effects of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) on its production and secretion in these cells. Under serum-free conditions, both myocytes and nonmyocytes secreted immunoreactive (ir-) AM into the culture medium in a time-dependent manner. The secretion rates of ir-AM from myocytes and nonmyocytes per 105 cells were almost equivalent. The expression of AM messenger RNA was also observed in cultured myocytes and nonmyocytes. The peptide secretion and messenger RNA level of AM in cardiac myocytes were increased after stimulation with IL-1β. In nonmyocytes, IL-1β and TNFα remarkably augmented both the release of ir-AM into the medium and AM gene expression after 24 and 48 h of incubation. These observations indicate that cardiac ventricular cells (i.e. myocytes and nonmyocytes) actively produce AM a...