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Biomedical subjects

M Shibasaki

Publications and source records attributed to M Shibasaki.

At least 109 records · Page 6Linked to original sources
PubMed1998

Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives.

A novel series of nonpeptide angiotensin II antagonists containing the acrylamide group at the 4-position of the imidazole ring was synthesized and their antagonistic activity was examined by functional assay in rabbit aorta. The acrylamide group was selected as a large lipophilic surrogate for the chloro group of EXP3174. A structure-activity relationship study of the acrylamide moiety has shown that substitution at the 4-position with the N-methyl-3,3-dimethylacrylamide group resulted in the optimal compound, 2-butyl-4-[(3,3-dimethylacryloyl)methyl-amino]-1-[[2'-(1H-tetra zol-5- yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (1), which was superior to EXP3174 in vitro. Since 1 showed only poor activity against angiotensin II-induced pressor response in rats after oral administration, the carboxylic acid function of 1 was converted into prodrug esters (13). Among these, the 1-[(ethoxycarbonyl)oxy]ethyl ester (13a) showed the most potent and longest-lasting activity when given orally to rats. When administered orally to conscious furosemide-treated dogs, 13a showed an approximately 3-fold increased hypotensive activity in comparison with DuP 753. These data suggest that 13a may be an useful agent for the treatment of angiotensin II-dependent diseases, such as hypertension.

Acrylamides↗
PubMed1998

Control of circadian variation in skin blood flow response to heat stress.

Six male subjects had their lower legs immersed in water at 42 degrees C for 60 min at 4 different times of the day to study whether the skin blood flow response to passive heat stress shows circadian variation in the relationship between skin blood flow and local sweating rate. When skin blood flow was plotted against local sweating rate, three distinct phases were observed. Phase A, an increase in skin blood flow without sweating was maximal at night. But the slope of the regression line did not change over the day in Phase C. These findings suggest that there is circadian variation in the skin blood flow response before onset of sweating during passive heat stress. This variation might be related, in part, to the circadian rhythm in vasoconstrictor activity.

Adult↗
PubMed1997

Circadian variation in skin blood flow responses to passive heat stress.

To examine whether there is a circadian variation in skin blood flow response to passive heat stress and maximal skin blood flow, which was measured by local warming to 42 degrees C for 45 min, we studied six men at an ambient temperature of 28 degrees C at four different times of day [0400-0700 (morning), 1000-1300 (daytime), 1600-1900 (evening), and 2200-0100 hours (night)], each time of day being examined on separate days. Heat stress at rest was performed by immersing the legs below the knee in hot water (42 degrees C) for 60 min. The esophageal temperature (Tes) at rest was significantly higher in the evening than in the morning. The maximal skin blood flow (SkBFmax) on both sites, back and forearm, did not show a significant difference among the four times of day. The variation in Tes thresholds for cutaneous vasodilation to heat stress was similar to the circadian rhythm in resting Tes. The relationship of the percentage of SkBFmax (%SkBF) with Tes was significantly lower in the morning than in the evening. The results suggest that the maximal skin blood flow during local warming does not show variation over the day, but the sensitivity of vasodilation to passive heat stress shows a circadian variation.

Adult↗
PubMed1997

Pharmacological profile of YM358, a novel nonpeptide angiotensin AT1 receptor antagonist.

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a novel non-peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [125I][Sar1, Ile8]angiotensin II for angiotensin AT1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [125I][Sar1, Ile8]angiotensin II to the angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration-response curve for angiotensin II with a pA2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F2alpha or endothelin-1 even at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues, YM358 was approximately 3-10 times more potent than losartan in antagonizing angiotensin AT1 receptors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of angiotensin II in a dose-dependent manner. In conscious normotensive rats, YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced pressor response in a dose-dependent manner. YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that YM358 is a potent, AT1-selective and competitive nonpeptide angiotensin receptor antagonist. Moreover, YM358 is both orally active and long-lasting. This pharmacological profile suggests that YM358 would be suitable for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.

Angiotensin II↗
PubMed1997

Antihypertensive activity of a nonpeptide angiotensin II receptor antagonist, YM358, in rats and dogs.

The antihypertensive activity of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a new nonpeptide angiotensin II receptor antagonist, was characterized in rats and dogs. In conscious rats, YM358 after a single oral administration (1-30 mg/kg) lowered blood pressure. The rank order of hypotensive potency of YM358 in conscious rats was 2-kidney, 1-clip renal hypertensive rats > spontaneously hypertensive rats > normotensive rats on the basis of maximum hypotension. YM358 also caused decreases in blood pressure in 2-kidney, 1-clip renal hypertensive dogs and furosemide-treated dogs. Repeated administration of YM358 to 2-kidney, 1-clip renal hypertensive rats for 28 days produced a stable and long-lasting antihypertensive effect without influencing circadian blood pressure and heart rate rhythms. No reflex tachycardia was observed in any animals of either species treated with YM358. Therefore, the pharmacological profile of this compound indicates that YM358 has potential as a useful antihypertensive agent.

Angiotensin II↗
PubMed1997

Human alveolar macrophages synthesize endothelins by thrombin.

Alveolar macrophages (AM) play pivotal roles in the defense mechanism and the regulation of inflammatory processes in the airways. Macrophages express receptors for thrombin on their surfaces, and thrombin induces the chemotaxis and the proliferation of macrophages. Thrombin acts on vascular endothelial cells to synthesize endothelin (ET)-1. AM have been known to express prepro ET-1 mRNA. Thus, we hypothesized that thrombin stimulates AM so as to synthesize ET. Surgically resected human lungs were irrigated by saline to remove intravascular blood, then saline was instilled into the bronchus, and the fluids were recovered. AM were separated by Percoll density centrifugation (density, 1.060 g/ml). AM were resuspended in culture medium without FCS in the presence or absence of thrombin. ET was synthesized by thrombin in a concentration-dependent manner, and the amounts of ET synthesized by thrombin (10 U/ml) were equivalent to those by LPS (10 microg/ml). Dexamethasone (10(-6)-10(-10) M), IL-4 (100 U/ml), and TGF-beta (10 ng/ml) significantly suppressed the ET synthesis by thrombin (p < 0.05). In contrast, 1,25-dihydroxyvitamin D3 (10(-8)-10(-10) M) enhanced the ET synthesis up to approximately 300%. The analysis using high pressure liquid chromatography revealed that AM-derived ET consists of ET-1, ET-2, and ET-3. Major constituents were ET-2 and ET-1, and the ratio of ET-2/ET-1 was 1.7 +/- 0.4 (mean +/- SE). These results indicate that thrombin is a potent agonist for AM to synthesize ET.

Cells, Cultured↗
PubMed1997

Thermoregulatory responses of prepubertal boys and young men during moderate exercise.

Seven prepubertal boys (aged 10-11 years) and eleven young men (aged 21-25 years), matched for skinfold thickness and maximal oxygen uptake (VO2max) per unit of mass, cycled at an intensity of approximately 40% VO2max for 45 min in a warm condition (30 degrees C, 45% relative humidity). During exercise no age-related differences were observed for the increases in rectal temperature (Tre) and heart rate (HR), although the absolute Tre and HR were significantly greater for the boys because of a higher initial baseline (P < 0.05). Total body sweating rate [181 (SEM 12) vs 245 (SEM 12) g.m-2(.)45 min-1; P < 0.002] and local sweating rates (msw) on chest, back, and forearm were significantly lower for the boys (P < 0.001), as was metabolic heat production [203 (SEM 9) vs 276 (SEM 9) W.m-2; P < 0.01]. The lower msw in the boys was due to a lower output per activated sweat gland, even though they had a higher activated sweat gland density regardless of site. In contrast, cutaneous blood flow by laser Doppler flowmetry (LDF) in the boys was significantly greater on the chest and back, compared to the men (P < 0.003). The age-related differences in cutaneous vascular conductance (CVC) were more marked because of lower mean arterial pressure in the boys during exercise. However, forearm LDF and CVC were significantly lower for the boys (P < 0.008). No significant differences in LDF among sites were observed for the boys, whereas for the men LDF on the forearm was significantly greater than on the chest and back (P < 0.01). The boys showed lower mean skin temperatures (especially on the back and chest despite greater increments of LDF) after starting to sweat, whereas the men remained unchanged, suggesting that the heat loss on the trunk in the boys was promoted by greater increments of LDF despite lower msw, compared to the young men. It was concluded that during moderate exercise in an air temperature at 30 degrees C, prepubertal boys could thermoregulate as efficiently as young men by greater vasodilatation on their trunk despite lower msw. Furthermore regional differences may exist in the maturation-related modification of vasodilatation.

Adult↗
PubMed1997

Mechanisms of underdeveloped sweating responses in prepubertal boys.

To approach the mechanisms underlying the underdeveloped sweating responses of prepubertal boys, 8 boys (7-11 years old) and 11 men (21-25 years old) were exposed to a standard heat stress for 60 min. The test consisted of placing the subjects' lower legs into a 42 degrees C water bath while they sat in otherwise constant environmental conditions (ambient temperature 25 degrees C and 45% relative humidity). Rectal (T[re]) and skin temperatures, local sweating rates (mSW: on the chest, back, forearm and thigh) and the frequency of sweating expulsions (fSW: as an indicator of central sudomotor activity) were measured during the test. During the passive heating, no group differences were observed for the increase in T(re), mean skin temperature and metabolic heat production. However, mean body temperature (Tb) during heating was significantly higher for the boys (P < 0.001) because of a higher baseline T(re). The boys had lower mSW on the chest (P < 0.004) and thigh (P < 0.001) during the latter half of the 60-min exposure compared to the young men, although a similar mSW was observed between the groups during the first half of the test. The group difference of mSW on the back was similar to that of the chest and thigh, but the difference was not significant (P = 0.10). In contrast, the boys had a greater mSW on the forearm throughout the heating (P < 0.03). The slope of the mSW vs fSW relationship was significantly lower for the chest and thigh in the boys compared to the men (P < 0.05), and the same tendency was observed for the back (but was not significant, P = 0.10). In contrast, no difference was observed between the groups for the slope of mSW vs fSW for the forearm. Furthermore, a lower sweat output per gland was also observed on the chest, back, and thigh in the boys (P < 0.01), but not on the forearm. No group difference was observed for the slope of the fSW vs Tb relationship. These results suggest that the lower mSW observed in the prepubertal boys were due possibly to underdeveloped peripheral mechanisms, including the sweat glands and their surrounding tissues, rather than to an underdeveloped central drive activity related to sudomotor function. Regional differences may well exist in any underdeveloped peripheral mechanism associated with maturation.

Adult↗
PubMed1997

The effect of change in skin temperature due to evaporative cooling on sweating response during exercise.

The purpose of this study was to investigate whether there are any effects of skin temperature changes on sweating response in the first few minutes of mild exercise. Six healthy males performed a bicycle exercise at 100 W (50 rpm) for 30 min under an ambient temperature of 23 degrees C (40% RH). Esophageal temperature (Tes), mean skin temperature (Tsk), local skin temperature at the lower left scapula (Tsl), local sweating rate (Msw) and cutaneous blood flow by laser-Doppler flowmetry (LDF) were measured continuously. Although Tsl decreased markedly just after the onset of sweating, Tsk did not change. Msw did not increase constantly in the early stages of exercise, and there was a temporary interruption in the increase of Msw. This interruption in sweating was affected by the rate of change in Tsl rather than by the absolute value of Tsl, since there was a positive and significant correlation between the time of the interruption in the increase of Msw and the rate of decrease in Tsl (y = 6.47 x +0.04; r = 0.86, P < 0.05). The results suggest that sweating response in the early stages of exercise may be influenced by changes in local skin temperature due to evaporative cooling.

Adult↗
PubMed1997

Effects of reduced muscle temperature on the oxygen uptake kinetics at the start of exercise.

The purpose of this study was to examine the effects of reduced muscle temperature (Tm) on gas exchange kinetics and haemodynamics at the start of exercise. Six male subjects performed moderate cycle exercise under reduced (C) and normal (N) Tm conditions. Tm and rectal temperature were significantly reduced by immersion in cold water (by 6.6 degrees C and 1.8 degrees C, respectively). The increases in oxygen uptake (Vo2) and oxygen pulse (Vo2/HR) during phase 1 (abrupt increase after the start of exercise) were significantly lower under C than under N. The time constant for O2 under C (36.0 +/- 7.7 (SD)s) was significantly greater than under N (27.5 +/- 4.4 s); however, the time constants of cardiac output under C (38.3 +/- 16.6 s) and N (33.7 +/- 18.5 s) were similar. These results suggest that the slower Vo2 on-response under reduced Tm conditions is caused by decreased O2 extraction in working muscle and/or by impairment of oxidative reactions by reduced muscle temperature.

Adult↗
PubMed1997

Circadian variation of sweating responses to passive heat stress.

The aim of present study was to examine whether sweating responses to passive heat stress change with the circadian rhythm of internal temperature. Six men had their legs immersed in water at 42 degrees C for 60 min in an ambient temperature of 28 degrees C on four separate days. Experiments were conducted at four different times [06.00 h (morning), 12.00 h (daytime), 18.00 h (evening) and 24.00 h (night)]. We measured oesophageal temperature (Toes), mean body temperature (Tb), local sweating rate (msw) on the forehead, back, forearm and thigh, the densities of activated sweat gland (ASG) on the back, forearm and thigh, and the frequency of sweat expulsion per minute (Fsw) which has been suggested to represent central sudomotor activity. Sweat gland output (SGO) on each site was calculated by dividing msw by ASG. ASG was significantly higher on the forearm than on the back and thigh, and SGO was significantly lower on the forearm than on the back and thigh. However, ASG and SGO did not significantly change over the day. Tb and Toes thresholds for the onset of sweating showed a significant change with both the temperature rhythms at rest prior to each procedure, while the slopes of the relationships Fsw-Tb and msw-Fsw showed no significant difference over the day. We suggest that the circadian variation of sweating response to passive heat stress is regulated by a central sudomotor mechanism rather than by sweat gland function.

Adult↗
PubMed1997

Significance of monitoring plasma levels of amitriptyline, and its hydroxylated and desmethylated metabolites in prediction of the clinical outcome of depressive state.

The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 inpatients. Discriminant analysis of drug concentrations (at two weeks after initiation of drug treatment) and clinical outcome revealed that increasing the plasma levels of amitriptyline, cis-isomers of hydroxylated metabolites (Z-10-hydroxyamitriptyline and Z-10-hydroxynortriptyline) predicted a better clinical outcome, while increasing of plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites (E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline) were shown to predict a poor clinical outcome in the depressive episode of the subjects, and that clinical outcome of approximately 73% of the subjects could be correctly predicted.

Adult↗
PubMed1997

Immune response to food antigens: kinetics of food-specific antibodies in the normal population.

The role of food-specific antibodies in the pathogenesis of food allergy is controversial. The first step in solving this controversy may be the assessment of antibody response to food antigens in the normal population. Most of the existing data in this field come from studies that used assays of different standards. This study investigated food-specific antibodies in the normal population using standardized assays. Normal levels of antibody titers were also derived for use as reference. Two hundred and eight individuals from different age groups participated. Immunoglobulin G (IgG) antibodies to cow's milk and its component proteins, and to hen's egg ovalbumin, IgA and IgM antibodies to beta-lactoglobulin and ovalbumin were measured by enzyme-linked immunosorbent assay. The sepharose-radioallergosorbent test was used to measure IgE antibodies to cow's milk and ovalbumin. Titers of IgG antibodies to cow's milk and its component proteins revealed an age-related trend, peaking in the 5 months-1 year age group and then decreased to negligible values in adults. A similar trend was observed with IgG anti-ovalbumin antibodies. Temporal association was less evident for antibodies of other classes. Only six subjects had positive IgE antibodies to cow's milk, while none had positive IgE anti-ovalbumin antibody. The prevalences of IgG antibodies to cow's milk, its component proteins, and ovalbumin are influenced by age and feeding habits. Cross-reactivity to related food antigens is common. The presence of IgE antibodies to food antigens is not a physiological phenomenon.

Animals↗
PubMed1997

IgE responsiveness to Dermatophagoides farinae in asthma and atopic dermatitis.

Using Western blotting and RAST, this study examined IgE reactivities to Dermatophagoides farinae (Df) extract in three groups of children with either asthma, atopic dermatitis (AD) or a combination of both. The Df antigen presented at least nine distinct IgE-binding bands, with apparent molecular weights of 15, 25, 30, 40, 48, 59, 67, 80 and 110 kD. Positive IgE binding reactions to 15-kD proteins were found in more than 85% of subjects in all three groups, and positive reactions to 25-, 30- and 110-kD proteins in 35-45% in each group. The frequencies of positive IgE binding reaction to other components were generally low in all three groups. The pattern of IgE reactivity to Df components did not differ significantly between the three groups of subjects. IgE-binding activities to two major allergens, Der f1 and Der f2, were also examined by RAST, using recombinant antigens. High RAST reactivities to Der f1 and Der f2 were found in three groups, and the average RAST levels for Der f1 and Der f2 did not differ significantly between the three groups. These findings suggest that a difference in IgE responsiveness to house dust mite antigen is not a major discriminative factor in determining the difference between asthma and AD.

Adolescent↗
PubMed1997

Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population.

Susceptibility to the development of asthma and other atopic diseases is known to be associated with genetic components, and several candidate genes have been reported to be linked to atopy in Caucasian populations. We conducted a study of linkage between asthma and markers on chromosomes 5q31-q33 and 11q13 in 68 Japanese families (306 members) by affected sib-pair analysis. Families for the linkage study were ascertained through asthmatic children visiting the allergy clinic. The results provide supportive evidence for linkage between asthma and gene markers in or near the interleukin-4 (IL-4) gene, the IL-9 gene, and D5S393 on chromosome 5q31-q33 (p = 0.0013, p = 0.018, and p = 0.0077, respectively). Linkage between atopic phenotype and these genetic markers was also suggested (p = 0.006, p = 0.01, and p < 0.0001 for atopy, respectively). However, we failed to find evidence for linkage of asthma or atopy to the IgE high-affinity receptor gene on 11q13 (p > 0.1). These findings indicate that beyond ethnicity, there are specific loci that contribute to susceptibility to atopy on chromosome 5q31-q33. In addition, our findings suggest that loci on chromosome 5q31-q33 are linked to the development of asthma in childhood.

Adolescent↗
PubMed1997

Circulating antibodies to common food antigens in Japanese children with IDDM.

OBJECTIVE: To investigate the humoral immune response to common food antigens in Japanese children with IDDM. RESEARCH DESIGN AND METHODS: IgG antibodies to cow's milk, beta-lactoglobulin, bovine serum albumin (BSA), alpha-lactalbumin, and hens egg ovalbumin were examined by enzyme-linked immunosorbent assay in the sera of 33 patients with IDDM, ages 11.8 +/- 3.4 years. The data were compared with that of 50 normal subjects, ages 10.3 +/- 5.1 years, who acted as control subjects. A positive antibody to a food antigen was defined as an antibody titer greater than the 95th percentile value in normal subjects. RESULTS: Children with IDDM had significantly higher median titers of IgG antibodies to beta-lactoglobulin and ovalbumin (P = 0.03 and P = 0.0005 respectively). More children with IDDM than control subjects had positive IgG antibody to ovalbumin (21 vs. 6%, P = 0.04). Titers, as well as the number of positive antibodies to other food antigens, including BSA, did not differ between the two groups. CONCLUSIONS: Japanese children with IDDM show an enhanced humoral immune response to beta-lactoglobulin and ovalbumin, a phenomenon that may be related to the pathogenesis of the disease.

Adolescent↗
PubMed1997

Distribution of IgE and IgG antibody levels against house dust mites in schoolchildren, and their relation with asthma.

Although asthmatic patients are known to have increased levels of IgG antibody against house dust mite (HDM), it is not clear whether or not the presence of HDM-specific IgG antibody is associated with the etiological mechanism of asthma. To address this problem, we evaluated the relationship between HDM-specific IgG antibody levels and incidence of asthma in a general pediatric population. IgE and IgG antibody levels against Dermatophagoides farinae (Df) were examined by RAST and ELISA in a total of 722 randomly selected schoolchildren including 26 subjects with asthma, and the relative prevalence rates of asthma in this population were evaluated in relation to both Df-specific IgE and IgG levels. The incidence of asthma correlated not only with levels of Df-specific IgE, but also with those of Df-specific IgG. There was a significant correlation between Df-specific IgE and IgG levels both in the total population and in the asthmatic children. Because IgG and IgE responses occurred in parallel in this population, the clinical significance of HDM-specific IgG anti-body remains unclear. However, our findings have suggested that clinical expression of asthma in children is primarily dependent on their capacity to mount a immune response to HDM, which includes both IgE and IgG responses.

Adolescent↗