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Biomedical subjects

T Kushiro

Publications and source records attributed to T Kushiro.

At least 37 records · Page 2Linked to original sources
PubMed1998

Beta-amyrin synthase--cloning of oxidosqualene cyclase that catalyzes the formation of the most popular triterpene among higher plants.

Beta-amyrin, a typical pentacyclic triterpene having an oleanane skeleton, is one of the most commonly occuring triterpenes in nature and is biosynthesized from (3S)-2,3-oxidosqualene. The enzyme, beta-amyrin synthase, catalyzing the cyclization of oxidosqualene into beta-amyrin, generates five rings and eight asymmetric centers in a single transformation. A homology-based PCR method was attempted to obtain the cDNA of this enzyme from the hairy root of Panax ginseng which produces oleanane saponins together with dammarane-type saponins. Two sets of degenerate oligonucleotide primers were designed at the regions which are highly conserved among known oxidosqualene cyclases (OSCs). Nested PCRs using these primers successfully amplified the core fragment which revealed the presence of two OSC clones PNX and PNY. Specific amplification of each clone by 3'-RACE and 5'-RACE was carried out to obtain the whole sequences. The two clones exhibited 60% amino acid identity to each other. A full-length clone of PNY was ligated into the yeast expression vector pYES2 under the GAL1 promoter to give pOSC(PNY). Beta-amyrin production was observed with the mutant yeast lacking lanosterol synthase, transformed by this plasmid. The sequence of pOSC(PNY) contains an open reading frame of 2289 nucleotides which codes for 763 amino acids with a predicted molecular mass of 88 kDa. Sequence comparison with other OSCs showed a high level of similarity with lanosterol, cycloartenol and lupeol synthases. The other clone, pOSC(PNX), was shown to be cycloartenol synthase by similar expression in yeast. The present studies have revealed that distinct OSC exists for triterpene formation in higher plants, and the high level of similarity with cycloartenol synthase indicates close evolutional relationship between sterol and triterpene biosynthesis.

Amino Acid Sequence↗
PubMed1998

Variations in insulin sensitivity in spontaneously hypertensive rats from different sources.

We investigated the possibility of variations in the genetic transmission of insulin sensitivity in the offspring of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs) obtained from different sources (Charles River, Tokyo, Japan [NCrj]; and Funabashi Farm, Chiba, Japan [Izm]) with the insulin suppression test (IST) using a somatostatin analog, glucose, and insulin. The steady-state blood glucose (SSBG) in the IST and the glucose infusion required (GIR) in the euglycemic-hyperinsulinemic clamp differ significantly between obese and lean Zucker rats, indicating that both methods are useful for identifying insulin resistance. The fasting blood glucose and SSBG of the IST were significantly higher in SHR/Izm than in WKY/Izm. We did not observe a significant difference between SHR/NCrj and WKY/NCrj. These results indicate that the genetic transmission of hypertension and impaired insulin sensitivity may be variable and that insulin resistance does not play an important role in the pathogenesis of hypertension in the SHR.

Animals↗
PubMed1998

Left ventricular geometric patterns and QT dispersion in borderline and mild hypertension: their evolution and regression.

To investigate whether QT dispersion increases in borderline and mild hypertension during a longitudinal observation of > 3 years and whether it is improved with medications, left ventricular geometric patterns and QT dispersion were studied with special regard to their longitudinal changes in 85 male borderline and mild hypertensive subjects with left ventricular mass index < 125 g/m2. These subjects were followed for > 3 years without medication. Thirty-two patients with a left ventricular mass index > 125 g/m2 at the end of follow-up period were further observed using antihypertensive drugs for an additional 3 years. Echocardiograms and electrocardiograms were obtained at the beginning and end of the follow-up period. At the end of the follow-up period, subjects were classified into four groups based on ventricular geometric patterns determined by left ventricular mass index and relative wall thickness in diastole. The QT dispersion was greater in patients with concentric hypertrophy (56+/-18 msec) than in patients with normal geometry (41+/-17 msec) (P < .05) and increased significantly in the former group during the follow-up period. After medication, the left ventricular mass index regressed and the QT dispersion decreased (from 55+/-21 to 50+/-26 msec, P < .01) in these patients. Thus, these findings suggest that changes in the QT dispersion reflect both concentric evolution and regression of left ventricular hypertrophy.

Adult↗
PubMed1998

Relationship between endothelial function and fibrinolysis in early hypertension.

Abnormalities in fibrinolysis, endothelial function, and glucose and lipid metabolism have been reported in hypertension. This study was conducted to examine the interrelationships between fibrinolytic factors, glucose and lipid metabolism, and endothelial function in hypertension. The effects of administering an angiotensin converting enzyme inhibitor, benazepril, were also examined. Blood levels of the following substances were measured in patients with borderline and mild hypertension (n=50, 51+/-19 years) and in age-matched controls (n=10): total cholesterol, triglycerides, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen. Insulin sensitivity was assessed by oral glucose tolerance test, and endothelial function was assessed by evaluating changes in diameter of the brachial artery during reactive hyperemia as observed by ultrasonography. Activities of tissue plasminogen activator and plasminogen activator inhibitor type 1 were both elevated in the hypertensive patients. Stepwise multiple regression analysis showed that plasminogen activator inhibitor type 1 antigen correlated with insulin sensitivity, total cholesterol levels, and triglycerides levels (P<.01). Endothelial function was negatively correlated with tissue plasminogen activator activity and antigen (P<.01). The chronic administration of benazepril (5-10 mg/d) for 20 weeks improved insulin sensitivity, endothelial function (6.6+/-3.4-->9.0+/-2.5%, P<.01), and tissue plasminogen activator activity and antigen. These results indicate that abnormalities in fibrinolysis are associated with endothelial dysfunction as well as disorders of glucose and lipid metabolism in patients with borderline and mild hypertension. The treatment of such patients with benazepril appeared to improve the impairment in fibrinolysis and endothelial dysfunction.

Adult↗
PubMed1998

[Effects of doxazosin and hydralazine on insulin sensitivity and sympathetic function in spontaneously hypertensive rat (SHR)].

Since insulin resistance and/or hyperinsulinemia may contribute to structural changes of the vascular wall, the influence of antihypertensive agents on insulin sensitivity could interfere with the long term outcome of blood pressure reduction. Although it is postulated that increased peripheral circulation due to vasodilating agents improves insulin sensitivity, reflex sympathetic activation elicited by blood pressure reduction may influence insulin sensitivity. Thus we investigated the different effects of an alpha blocker (doxazosin) as well as a direct vasodilation (hydralazine) on insulin sensitivity and on sympathetic function in spontaneously hypertensive rats (SHR). Doxazosin and hydralazine decreased mean arterial pressure to a similar extent. Doxazosin, but not hydralazine decreased steady state blood glucose. Plasma norepinephrine increased in doxazosin and hydralazine treated groups as compared to the control group. Thus, despite their similar effects on blood pressure and plasma norepinephrine, alpha-1 blocker improved insulin sensitivity while the direct vasodilator failed to do so, and this difference is probably related to blockade of the alpha-1 receptor rather than to peripheral vasodilation.

Adrenergic alpha-Antagonists↗
PubMed1997

The relationship of hyperinsulinemic state to left ventricular hypertrophy, microalbuminuria, and physical fitness in borderline and mild hypertension.

The relationship of the hyperinsulinemic state to left ventricular hypertrophy, left ventricular geometric patterns, microalbuminuria, and physical fitness were studied in 52 middle-aged unmedicated men with borderline and mild hypertension. Left ventricular mass index and relative wall thickness were assessed by echocardiography. Physical fitness was determined by symptom-limited maximal treadmill stress testings. The urinary concentration of microalbumin and C-peptide was measured in 24-h urine samples by radioimmunoassey. The 24-h urinary C-peptide excretion rate was correlated with left ventricular mass index (r = 0.46), relative wall thickness (r = 0.41), treadmill time (r = -0.35), normalized treadmill time (r = -0.52), systolic blood pressure at peak exercise (r = 0.29), and 24-h urinary microalbumin excretion (r = 0.48). Stepwise multiple regression analysis identified the left ventricular mass index, the 24-h urinary albumin excretion, and the normalized treadmill time as variables in the equation for the 24-h urinary C-peptide excretion. Thus, the hyperinsulinemic state is related to left ventricular hypertrophy, microalbuminuria, and impaired physical fitness in patients with borderline and mild hypertension.

Adult↗
PubMed1997

In vitro conversion of 2,3-oxidosqualene into dammarenediol by Panax ginseng microsomes.

(RS)-[3-3H]-2,3-Oxidosqualene (1) was converted into (20S)-dammarenediol (2) and not to (20R)-dammarenediol by a microsomal fraction prepared from the hairy root of Panax ginseng. The enzyme activity was highest at pH 6.0 and was not increased by the addition of any detergents. These properties differed significantly from those of other 2,3-oxidosqualene cyclases reported from higher plants and animals.

Cyclization↗
PubMed1997

Effects of long-term antihypertensive therapy on physical fitness of men with mild hypertension.

This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.

Acebutolol↗
PubMed1996

Prospective studies on left ventricular geometric patterns and exercise tolerance in unmedicated men with borderline and mild hypertension.

OBJECTIVE: This study was designed and conducted to assess the clinical significance of left ventricular geometric patterns and physical fitness in subjects with untreated borderline and mild hypertension. METHODS: Symptom-limited maximal treadmill stress testings and echocardiographic examinations were administered to 192 previously unmedicated men. Left ventricular geometric patterns were determined by the combined criteria of left ventricular mass index and relative wall thickness. Subjects whose left ventricular mass index was < 125 g/m2 were followed up for more than 3 years. RESULTS: Normalized treadmill time was lower and pressure rate products at peak exercise were higher in patients with concentric hypertrophy than in those with normal geometry. Of the 77 patients who revealed left ventricular mass index at baseline < 125 g/m2 and who were successfully followed without medication for more than 3 years, 18 demonstrated concentric hypertrophy at the final follow-up examination. During the follow-up period, these 18 patients had significant further augmentation of concentric geometric features, significant decreases in both cardiac output and normalized treadmill time, and significant increases in casual blood pressure and total peripheral resistance compared with those at baseline. CONCLUSION: Patients with concentric hypertrophy exhibited slightly but significantly impaired levels of physical fitness and cardiac work efficiency, and the progression of concentric hypertrophy demonstrated further impairments of these conditions. Therefore, not only lowering blood pressure, but also improving left ventricular hypertrophy, cardiovascular hemodynamics, and physical fitness might be required in patients with concentric hypertrophy.

Adult↗
PubMed1996

Long-term reproducibility and usefulness of daytime recording of noninvasive 24-hour ambulatory blood pressure monitoring in borderline hypertension: a two-year follow-up study.

We investigated the long-term reproducibility of noninvasive 24-hour ambulatory blood pressure monitoring (ABPM) compared with casual blood pressure measurements in 54 individuals (47 +/- 11 years) with borderline hypertension. ABPM and casual blood pressure measurements were obtained 3 times over 2 year period. ABPM data were analyzed to determine the average 24-hour blood pressure (24-BP), the average blood pressure during the waking hours (Day-BP), and the average blood pressure from the time the subject went to bed until he awoke (Night-BP). ABPM measurements were similar for Year 1, 2, and 3 (24-BP: Year 1; 130 +/- 10/79 +/- 6 mmHg; Year 2; 130 +/- 10/79 +/- 7 mmHg; and Year 3; 130 +/- 10/78 +/- 7 mmHg). Bland-Altman analysis and standard deviation of the difference also indicated the reproducibility of 24-BP was better than casual pressure. The 24-BP was significantly correlated with both Day-BP and Night-BP for each year. Day-BP showed the stronger correlation. Our results suggest that Day-BP provides reproducible estimation in subjects with borderline hypertension.

Adult↗
PubMed1996

[Clinical effects of beni-koji in mild essential hypertension--a multi-center double-blind comparison with placebo].

Antihypertensive effects of beni-koji were studied using 29 outpatients with mild hypertension in a placebo-controlled double-blind comparative fashion. After a 4-week vehicle (apple juice) run-in period, 13 patients were assigned to receive beni-koji aqueous extracts containing juice once daily (27 g of beni-koji eq. per day) for 8 weeks and 16 were assigned to vehicle. Two patients assigned to the vehicle group did not complete the study. In addition to casual blood pressure, 24-hr non-invasive ambulatory blood pressure (ABP) was monitored in 6 patients given the beni-koji drink and 5 patients given the vehicle. 1) In the beni-koji group, both casual systolic and diastolic pressure decreased significantly during the treatment period (from 150 +/- 10/96 +/- 6 mmHg to 140 +/- 10/89 +/- 10 mmHg, p < 0.01). The averages of the 24-hr blood pressure recorded in ABP (24-BP) also significantly decreased (from 141 +/- 17/95 +/- 13 mmHg to 132 +/- 21/86 +/- 10 mmHg, p < 0.05) when compared with those of the control period. Casual pressure normalized (less than 140/90 mmHg) in 4 patients who received beni-koji. Circadian variation of the blood pressure by ABP showed a significant decrease during the daytime. 2) In the vehicle group, casual systolic pressure did not change significantly (from 155 +/- 8 mmHg to 151 +/- 12 mmHg), but diastolic pressure decreased significantly (98 +/- 7 mmHg to 93 +/- 6 mmHg). Casual blood pressure did not normalize in any of the patients and 24-BP did not change significantly. 3) Summative evaluation of safety showed that no problems appeared in the beni-koji group. In conclusion, beni-koji appears to be an effective and safe food material for mild essential hypertension. The mechanism of the antihypertensive effect of beni-koji still remains to be investigated.

Antihypertensive Agents↗
PubMed1995

Changes in the E/A ratio induced by handgrip-exercise are related to changes in the plasma atrial natriuretic peptide level, but not to changes in brain natriuretic peptide in mild essential hypertension.

We investigated the relationship between changes in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and changes in cardiac function during mild exercise in patients with mild hypertension. The handgrip test (HGT) was performed by 21 untreated, mildly hypertensive patients, mean age 45 +/- 5 years. M-mode and pulse Doppler echocardiograms were recorded before and during HGT. In 7 patients (Group A), diastolic function, which was determined by the peak early velocity and peak atrial velocity (E/A) ratio using Doppler echocardiography was attenuated during HGT (1.19 +/- 0.21 TO 1.04 +/- 0.16, p < 0.05). There was no change in diastolic function in the remaining 14 patients, left atrial diameter, cardiac index, ejection fraction, plasma renin activity, plasma norepinephrine, blood pressure, nor heart rate were different between the two groups. While ANP was increased in Group A during HGT (from 41.0 +/- 18.2 to 54.0 +/- 24.1 pg/ml, p < 0.05) it was unchanged in Group B (36.8 +/- 16.3 to 33.5 +/- 11.9 pg/ml). BNP did not change in either Group (Group A: 2.9 +/- 3.1 to 3.0 +/- 3.4 pg/ml, Group B: 2.6 +/- 1.6 to 3.6 +/- 4.8 pg/ml). The percent change in ANP during HGT did not correlate with the percent change in BNP. Thus, the impairment of cardiac functional reserve appeared to influence ANP excretion in patients with mild hypertension.

Adult↗
PubMed1994

Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor.

Although angiotensin converting enzyme inhibitors and alpha 1-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an alpha 1-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128 +/- 1 mmHg) and doxazosin (132 +/- 2 mmHg) decreased mean blood pressure compared with control levels (148 +/- 1 mmHg) (P < .01). The glucose requirement for the clamp test during the administration of enalapril (25.8 +/- 0.5 mg/kg per minute) or doxazosin (28.6 +/- 0.7 mg/kg per minute) was higher than that of the control group (19.8 +/- 0.5 mg/kg per minute) (P < .05). Although Hoe 140 did not alter the glucose requirement of doxazosin (27.8 +/- 0.5 mg/kg per minute), it decreased that of enalapril (22.6 +/- 0.9 mg/kg per minute) (P < .05) without affecting the changes in mean blood pressure induced by enalapril. In addition, losartan decreased mean blood pressure but did not affect the glucose requirement. Thus, the improvement in insulin sensitivity produced by an angiotensin converting enzyme inhibitor is mostly dependent on kinins but not on angiotensin II antagonism, and an alpha 1-blocker improves insulin sensitivity irrespective of kinins.

Analysis of Variance↗
PubMed1993

Management problems in continuous care of male patients with mild hypertension with special reference to alcohol-intake.

Forty two male patients with borderline and mild hypertension were followed up for 3.9 years without medication. During this period, all subjects had nonpharmacological interventions including salt restriction, weight reduction, anti-smoking or anti-alcohol instruction, and physical exercise after the established protocol. Comparisons of biomedical data between pre- and post-observation revealed no significant improvements. Although the smoking habit decreased during this period, the drinking habit rarely changed and even significant increase of the total amount of alcohol ingestion was observed. These data indicate great limitation of nonpharmacological intervention in the care of these asymptomatic hypertensive patients for a lifelong base.

Adult↗
PubMed1992

Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.

Animals↗