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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.

Apolipoprotein (apo) E modulates the catabolism of chylomicrons and of very low density lipoprotein remnants. It has three major isoforms (apo E2, E3, E4) and some rare variants. To detect the variants of apo E, blood specimens from 1269 Japanese subjects were analyzed using isoelectric focusing with immunoblotting. The E5 and E7 variants were identified by IEF in 2 and 18 subjects, respectively. Both E5 (Glu3-->Lys) carriers were confirmed by PCR-mediated site-directed mutagenesis, and all E7 (Glu244-->Lys, Glu245-->Lys) carriers were confirmed by the amplification refractory mutation system. The relative frequencies of the epsilon 5 and epsilon 7 alleles were 0.001 and 0.007, respectively. High concentrations of total cholesterol (> 220 mg/dl) were detected in five of the subjects expressing apo E7 and one subject expressing apo E5, and eight subjects heterozygous for apo E7 showed elevated plasma triglyceride concentrations (> 150 mg/dl). In 621 healthy subjects, the mean triglyceride concentration in subjects with apo E7/3 appeared to be higher than in those with apo E3/3, but the difference was not statistically significant.

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 (

Objective: The role of chymase (a mast cell-derived angiotensin II-forming serine proteinase) in aortic lipid deposition was investigated using an orally active, non-peptide chymase inhibitor, SUN-C8257. Methods: Male golden Syrian hamsters, 8 weeks old, were fed with a standard rodent meal supplemented with or without 0.5% cholesterol and 10% coconut oil for 12 weeks. The hamsters fed high cholesterol diet were further separated into two groups treated with or without SUN-C8257 for 12 weeks. The aortic lipid deposition was visualized by Oil red O staining and planimetrically measured. Immunohistochemical staining for angiotensin II (Ang II) of the aortic root region was performed. Aortic Ang II-forming activity was measured using Ang I as a substrate. Plasma total-, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol and triglyceride were quantified by enzymatic methods. Plasma Ang I and Ang II were measured by radioimmunoassay. Results: After 12 weeks of high cholesterol diet, aortic chymase activity in the untreated group increased significantly and showed a positive correlation with plasma total- and LDL-cholesterol. This group of hamsters developed marked lipid deposits in the aortic intima. However, treatment with SUN-C8257 significantly suppressed aortic lipid deposition without changing body weight, blood pressure, plasma LDL-cholesterol and Ang II levels. The level of the adventitial Ang II-immunoreactivity was markedly inhibited in the group treated with SUN-C8257. Conclusion: Our results suggest that arterial chymase may participate in the acceleration of lipid deposition in arterial walls exposed to high plasma cholesterol and that inhibition of arterial chymase may retard the progression of atherosclerosis.

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

Renal sodium handling is important for regulating BP, and renal dopamine and adenosine play an important role in renal sodium handling, however the interaction of these hormones in the kidney was not clarified. In in vivo experiments, adenosine significantly increased water and sodium excretion by 50% compared with vehicle when infused into the left renal artery, accompanied by an increase in urinary dopamine excretion in the left kidney. Neither water-sodium excretion nor dopamine excretion changed in the vehicle-infused kidney. Aromatic L-amino acid decarboxylase activity in the left kidney was significantly higher than that in the noninfused right kidney. The increase in water-sodium excretion induced by adenosine was significantly inhibited by SCH23390, a selective D1 receptor antagonist. In in vitro experiments, porcine renal proximal tubular cells were incubated with 250 microM L-dopa and N(6)-cyclohexyladenosine, an adenosine type 1 receptor agonist, after treatment with adenosine deaminase. N(6)-cyclohexyladenosine significantly increased dopamine formation at a concentration of 10(-9) to 10(-7) M, and this was completely inhibited by 1,3-dipropyl-8-cyclopentylxanthin, an adenosine A1 antagonist. These results show that renal dopamine synthesis is stimulated by adenosine through the activation of aromatic L-amino acid decarboxylase and suggest that adenosine leads to an increase in renal dopamine and natriuresis.

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.

Although there have been suggestions that the glycation and oxidation of low density lipoprotein (LDL) might increase its atherogenic potential, little is known about the presence of glycoxidative LDL in human atherosclerotic lesions. We developed specific antibodies against different immunological epitopes of AGE structures, including N o -(carboxymethyl)lysine-protein adduct (CML), a glycoxidation product, and structure(s) other than CML (nonCML), and a monoclonal antibody against oxidized phosphatidylcholine (oxPC), as an epitope of oxidized LDL. Immunohistochemical analysis demonstrated that the CML- and oxPC-epitopes were accumulated mainly in macrophage-derived foam cells in atherosclerotic lesions, including fatty streaks and atherosclerotic plaques. On the other hand, the nonCML-epitope and apolipoprotein B were localized mainly in extracellular matrices of atherosclerotic lesions. The CML- and oxPC-epitopes were characterized by a model antigen-generating system using the copper ion-induced peroxidation and:or glucose-induced glycation of LDL. The glycoxidation of LDL caused the formation of CML-epitope with increasing concentrations of copper ion and glucose. It was also formed to some extent in LDL incubated with high concentrations (500 mM) of glucose. However, no CML-epitope was observed in oxidized LDL induced by copper ion alone. On the other hand, the formation of oxPC-epitope in LDL was dependent on copper ion-induced peroxidation, but independent of glucose-induced glycation. The addition of chelators, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, reduced the increase in electrophoretic mobility and TBARS caused by the peroxidation and glycoxidation of LDL, but had no effects on the formation of fructosamine caused by the glycation and glycoxidation of LDL. Chelators as well as aminoguanidine protected the formation of CML-epitope in glycated or glycoxidative LDL. Although the formation of oxPC-epitope was completely inhibited by the addition of chelators, it was partially protected by aminoguanidine. These in vitro results suggest that the glycoxidative modification of LDL may occur in the arterial intima, and may contribute to the development of human atherosclerotic lesions. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

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

We previously purified a kallikrein-like enzyme from the dog heart and demonstrated that it is not only able to form kinins but can also convert angiotensin (Ang) I to Ang II. The aim of the present study was to clarify the structure and tissue localization of this enzyme. Western blot analysis of various canine tissues was performed with antiserum against the purified dog heart enzyme. The purified enzyme was subjected to a determination of its amino acid composition and a sequence analysis. Western blotting indicated that this enzyme was present in the heart, aorta, kidney, pancreas, lung, liver, spleen, small intestine, and skeletal muscle. The amino acid composition of the enzyme was different from that of dog urinary kallikrein. Amino acid sequence analysis indicated that it is likely to be N-terminally blocked. The present study showed that this kallikrein-like enzyme is different from previously reported kallikrein and is distributed not only in the heart, but also in other tissues such as the aorta, kidney, lung, liver, spleen, small intestine, and skeletal muscle. This enzyme may exert local effects by generating kinins and Ang II.

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.

Abstract —A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu235→0) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli . Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with [ 3 H]cholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235→0) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels.

Abstract —Locally formed angiotensin II (Ang II) and mast cells may participate in the development of atherosclerosis. Chymase, which originates from mast cells, is the major Ang II–forming enzyme in the human heart and aorta in vitro. The aim of the present study was to investigate aortic Ang II–forming activity (AIIFA) and the histochemical localization of each Ang II–forming enzyme in the atheromatous human aorta. Specimens of normal (n=9), atherosclerotic (n=8), and aneurysmal (n=6) human aortas were obtained at autopsy or cardiovascular surgery from 23 subjects (16 men, 7 women). The total, angiotensin-converting enzyme (ACE)-dependent, and chymase-dependent AIIFAs in aortic specimens were determined. The histologic and cellular localization of chymase and ACE were determined by immunocytochemistry. Total AIIFA was significantly higher in atherosclerotic and aneurysmal lesions than in normal aortas. Most of AIIFA in the human aorta in vitro was chymase-dependent in both normal (82%) and atherosclerotic aortas (90%). Immunocytochemical staining of the corresponding aortic sections with antichymase, antitryptase or anti-ACE antibodies showed that chymase-positive mast cells were located in the tunica adventitia of normal and atheromatous aortas, whereas ACE-positive cells were localized in endothelial cells of normal aorta and in macrophages of atheromatous neointima. The density of chymase- and tryptase-positive mast cells in the atherosclerotic lesions was slightly but not significantly higher than that in the normal aortas, and the number of activated mast cells in the aneurysmal lesions (18%) was significantly higher than in atherosclerotic (5%) and normal (1%) aortas. Our results suggest that local Ang II formation is increased in atherosclerotic lesions and that chymase is primarily responsible for this increase. The histologic localization and potential roles of chymase in the development of atherosclerotic lesions appear to be different from those of ACE.

Abstract —Apolipoprotein (apo) A1 plays a central role in the metabolism of HDL. We describe a novel genetic variant of the apoA1 gene identified in a patient with low concentrations of plasma HDL cholesterol. The proband, a 12-year-old Japanese boy, exhibited markedly low levels of both plasma apoA1 and HDL cholesterol. Genomic DNA sequencing of apoA1 genes of the patient showed a compound heterozygosity for an A to C substitution at 27 bp upstream of the transcription start site of 1 apoA1 allele, and a C to T substitution in another allele at residue 84 resulting in aberrant termination. The point mutation at nucleotide position –27 changed ATAAATA of the putative TATA box signal sequence to ATACATA. In addition to this mutation, the patient was heterozygous for a G to A substitution at position –75. Immunoblotting of an isoelectric focusing electrophoresis gel of the proband’s plasma showed a trace amount of normal apoA1. No measurable plasma apoA1 and HDL cholesterol in a patient with homozygosity for nonsense mutation at residue 84 has been reported previously. To determine the effects of substitution either at position –27 or –75, plasmids containing the 5′-flanking region of the human apoA1 promoter fused to the CAT reporter gene were constructed and transfected in HepG2 cells. A construct with the A to C substitution at position –27 showed 41.8±4.2%, and G to A substitution at position –75 showed 72.8±15.2% (means±SD, n=3) of CAT activities, compared with the wild-type promoter sequence. A construct with the double substitutions at positions –27 and –75 showed only 22.8±1.3% (mean±SD, n=3) activity relative to the wild type. Our patient is the first case with a TATA box mutation etiologically related to lipoprotein disorders.

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.

Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p

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

Abstract —Angiotensin (Ang) II plays an important role in cardiovascular homeostasis, not only in the systemic circulation but also at the tissue level, and is involved in the remodeling of the heart and vasculature under pathological conditions. Although alternative Ang II–forming pathways are known to exist in various tissues, the details of such pathways remain unclear. The aim of this study was to examine tissue Ang II–forming activities and to identify the responsible enzyme in several organs (lung, heart, and aorta) in various species (human, hamster, rat, rabbit, dog, pig, and marmoset). Among the organs examined, the lung contained the highest Ang II–forming activity. The responsible enzyme for pulmonary Ang II formation was angiotensin I-converting enzyme (ACE) in all of the species except the human lung, in which a chymaselike enzyme was dominant. In the heart, the highest total Ang II–forming activity was observed in humans, and a chymaselike enzyme was dominant in all of the species except rabbit and pig. Aorta exhibited a relatively high total Ang II–forming activity, with a predominance of chymaselike activity in all of the species except rabbit and pig, in which ACE was dominant. Our results indicate that there were remarkable differences in Ang II–forming pathways among the species and organs we examined. To study the pathophysiological roles of ACE-independent Ang II formation, one should choose species and/or organs that have Ang II–forming pathways similar to those in humans.

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.

Abstract —We analyzed the genetic defect in a 67-year-old Japanese male patient with apolipoprotein (apo) A-I and high density lipoprotein (HDL) deficiencies, corneal opacities, and coronary artery disease. The plasma concentrations of apoA-I and HDL cholesterol were 2.9 to 7.3 mg/dL and 0.08 to 0.19 mmol/L, respectively. The lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate were

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.

Apolipoprotein A-IV (apo A-IV) is involved in the metabolism of both triglycerides and high-density lipoproteins (HDLs). Apo A-IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A-IV has made the use of genetic apo A-IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon -8 (G-->A, non-synonymous) allele 2 = 0 (n = 105); (b) codon 9 (A-->G, synonymous) allele 2 = 0.388 (n = 152); (c) codon 347 (A-->T, non-synonymous) allele 2 = 0 (n = 900); (d) codon 360 (T-->G, non-synonymous) allele 2 = 0 (n = 800); (e) VNTR exon 3 [(CTGT)3 and (CTGT)4] (CTGT)3 = 0.262 (n = 105); and (f) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2 = 0.096 (n = 193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A-IV. The apo A-IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2 = 0.329 (n = 217); VNTR exon 3 (CTGT)3 = 0.262 (n = 84); MspI within intron 2, allele 2 = 0.092 (n = 222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender-specific effects of apo A-IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A-IV gene is not a major determinant of the risk for CHD in Japanese.