Search

The OSCAR study was a multicenter prospective randomized study that examined the relative benefit of combined ARB (olmesartan 20 mg per day) plus calcium channel blocker (CCB) therapy vs. high-dose ARB monotherapy (olmesartan 40 mg per day) for prevention of cardiovascular events in elderly Japanese hypertensive patients. The present subanalysis of patients enrolled in the OSCAR study (n = 1078) was performed to assess whether baseline eGFR coupled with cardiovascular disease (CVD) could predict the relative benefit of these two treatments. Patients with baseline CVD (n = 769) and patients without baseline CVD (n = 309) were divided into two groups based on baseline eGFR; (i) patients with eGFR of < 60 ml min(-1) 1.73 m(-)(2) and (ii) those with eGFR of ⩾ 60 ml min(-1) 1.73 m(-2). There was a significant treatment-subgroup interaction among these four subgroups in relation to the incidence of primary outcome events(P = 0.007 for interaction). In patients with CVD and with eGFR of

The OlmeSartan Calcium Antagonists Randomized (OSCAR) study is a multicenter, prospective, randomized, open-label, blinded, end point study of elderly hypertensive Japanese patients that compared the efficacy of a high-dose angiotensin II receptor blocker (ARB) treatment to an ARB plus calcium channel blocker (CCB) combination. In this pre-specified subgroup analysis, we compared the response to such therapy according to sex. A total of 1164 patients (515 (44%) men and 649 (56%) women) were included, and each gender was split into two nearly equal treatment groups. The primary end point was a composite of cardiovascular events and non-cardiovascular death. The baseline characteristics between the two treatment groups in each sex were similar, except for some variables. Male patients had lower systolic and higher diastolic blood pressure than female patients (156.8/85.7 vs. 158.5/84.2 mm Hg). At the end of the study, the mean systolic pressure was higher in the ARB group (134.4 mm Hg) than in the ARB plus CCB group (131.5 mm Hg; P=0.03) for men but not for women (135.4 vs. 133.4 mm Hg; P=0.12). For men, the primary outcome events tended to be higher in the ARB group than in the ARB plus CCB group (hazard ratio (HR)=1.66; P=0.055) but not for women (HR=0.97; P=0.92). This difference in men was due to cardiovascular events (HR=1.86; P=0.03). The interaction between sex and treatment group was not significant (P=0.17). These findings suggest that, in addition to blood pressure control, appropriate patient risk assessment is important for the treatment of hypertension, especially in male patients, as opposed to possible sex differences in treatment effects.

Background It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. Methods The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. Results During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=. 17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=. 03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=. 14). This treatment-by-subgroup interaction was significant ( P=. 02). Conclusion The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.

Excess daily salt intake impairs vasodilatation and enhances vasoconstriction, resulting in reduction of regional blood flow and elevation of blood pressure in healthy individuals and hypertensive patients with either salt sensitivity or not tested for salt sensitivity or not evaluated for salt sensitivity. The mechanism may involve decreased production of nitric oxide via endothelial nitric oxide synthase (eNOS), impaired bioavailability of nitric oxide, and elevated plasma levels of asymmetric dimethylarginine (ADMA). Experimental animals, irrespective of salt sensitivity, although less extensive in those with salt-resistance, fed a high-salt diet have deteriorated endothelial functions; the mechanisms involved include an impairment of eNOS activation, a decrease in eNOS expression, and an increase in oxidative stress and ADMA. The imbalance of interactions between nitric oxide and angiotensin II is also involved in salt sensitivity. Deficiency of nitric oxide formed via neuronal NOS and inducible NOS may contribute to salt-induced hypertension. Reduced daily salt intake, therefore, would be the most rational prophylactic measure against the development of hypertension.

Background. For patients with hypertension, effective 24-hour blood pressure (BP) control is vital to ensure protection against the early morning surge in BP and the associated increased risk of cardiovascular events. The aim of this analysis was to assess the 24-hour antihypertensive efficacy of olmesartan medoxomil (20 mg once daily) compared with candesartan cilexetil (8 mg once daily), with particular emphasis on BP control during the early morning period.Methods. This is an additional analysis of a previously reported randomised, double-blind study in which 635 patients with mainly mild to moderate hypertension were randomised to 8 weeks of treatment with either olmesartan medoxomil 20 mg/day or candesartan cilexetil 8 mg/day. Changes from baseline during the last 4 and 2 hours of ambulatory BP measurement (ABPM) after 1, 2 and 8 weeks of treatment were compared between the two groups. In addition, the proportions of patients who achieved various ABPM goals, including those suggested by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) [Results.After 8 weeks, significantly greater proportions of patients treated with olmesartan medoxomil 20 mg achieved 24-hour and daytime ABPM goals recommended by the guidelines of the ESH/ESC (25,6 % and 18,3 %, respectively) and JSH (37,5 % and 26,6 %, respectively) compared with candesartan cilexetil 8 mg (24-hour ESH/ESC goal 14,9 %,pp=0,003; daytime ESH/ESC goal 9,6 %,p=0,002; daytime JSH goal 16,4 %,p=0,002). During the last 4 hours of 24-hour ABPM, the proportions of patients who achieved the ESH/ESC and JSH ABPM goals were significantly greater with olmesartan medoxomil (33,3 % and 39,1 %, respectively) than with candesartan cilexetil (22,9 %,pp=0,047, respectively). Similarly, during the last 2 hours of 24-hour ABPM, the proportions of patients who achieved these BP goals were either significantly greater (JSH) or approached statistical significance (ESH/ESC) with olmesartan medoxomil (26,9 % and 19,9 %, respectively), compared with candesartan cilexetil (19,6 %,p=0,028 and 14,3 %,p=0,061, respectively).Conclusion. Compared with candesartan cilexetil 8 mg, greater proportions of olmesartan medoxomil-treated patients (20 mg) achieved ESH/ESC and JSH ABPM goals over 24 hours. The superior BP control of olmesartan medoxomil was also reflected in the larger proportions of olmesartan medoxomil-treated patients who achieved the ESH/ESC and JSH ABPM goals during the early morning surge period. This not only demonstrates that olmesartan medoxomil 20 mg provides superior 24-hour BP reduction, but also suggests that olmesartan medoxomil may provide greater protection against the increased risk of cardiovascular events associated with the early morning BP surge period.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

BACKGROUND: Hypertension is an important risk factor of coronary heart disease. A new guidelines for hypertension prevention and management in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the United States recommended lifestyle modification or medical treatment for subjects with prehypertension. However, whether prehypertension increases the risk of coronary atherosclerosis in the Japanese population is still unknown. METHODS: A cross-sectional study in a clinical setting was conducted. The subjects were 705 patients (417 males and 288 females) aged 30 years and older who underwent a first-time coronary angiography for suspected or known coronary heart disease at 5 major cardiology departments in the Fukuoka metropolitan area between September 1996 and August 1997. RESULTS: Compared to subjects with normal blood pressure, those with prehypertension had an increased risk of coronary atherosclerosis even after adjusting for other factors. CONCLUSION: Prehypertension may be an important clinical entity which requires treatment in the Japanese population.

BACKGROUND Risk factors for cerebral infarction have not been well clarified, except for hypertension (HT), and few studies have examined the risk factors in the elderly. METHODS AND RESULTS Clinical and behavioral risk factors for cerebral infarction were examined in 4,349 Japanese men aged 45-74 years with a serum total cholesterol (TC) concentration of 220 mg/dl or greater who participated in the Kyushu Lipid Intervention Study. A total of 81 men developed definite cerebral infarction in a 5-year follow-up period. The Cox proportional hazards model was used with serum TC at baseline and during the follow-up, serum high-density lipoprotein-cholesterol (HDL-C), HT, diabetes mellitus (DM), and other factors as covariates. Serum TC during the follow-up, not at baseline, was positively associated with cerebral infarction, showing a stronger association in the elderly (>or=65 years old) than in the middle-aged (

This study examined the relation of Type A behavior pattern and its components to angiographically documented coronary atherosclerosis in 198 Japanese women. A questionnaire-based interview elicited psychosocial and other factors. Type A behavior pattern was measured by 12 questions. Significant coronary stenosis was defined when a 75% or greater luminal narrowing occurred at one or more major coronary arteries or 50% or greater narrowing occurred at the left main artery. Gensini's score also was calculated. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals with adjustment for traditional coronary risk factors and the presence of a job. Global Type A behavior pattern showed no material association with the severity of coronary atherosclerosis assessed by both Gensini's score and the presence of significant coronary stenosis. However, its subcomponents, enthusiasm and competitiveness, were positively related to the severity of coronary atherosclerosis, whereas self-confidence and perfectionism were negatively related. These findings suggest overall a null association between global Type A and coronary atherosclerosis as well as the presence of toxic or beneficial components of Type A behaviors in Japanese women.

We examined the antioxidative effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), on superoxide anion formation activated by angiotensin II (Ang II) in vitro. The effects of fluvastatin were also compared to simvastatin and a water-soluble analog of alpha-tocopherol, trolox. Treatment of human aortic smooth muscle cells (hASMC) with Ang II for 24 hours resulted in a 3.2 +/- 0.5-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. hASMC treated with clinical concentrations of fluvastatin (0-100 nM) showed a dose-dependent decrease in Ang II-activated superoxide anion formation. The addition of similar concentrations of trolox to hASMC inhibited Ang II-activated superoxide anion formation in a dose-dependent manner. However, simvastatin at similar doses failed to inhibit Ang II-activated superoxide anion formation by hASMC. Our results indicate that in addition to its hypocholesterolemic effect, fluvastatin may have direct antioxidative effects, suggesting its possible protective effect on atherosclerotic process.

Typical angioid streaks were found on routine ophthalmologic examination in a 42-year-old female with yellowish, coalescing papules on her neck without any symptoms. Biopsy of the cutaneous lesion showed degeneration and fragmentation of the elastic fibers and many basophilic-stained calcifications in mid-dermis, which are consistent with pseudoxanthoma elasticum. Twenty-four-hour Holter electrocardiography (ECG) showed sinus arrest for 2.5 seconds, and an electrophysiological study revealed sinus nodal dysfunction (sick sinus syndrome), whereas all of the coronary arteries were intact, despite a treadmill stress ECG test showing significant ST depressions. The association of pseudoxanthoma elasticum and sick sinus syndrome is very rare. One possible explanation for this association here is that the degeneration of elastic fiber in endomysium of the sino-atrial node may have affected heart conduction systems, resulting in sick sinus syndrome.

Reasearch Institute of Angiocardiology and Cardiovascular Clinic,Faculty of Medicine Kyushu University, Fukuoka, JapanOBJECTIVE: To investigate the relation of the obesity and body-fat distribution with angiographically defined coronaryatherosclerosis.DESIGN: Cross-sectional study in a clinical setting.SUBJECTS: Three hundred and twenty men (median age, 59y) and 212 women (median age, 67y) who underwent coronaryangiography for suspected or known coronary heart disease at 5 cardiology departments between September 1996 and August1997. Patients with disease duration >1y were excluded.MEASUREMENTS: The body mass index (BMI) and the waist to hip circumference ratio (WHR) were used as main exposurevariables, and either the presence of significant coronary stenosis or the Gensini’s score ( 10 vs

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

The present study evaluated the effect of hypertension (HT), dyslipidemia and diabetes mellitus (DM) on the development of coronary atherosclerosis in the Japanese population, using a cross-sectional study of 433 patients (254 men and 179 women) aged 30 years or older who underwent coronary angiography for suspected or known coronary heart disease angina at 5 cardiology departments in the Fukuoka area between September 1996 and August 1997. Patients with a disease duration of 6 months or more were excluded. The main outcome measure was angiographically defined coronary artery stenosis and was found to a significant degree in 146 patients (33.7%). HT, DM, low levels of high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia remained as significant coronary artery disease (CAD) risk factors even after controlling for age, sex, hospital, smoking, alcohol use, body mass index and leisure time physical activity. However, hypercholesterolemia was not a significant risk factor after adjusting for these variables. After controlling for these variables, DM, low HDL-C and hypertriglyceridemia were significant CAD risk factors for men, but only DM was a significant CAD risk factor in women. These results indicate that in Japan DM, low HDL-C and hypertriglyceridemia may be more important CAD risk factors than hypercholesterolemia.

A 51-year-old woman with a large uterine myoma suffered from acute pulmonary throm boembolism. Venography revealed thrombosis in the right common iliac vein and almost complete obstruction of the left common iliac vein. The ascending lumbar vein showed collateral drainage. Treatment was initiated with continuous intravenous heparin sodium, and a Greenfield filter was inserted to prevent the extension of the pulmonary embolism during and after hysterectomy. After a total hysterectomy, venography revealed restora tion of patency in the bilateral common iliac veins, and no flow was seen in the ascending lumbar vein. Thorough clinical examinations failed to identify any other prothrombotic conditions. These results suggest that a large uterine myoma compressed veins in the pelvis, and the resulting impaired blood flow caused deep venous thrombosis and pulmonary thromboembolism.

A 53-year-old male was found to have hypertension caused by the significant secretion of renin from an atrophic left kidney. He had undergone extracorporeal shock-wave lithotripsy (ESWL) for left renal lithiasis 11 years previously. A renal dynamic study with 99mTc-diethylenetriaminepentaacetic acid (DTPA) indicated that the rate of renal excretion and uptake was decreased in the left kidney and normal in the right kidney. Renal angiography demonstrated a normal right renal artery and a small but nonstenotic left renal artery. The ratio of PRA in the left renal vein to that in the right renal vein was 1.7. Blood pressure could be lowered to the range of 140-150/80-90 mmHg with imidapril, an ACE inhibitor. ESWL may cause hypertension via the well-known Page kidney effect. In this case, the kidney, atrophic probably due to ESWL, released a significant amount of renin.

We have previously shown that both renal dopamine (DA) and kallikrein-kinin systems are activated by exercise in mild hypertensives. We aimed to confirm the effects of exercise on the renal DA system and the stimulatory effects of DA on the renal kallikrein-kinin system in rats. In experiment 1, 12 male Dahl salt-sensitive (DS) rats given a 4% salt diet were divided into two groups. Rats in the exercise group were forced to run at 8 m/min, 60 min/day, 5 days/week for 4 weeks. Daily urinary volume, urinary excretion of sodium, free DA, and kallikrein activity were measured weekly. Renal aromatic-L-amino-acid decarboxylase (AADC) activities were assayed at the end of the experiment. In experiment 2, 15 male Sprague-Dawley (SD) rats were randomly divided into 3 groups, a DA-5 (5 microg of DA/kg/min), a DA-10 (10 microg of DA/kg/min), and a control group. DA or vehicle was administered subcutaneously with an osmotic pump for 2 weeks. Daily urinary volume, urinary excretion of sodium, aldosterone, DA, and kallikrein activity were measured weekly. Plasma renin activity, aldosterone concentration, and renal kallikrein mRNA levels were determined at the end of the experiment. In experiment 1, urinary excretion of free DA and renal AADC activities in the exercise group were significantly higher than those in the non-exercise group at week 4. In experiment 2, renal kallikrein mRNA levels and urinary volume were significantly increased in the DA-10 group compared to the control group, although there were no differences in urinary kallikrein activities. Plasma aldosterone concentration was significantly decreased in the DA-10 group compared to that in the control group despite a lack of differences in plasma renin activities. In conclusion, exercise increased the urinary excretion of free DA, probably through increased renal AADC activity in DS rats. DA amplified renal kallikrein mRNA levels and decreased plasma aldosterone levels, probably through its suppression of aldosterone in the adrenal glands. Activation of the kallikrein-kinin system might be counteracted by post-transcriptional modification of aldosterone. These results suggest that exercise enhances renal dopamine production by activating renal AADC activity, which in turn stimulates the renal kallikrein-kinin system.

Abstract —Apart from ACE, various angiotensin II (Ang II)–forming serine proteinases (eg, chymase, kallikrein, and cathepsin G) are known to exist in human tissues, but their clinical significance or the regulatory mechanisms that control their activities are not well established. A recent clinical study has shown that chymase activity was significantly increased in human atherosclerotic or aneurysmal aorta. The association between vascular Ang II–forming activities (AIIFAs) in the human internal thoracic artery (ITA) and various clinical parameters was studied with the use of ITAs obtained from 32 patients who underwent coronary artery bypass graft surgery. Total and ACE- and chymase-dependent AIIFAs in homogenates of ITAs were determined. Total AIIFA was 8.67±0.86 (nmol Ang II formed · min −1 · mg protein −1 [U]), and ≈95% of the activities were due to chymase. Serum total cholesterol level, but no other risk factors, significantly correlated with chymase- ( r =0.60, P r =0.35, P r =0.47, P

Resume La cerivastatine sodique, un inhibiteur pur et synthetique enantiomerique de l’hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, est consideree comme efficace dans le traitement de l’hypercholesterolemie primaire legere a moderee (cholesterol total ≤ 220–259 mg/dL). Nous avons compare l’efficacite et la tolerance d’une posologie de 0,3 mg/j a celles d’une posologie de 0,15 mg/j chez des patients presentant une hypercholesterolemie primaire severe (taux serique de cholesterol total ≥ 260 mg/dL). Apres une periode minimum de quatre semaines de preinclusion sous placebo, 73 de ces patients ont ete randomises pour l’attribution d’un traitement par cerivastatine sodique, a la posologie de 0,15 ou de 0,3 mg/j en une seule prise apres le diner, pendant 12 semaines. Chez 58 patients, la prise de ce medicament a ete prolongee aux doses de 0,15 ou de 0,3 mg/j pendant 36 semaines supplementaires ou plus, afin d’evaluer l’efficacite et la tolerance a long terme de ce produit. Durant la periode de traitement de 12 semaines, les taux seriques de cholesterol total ont significativement diminue par rapport aux taux de base dans les deux groupes. Mais la reduction en pourcentage etait significativement plus elevee dans le groupe 0,3 mg (−24,4 %) que dans le groupe 0,15 mg(−21,6 %). La reduction en pourcentage des taux de cholesterol des lipoproteines basse densite (LDL-C), de triglycerides, d’apolipoproteines B et l’augmentation en pourcentage des taux de cholesterol des lipoproteines haute densite (HDL-C), ont ete significativement plus elevees dans le groupe 0,3 mg que dans le groupe 0,15 mg. Lorsque les resultats des deux groupes ont ete combines, les variations en pourcentage de la lipidemie a 48 semaines sont restees aussi stables qu'a 12 semaines. Aucune reaction indesirable grave n'a ete observee. Nous en avons conclu que, dans le traitement de patients presentant une hypercholesterolemie primaire severe, la dose plus elevee de cerivastatine sodique etait plus efficace que la dose plus faible, avec un profil de tolerance comparable.

Objectives To examine the association between the fractional esterification rate of cholesterol (C) in low density lipoprotein- and very low density lipoprotein-depleted plasma (FERHDL) and coronary artery disease (CAD) and the influence of serum HDL-C levels. Background The function of HDL in reverse cholesterol transport is involved in the antiatherogenic action of HDL, and FERHDLis a newly established quantitative measure of HDL function in vivo. Methods Cases (n = 185, F/M: 43/142) and controls (n = 74, F/M:27/47) were defined as subjects with/without angiographically proven CAD, respectively. Results The cases had significantly (p < 0.05) higher FERHDLvalues (13.2 ± 0.3 %/h vs. 12.1 ± 0.5 %/h) and lower HDL-C levels (39.0 ± 1.0 mg/dL vs. 46.8 ± 1.4 mg/dL) than the controls. The associations of FERHDLand HDL-C with CAD were linear and significant (p < 0.05). Multiple logistic regression analysis indicated that the association of FERHDLwith CAD varied with the HDL-C level: significant for the low HDL-C tertile (chi-square = 6.20, p < 0.05) but not significant for the middle and high HDL-C tertiles (chi-square = 0.08 and 0.03, n.s.). The risk of CAD, relative to that in patients with low FERHDLand high HDL-C, was higher in patients with low FERHDLand low HDL-C (odds ratio [95% confidence interval]: 2.37 [1.12–4.97], p < 0.05) and was highest in patients with high FERHDLand low HDL-C (3.85 [1.84–8.06], p < 0.01). Conclusions The functional assay of HDL (FERHDL) is an independent risk factor for CAD. The combination of FERHDLand HDL-C could be a potent indicator for CAD, and may reflect a potential mechanism of atherosclerosis.

To compare the incidence of cough between two angiotensin converting enzyme (ACE) inhibitors, imidapril and enalapril, comparative crossover study was performed in 489 patients (228 men and 261 females) with essential or renal parenchymal hypertension. Patients were randomly assigned to one of two treatment groups, a group receiving imidapril for 12wk (Period I) followed by enalapril for 12wk (Period II), and a group in which the order of drugs was reversed. The occurrence of cough during treatment was monitored by questionnaire in all cases. There were no differences in background characteristics between the two groups. The incidence of cough during Period I was 15.2% (32/210) in the group initially treated with imidapril (Group IE) and 38.6% (85/220) in the group initially treated with enalapril (Group EI), the difference being statistically significant (p

Clinical trials of candesartan cilexetil conducted in Japan are reviewed. Candesartan cilexetil inhibited the pressor response to intravenous angiotensin II in healthy volunteers, with peak effects observed at 4 or 8 h after oral dosing; suppressing effects persisted up to 24 h. In 14 multicentre studies with 928 hypertensive patients treated for 8 to 12 weeks, candesartan cilexetil had an efficacy rate (reduction of systolic/diastolic blood pressure > or = 20/10 mm Hg and/or mean blood pressure > or = 13 mm Hg) of 72% and 63%, and an adverse effect rate of 9.9% and 7.3%, in patients with mild-to-moderate essential hypertension and those with impaired renal function, respectively. When data for elderly patients were analysed, there was no difference in efficacy and tolerability compared to non-elderly patients. In a double-blind comparative study, candesartan cilexetil was superior to enalapril in hypertensive patients: efficacy rate, 74% vs 66% (NS); adverse symptom rate, 10.4% vs 27.3% (P < 0.01); incidence of cough, 1.5% vs 14.8% (P < 0.01). Treatment with 2-8 mg of candesartan cilexetil once daily for 8 to 12 weeks reduced the left ventricular mass index without deterioration of cardiac function. In conclusion, 4-12 mg of candesartan cilexetil once daily is effective and well tolerated in patients with essential hypertension, including elderly patients, those with severe hypertension, and hypertensive patients with renal insufficiency. Its improved tolerability profile over angiotensin-converting enzyme inhibitors, as well as its end-organ protective effects, suggest that candesartan cilexetil is useful as a first-line antihypertensive drug.

Adhesion molecules on the endothelial cell membrane play an important role in the pathogenesis of atherosclerosis. Levels of soluble forms of cell adhesion molecules are reportedly elevated in patients with peripheral artery vessel disease and in patients with an atherosclerotic aorta. The present study investigated the association of serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), and soluble P-selectin (sP-selectin) with coronary heart disease (CHD) and the extent of coronary atherosclerosis, and examined the influence of serum levels of lipids, lipoproteins and apolipoproteins (apo) in subjects with (n=52, M/F: 43/9) and without (controls, n=40, M/F:25/15) angiographically proven coronary atherosclerosis. After controlling for age and gender, levels of sVCAM-1 (least squares mean ± std error: 565±36 ng/ml vs 540±41 ng/ml, ns), sICAM-1 (261±17 ng/ml vs 247±19 ng/ml, ns), and sP-selectin (142 ±8 ng/ml vs 149±10 ng/ml, ns) in patients with coronary atherosclerosis were not different from those in controls, as assessed by an analysis of covariance. After also adjusting for body mass index, hypertension, diabetes mellitus, and smoking by a multiple logistic function analysis, the association of sVCAM-1, sICAM-1, and sP-selectin with CHD was still not significant. Levels of sVCAM-1, sICAM-1, and sP-selectin were also not related to the extent of coronary atherosclerosis as judged by the number of stenosed vessels. However, inverse (p

SUMMARY 1. To determine whether total interruption of the local cardiac renin-angiotensin system by angiotensin II (AngII) receptor antagonist limits myocardial ischaemia, intracoronary (i.e.) or intravenous (i.v.) infusion of Angll receptor antagonists was compared in ischaemic dogs. 2. Dogs subjected to 90min coronary artery occlusion and 270 min reperfusion assigned to saline (n= 10) or i.e. low dose (LD, n= 10), i.v. low dose (n= 10) or i.v. high dose (HD, n= 10) of AngII AT1-receptor antagonist, CV-11974. The CV-11974 was infused from 15 min pre-occlusion for 180 min. Cardiac and regional function, area at risk and infarct size were measured. 3. Although i.e. CV-11974 did not cause systemic haemodynamic changes, it abolished reduction in coronary blood flow induced by i.e. AngII injection. Elevation in LV end-diastolic pressure during ischaemia was smaller in both i.e. and i.v.-HD CV-11974 dogs than in i.v.-LD and control dogs. Regional wall thickening was not different among the four groups. With comparable area at risk, i.e. CV-11974 reduced infarct size to the same extent as i.v.-HD CV-11974 (18 vs 21%), which was smaller than i.v.-LD CV or the controls (38 and 42%). 4. The results indicate that AngII receptor antagonist can reduce ischaemia-reperfusion injury in experimental ischaemia. These cardioprotective effects might be mediated through direct inhibition of local angiotensin action in the heart. Local cardiac AngII formation may play a crucial role in cardiac injury during ischaemia and reperfusion.

To clarify the ability of clinical and laboratory parameters to reflect target organ damage, especially left ventricular hypertrophy (LVH), we investigated which of these parameters might correlate to LVH as determined by electrocardiographic voltage at the first clinic visit in 108 (53 males and 55 females, average age 52 +/- 10 years) untreated essential hypertensives. The sum of the amplitude of the S wave in lead V1 plus that of the R wave in lead V5 or V6 (SV1 + R(V5, V6)) was correlated with blood pressure in both males and females. In subjects with LVH (SV1 + R(V5, V6) > or = 3.5mV), a stepwise multiple regression analysis revealed that SV1 + R(V5, V6) was associated with plasma renin activity (PRA) in both males and females, and with creatinine concentration (Cr) in males. These results suggest that PRA at the first visit could be a useful predictor of LVH in patients with essential hypertension.

While class Ic antiarrhythmic drugs are effective in treating patients with atrial fibrillation, their mechanism of action is poorly understood. We performed electrophysiological studies before and after their administration to 22 patients with paroxysmal atrial fibrillation. Atrial refractoriness, maximal interatrial conduction delay and the wavelength index were measured at two basic cycle lengths (600 or 400 ms). Both drugs studied increased atrial refractoriness and wavelength index. Flecainide reduced the maximal interatrial conduction delay, but pilsicainide did not. Each drug increased the wavelength index in a tachycardia-dependent manner. Class Ic drugs may reduce atrial vulnerability by increasing the wavelength of the reentrant circuit during periods of rapid heart rate.

Both the systemic and the tissue renin–angiotensin system (RAS)-are heavily involved in cardiovascular homeostasis, but their excess activation seems to be associated with increased morbidity and mortality in various stages of cardiovascular diseases, since angiotensin-converting enzyme (ACE) inhibitors have been shown to improve hypertension, congestive heart failure, and acute myocardial infarction. A clinical megastudy (ELITE) of elderly patients has recently shown that an AT1 receptor antagonist was superior to an ACE inhibitor for improvement of patients' prognosis. One of the possible mechanisms of this beneficial effect of the AT1 receptor antagonist compared to the ACE inhibitor could be the blockade of all the angiotensin (Ang) II formed not only by ACE but also by alternative pathways. Recent studies have disclosed that chymase, the most abundant Ang II-forming enzyme in human tissues, could be involved in the development of atherosclerosis, the remodeling of the myocardium after infarction or hypertrophy, restenosis after vascular injury, and chronic inflammatory conditions. Kallikrein-dependent Ang II formation also seems to take place under various ischemic conditions, as shown in the ischemic dog heart after ligation of a coronary artery, human leg circulation of patients with arteriosclerosis obliterans, or systemic circulation during a graded exercise. However, detailed mechanisms of non-ACE Ang II-forming enzymes involved in these pathological changes are not known. Current knowledge about ACE and non-ACE Ang II-forming enzymes in cardiovascular diseases are reviewed in this article.

The role of basal parasympathetic tone in reducing the heart rate and causing electrocardiographic (ECG) changes during right coronary angioplasty was evaluated in 19 patients with angina pectoris. To measure parasympathetic tone, time and frequency domain parameters of heart rate variability were assessed using 24 h of ambulatory ECG data recorded before angioplasty. There was an age-dependent reduction in heart rate. However, no parameters of heart rate variability were responsible for the changes in heart rate. In contrast, the degree of ST segment elevation during angioplasty correlated significantly with the high-frequency component of heart rate variability. Therefore, the increased parasympathetic tone, as assessed by spectral analysis, may augment the early ST segment elevation induced by right coronary occlusion.

Hyperinsulinemia has been demonstrated in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia, and in rats with hereditary hypertriglyceridemia. In addition, hyperinsulinemia causes dyslipidemia in individuals with metabolic syndromes, and troglitazone, a newly developed drug that can improve insulin resistance, reduces hypertriglyceridemia in fructose-fed rats. Our previous study demonstrated that troglitazone improves hyperinsulinemia and increases insulin sensitivity in WHHL rabbits. The present controlled study investigated the effects of troglitazone, administered as a food admixture (24 mg/d per animal) for 6 months, on serum levels of lipids and lipoprotein subfractions in 12 WHHL rabbits to clarify whether improved hyperinsulinemia (insulin resistance) could reduce hyperlipidemia (hypertriglyceridemia) in this model. Fasting levels of serum lipids and lipoprotein subfractions did not correlate with fasting plasma insulin concentrations or insulin sensitivity before treatment. Troglitazone increased serum levels of triglyceride, and low-density lipoprotein triglyceride and very-low-density lipoprotein subfractions despite improved hyperinsulinemia and insulin resistance. These findings suggest that hyperinsulinemia may not be involved in the etiology of hyperlipidemia in WHHL rabbits, which contrasts with the results in individuals with metabolic syndrome or patients with non—insulin-dependent diabetes mellitus.

Objective To purify and characterize a kinin-forming enzyme in the dog heart and to examine the ability of this enzyme to generate angiotensin (Ang) II from Ang I. Methods The enzyme was isolated from heart homogenate using a diethylaminoethyl-Sepharose column, an aprotinin affinity column and a wheat germ lectin-Sepharose 6MB column. Kininogenase activity was assessed with a kinin radioimmunoassay after samples had been incubated with bovine low-molecular-mass kininogen at 37°C for 1 h. Ang I-converting activity was assessed by the quantitation of Ang II formed by incubation of the sample with Ang I at 37°C for 3 h, using high performance liquid chromatography. The enzyme was subjected to 12.5% sodium dodecyl sulphate-polyacrylamide gel electrophoresis, stained by Coomassie brilliant blue and transferred electrically to a membrane with glycoprotein staining. Results The purified enzyme is a glycoprotein with an apparent relative molecular mass of 65 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Its kininogenase activity was approximately 20 μg bradykinin/h per mg protein at an optimal pH of 8.0. The enzyme also converted Ang I to Ang II at an optimal pH of 6.5. Its specific activity was approximately 2 μg Ang II/h per mg protein. Both activities were inhibited by aprotinin, a tissue kallikrein inhibitor. Western blot analysis using polyclonal antibody against this enzyme demonstrated that this enzyme exists both in the myocardium and in the coronary artery. Conclusions The present study showed that the kinin-forming enzyme in the dog heart is a kallikrein-like enzyme that is different from cathepsin D, cathepsin G and chymase. It is also able to convert Ang I to Ang II. This enzyme might play a role in regulating myocardial perfusion, mainly by generating kinins and in part by forming Ang II.

To investigate the mechanisms of the hypolipidemic effect ofmonatepil, a new class of calcium antagonists withα1-adrenergic blocking activity, we examined theeffects of the drug on low-density lipoprotein (LDL) receptor activity andthe level of LDL receptor mRNA present in cultured human skin fibroblasts.At concentrations of 2 × 10−5M, monatepilincreased the binding (248 ± 43% mean ± SD),internalization (374 ± 18%), and degradation (145 ±2%) of 125I-LDL in human skin fibroblasts (n =3, p

We evaluated the relation with nutritional state and methicillin-resistant Staphylococcus aureus (MRSA) infection of 20 patients who isolated Candida of 31 patients who were suspected as candidiasis. All of the patients who were hospitalized in internal medicine wards in our hospital between February 1993 and January 1994. All patients with hematological disease were excluded. MRSA is now gotten much attention as pathogen of hospital infection, but each MRSA is detected not only alone but also concomitant with other bacterium. In our hospital MRSA was detected alone 36.8% (39/106). Candida 9.4% (10/106) was frequent as mixed infectious pathogen concomitant with MRSA following Pseudomonas aeruginosa 19.8% (21/106) and Enterococcus faecalis 12.3% (13/106). Intension of host-immunity is a important factor as prevention of both infection. We evaluated the nutritional state of patients with 7 cases of infection group and 13 cases of colonization group. There was no significance between two groups as for serum total protein (mean) were 5.97 g/dl in infection group and 5.96% g/dl in colonization group. Furthermore there were significance (p < 0.01) for mean serum albumin (mean) were 3.11 g/dl v.s. 3.27 g/dl. But both serum total protein and serum albumin of these evaluated patients who isolated Candida were less than normal limit. Therefore we considered nutritional disturbance was important addition to over-use of antibiotics and severe underlying diseases as risk factor of candidiasis, and revealed the importance of improvement of nutritional state at the prevention and therapy.

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (apo) A-I metabolism and atherogenesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinetics, the fractional rate of cholesterol esterification in HDL (FERHDL), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in both groups had decreased to approximately 53%, 57%, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FERHDL (38% of the controls, P = 0.039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P < 0.05) and in the rate of apo A-I synthesis (1.6-fold, P< 0.05). The atherosclerotic intimal area was positively correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FERHDL. It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals.

The complement inhibitor nafamostat mesylate (6-amidino-2-naphthyl-4-guanidinobenzoate dimethane sulfonate) was used to treat an 18-year-old woman with systemic lupus erythematosus and nephrotic syndrome who was resistant to treatment with prednisolone, dipyridamole, and mizoribine. Nafamostat mesylate was effective in treating the patient's proteinuria and hypocomplementemia, but long-term treatment was not possible because of allergic reactions

The authors evaluated elements of the coagulation and fibrinolytic systems in 18 male patients with intermittent claudication vs 19 men matched for risk factors who served as controls. Prothrombin time and activated partial thromboplastin time did not significantly differ in the patients and the controls. The plasminogen level in the two groups was not significantly different. The level of lipoprotein(a) was significantly higher in the patients than in the controls. The levels of antigen and the activity of protein C did not differ significantly between the two groups. The thrombomodulin level was significantly higher in the patients than in the controls. There were no significant differences between the two groups in the levels of α2-macroglobulin, C1-inactivator, or antithrombin III. The levels of fibrinogen and α-antitrypsin were significantly higher in the patients vs the controls. Significantly lower levels of α2-plasmin inhibitor and higher levels of α2-plasmin inhibitor/plasmin complex and thrombin/antithrombin III complex were found in the patients vs the controls. These findings suggest that the levels of thrombin/antithrombin III complex, α2- plasmin inhibitor/plasmin complex, and thrombomodulin may perhaps serve as indica tors for injury to the peripheral endothelium and that the coagulation and fibrinolytic systems may be activated in patients with intermittent claudication.

We evaluated left anterior descending coronary artery stenosis by transesophageal echocardiography using the acute hemodynamic effects produced by administration of nitroglycerin (NTG) spray in 11 patients with stenosis and 8 subjects without stenosis (normal group). Before administration of NTG, there were no differences in systolic and diastolic blood pressure, heart rate, the diameter of the left main trunk, systolic flow velocity (SFV), diastolic flow velocity (DFV), or the ratio of diastolic flow velocity to systolic flow velocity (DFV:SFV) between the normal and stenosis groups. NTG administration significantly reduced systolic and diastolic blood pressures and significantly increased heart rate and the diameter of the left main trunk in each group. The increase in diameter of the left main trunk was significantly greater in the normal group compared with the stenosis group, despite the lack of significant differences in NTG-induced changes in blood pressure and heart rate between the two groups. NTG significantly increased peak SFV and DFV in both groups. The average NTG-induced change in SFV was similar in both groups, but the increase in DFV was significantly greater in the stenosis group compared with the normal group. Consequently, the DFV:SFV decreased significantly after NTG administration in the normal group but not in the stenosis group. The change in DFV:SFV was significantly different between the two groups. Our results suggest that NTG spray is potentially useful for enhancing the diagnostic utility of transesophageal echocardiography for stenosis of the left descending coronary artery.

Clinical efficacy of fluconazole on fungal infections was evaluated. Fluconazole was administrated orally or intravenously to 16 cases with fungal infections (chronic renal failure 4, congestive heart failure 2, cerebral infarction 2, etc). All cases were suspected of mycosis. The details of those administrated were 16 cases of pneumonia 3 cases, fungemia 9 cases (suspected 7 cases) and urinary tract infection 3 cases. Clinical efficacy rate was 71.4%. Side-effects were observed in only 1 case, and this consisted of transient increase of leukocytes and thrombocytes. Fluconazole is considered to be a potent, safe antifungal agent for the treatment of suspected fungal infection during intravenous hyperalimentation.

The objective of the study was to evaluate theefficacy and safety of fluvastatin in patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia, in a 1-year study (a 12-week open assessment, followed by 40 weeks of active treatment). Of the 337 patients enrolled in the study, the effects of fluvastatin were analyzed in 296 patients at baseline and at 12 weeks. Of these, 265 were receiving 20 mg/day fluvastatin at week 12 and in 20 patients the dose had been increased to 30 mg/day; 11 patients violated the dosing protocol. A total of 229 patients continued into the 40-week, long-term phase, and 212 patients were analyzed at baseline and after 24 and 52 weeks. At the end of treatment, 153 evaluable patients were still taking 20 mg/day fluvastatin, 1 was taking 10 mg/day, and 48 patients were taking 30 mg/day, and 10 were taking 40 mg/day. In the 20 mg/day fluvastatin group, low density lipoprotein cholesterol (LDL-C) levels decreased by 24.1 % at week 12 and by 29.3% at week 52. In those patients requiring the higher doses, the corresponding reductions in LDL-C were 20.2% (week 12) and 26.7% (week 52). Total cholesterol was also reduced at week 12 by 17.0% (20 mg/day) and 15.7% (20–30 mg/ day), and at week 52 by 20.4% (≤20 mg/day) and 19.2% (≥30 mg/day). Throughout the study, fluvastatin was generally well tolerated and no serious clinical adverse events were observed. In conclusion, long-term treatment of hypercholesterolemia with fluvastatin at dosages of 20–40 mg daily can be considered both safe and effective.

We identified human leukocyte alloantigens (HLA) class II alleles in 24 Japanese children with steroid-sensitive nephrotic syndrome (SSNS) by deoxyribonucleic acid (DNA) typing. The DQA1 and DQB1 alleles were identified using sequence-specific oligonucleotide probes for DQA and DQB. The frequency of DQB1*0302 was significantly higher in the patients than in the controls (54.0 vs. 16.0%, respectively; relative risk, RR = 6.2; pc0.00009. We also found that the frequency of DQA1*0103 in the patients was significantly lower than in the controls (RR = 0.194, pc0.04). Several studies have identified an association between certain HLA by serotyping. In the present study, we investigated the HLAs of Japanese patients with SSNS by DNA typing and observed a significant increase in the frequency of DQB1*0302 in patients with the disease. HLA-DQ3, which was proven to be associated with SSNS, consists of HLA DQ7, 8 and 9. DQB1*0302 is a component of HLA-DQ8. So we proposed the increase of DQ3 was due to an increase in DQ8.

The effects of long-term low intensity aerobic training and detraining on serum lipid and lipoprotein concentrations were examined in 30 elderly men and women. These subjects were randomly divided into two groups. The training group [n=15; 7 men and 8 women; mean age 75.5 (SD 5.6) years] agreed to take part in physical training using a treadmill with an exercise intensity at the blood lactate concentration threshold for 30 min 3–6 times a week for 9 months. The other group [n=15; 7 men and 8 women; mean age 73.7 (SD 4.4) years] did not perform any particular physical training and was followed as the control. Following this training period the high density lipoprotein-cholesterol (HDL-C) had increased significantly (P

A 55-year-old Japanese woman with familial hypobetalipoproteinemia associated with hypothyroidism was admitted to the hospital because of orthopnea and congestive heart failure. Thyroid function testing revealed hypothyroidism, but she exhibited low levels of serum cholesterol (111 mg/dl) and apolipoprotein (apo) B (48.5 mg/dl). No abnormal bands were detected with gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis of very low density lipoprotein, low density lipoprotein and high density lipoprotein followed by immunoblotting with anti apo B polyclonal antibody. In this case, apo B structural abnormality could not be identified.

To clarify the relationship between the dilatation of angiographically non-stenotic coronary artery segments in response to isosorbide dinitrate (ISDN), and serum lipids, 5 coronary segments in 7 patients with familial hypercholesterolemia (FH) and 43 patients with non-familial hypercholesterolemia (non-FH), who had either 1- or 2-vessel coronary heart disease, were investigated. The serum total cholesterol level was significantly greater in FH than in non-FH. Before and after the direct intracoronary injection of ISDN, coronary diameter was measured by a computer-assisted coronary angiography analysis system. The order of the dilative responses in coronary segments in non-FH patients (segments: #5 > #11 > #6 > #13 > #7) was exactly the same as the order of their original diameters, while the ratio of the increase in diameter (after/before ISDN injection) did not differ among any of the segments (mean: 1.08-fold increase). In the non-FH group, no correlation was found between the serum total cholesterol, triglyceride, low-density lipoprotein-cholesterol, or high-density lipoprotein-cholesterol, and the ratio of the coronary diameter after and before injection of ISDN. Moreover, hypercholesterolemia in non-FH did not affect the coronary dilative response to ISDN injection. In the FH group, although the original diameter of each segment did not differ from that in the non-FH group, the ratio of the diameter after and before injection of ISDN was significantly smaller in FH than in non-FH (p < 0.01). These results suggest that a non-stenotic coronary artery in FH has a lower capacity for vasodilation in response to ISDN. Although hypercholesterolemia was excluded as a factor which may suppress the capacity for coronary dilation in non-FH, spontaneous hypercholesterolemia in FH may affect medial smooth muscle functions of the coronary artery.

The association of the severity of coronary atherosclerosis with hypertension and dyslipidemia, independent of other known coronary risk factors, was examined in 313 men and 155 women who underwent coronary angiography. The severity of coronary atherosclerosis was quantified using Gensini's scoring system. The following criteria were used to define dyslipidemia : hypercholesterolemia (total serum cholesterol concentration ≥220 mg/dl), hypertriglyceridemia (serum triglyceride concentration ≥150 mg/dl), and low HDL-cholesterolemia (serum HDL-cholesterol concentration

We studied the relationship of cigarette smoking to the severity of coronary and thoracic aortic atherosclerosis in 116 men who received coronary angiography and transesophageal echocardiography. Severity of coronary atherosclerosis was assessed in terms of Gensini's score (GS), and that of thoracic aortic atherosclerosis was assessed by the average sclerotic length (ASL) and average sclerotic area (ASA). The plasma fibrinogen levels were significantly positively correlated with smoking, and fasting blood sugar levels tended to be positively associated with smoking. GS was inversely associated with serum levels of high density lipoprotein (HDL) cholesterol. ASL and ASA were positively associated with age, fasting blood sugar levels and plasma fibrinogen levels, and these associations were statistically significant. Analysis of covariance was used to examine the net association between cigarette smoking and GS, ASL or ASA controlling for age, total cholesterol, HDL cholesterol, fasting blood sugar and plasma fibrinogen. We found that GS, ASL, and ASA were all significantly increased with increasing number of cigarette years. Additional adjustment for other risk factors (triglyceride, uric acid, body mass index, alcohol use and hypertension) also showed a strong independent contribution of smoking to GS, ASL and ASA. We concluded that the cumulative exposure to cigarette smoking was an independent indicator of the severity of coronary atherosclerosis as well as thoracic aortic atherosclerosis.

Physical exercise is one of the life-style modifications used for lowering blood pressure. Except for diminished norepinephrine spill over, the mechanism by which physical exercise exerts its effects was not known. Based on our preliminary finding that the reduction of blood pressure was inversely correlated to the baseline plasma renin activity, we have consequently revealed that mild exercise reduces plasma volume and hence the cardiac index. In order to elucidate the mechanism, we have investigated all possible parameters relevant to plasma volume regulation. Among them, urinary free dopamine and urinary active kallikrein increased in the early stages (weeks 2-4) while atrio-natriuretic factor (week 4) and endogeneous ouabain-like substance (EOLS) consequently (weeks 7-10) decreased. Serum taurine increased and plasma norepinephrine decreased in the late stages. The conclusion reached is that mild exercise seems to first activate the renal dopamine and kallikrein systems and second trigger other mechanism, such as an increase in taurine and decreases in EOLS and norepinephrine. (Hypertens Res 1995; 18 Suppl. I: S73-S77)

The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR

The effects of monatepil, a new calcium antagonist with alpha 1-blocking activity, and nitrendipine on lipoprotein and carbohydrate metabolism in 86 patients with mild-to-moderate hypertension were examined in a randomized, open-label, multicenter (32 hospitals) study. Thirty-nine patients treated with monatepil and 33 patients treated with nitrendipine completed the 12-week study. Monatepil and nitrendipine each significantly decreased both systolic and diastolic blood pressure. Changes in heart rate were not seen in either group. Monatepil administration significantly decreased total cholesterol, low density lipoprotein (LDL) cholesterol, the LDL cholesterol to high density lipoprotein (HDL) cholesterol ratio, apolipoprotein (Apo) B levels, and HbA1c levels, whereas no changes in these measurements were observed in nitrendipine-treated patients. Monatepil also significantly decreased lipoprotein(a) levels, but there were no significant changes in HDL cholesterol, Apo-AI, or Apo-E levels. After nitrendipine treatment, the C peptide concentration decreased significantly, although no significant changes were observed in fasting blood glucose or immunoreactive insulin levels. On the basis of these results, it can be concluded that monatepil belongs to a new class of antihypertensive calcium antagonist with favorable carbohydrate metabolism and lipid-lowering activity, although the clinical importance of these findings has not been established.