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T Saruta

Publications and source records attributed to T Saruta.

At least 217 records · Page 12Linked to original sources
PubMed1996

Mechanism of glucocorticoid-induced hypertension.

Despite many previous studies, the mechanism of glucocorticoid-induced hypertension remains unknown. The present review will introduce the results of our studies on this subject in patients with Cushing's syndrome and in experimental animals. Our studies indicate that the following multiple factors are involved in glucocorticoid-induced hypertension in humans and animals: 1) activation of the renin-angiotensin (R-A) system due to an increase in plasma renin substrate (PRS); 2) reduced activity of depressor systems, including the kallikrein-kinin (K-K) system, prostaglandins (PGs), and the endothelium-derived relaxing factor nitric oxide (NO); and 3) increased pressor responses to angiotensin II (Ang II) and norepinephrine. Furthermore, our in vitro studies have revealed that the number of Ang II type 1 receptors of vascular smooth muscle cells (VSMCs) is significantly increased by glucocorticoids. It is concluded that the pathogenesis of glucocorticoid-induced hypertension is multi-factorial, involving the various mechanisms described above.

Animals↗
PubMed1996

Disparate effects of calcium antagonists on renal microcirculation.

Although calcium antagonists reduce systemic blood pressure, the effects of calcium antagonists on renal preglomerular and postglomerular microcirculation have been suggested to differ. In the present study we examined the vasodilator action of dihydropyridine-type calcium antagonists, including nifedipine, nicardipine, amlodipine, and efonidipine, on afferent and efferent arterioles during angiotensin II (A-II)- and norepinephrine (NE)-induced renal vasoconstriction. Isolated perfused hydronephrotic kidneys were used to directly visualize renal microcirculatory response to calcium antagonists. Both A-II and NE caused marked vasoconstriction of afferent (A-II, 27 +/- 2% decrement; NE, 28 +/- 2% decrement) and efferent arterioles (A-II, 25 +/- 4% decrement; NE, 22 +/- 2% decrement). The subsequent addition of nifedipine, nicardipine, and amlodipine reversed the afferent arteriolar vasoconstriction in a dose-dependent manner, and elicited complete vasodilation at 10(-6) M. In contrast, efferent arteriolar vasoconstriction was relatively refractory to the dilator action of these calcium antagonists; maximal dilation observed at 10(-6) M was 21 +/- 1% (A-II) and 22 +/- 3% (NE) for nifedipine, 25 +/- 3% (A-II) and 20 +/- 6% (NE) for nicardipine, and 39 +/- 6% (A-II) and 37 +/- 3% (NE) for amlodipine. In striking contrast, efonidipine dilated not only afferent arterioles, but also efferent arterioles in a dose-dependent manner. At 10(-6) M, efonidipine completely inhibited the afferent (A-II, 89 +/- 7% reversal; NE, 99 +/- 8% reversal) and efferent arteriolar vasoconstriction (A-II, 93 +/- 4% reversal; NE, 87 +/- 9% reversal). These findings clearly demonstrate that calcium antagonists dilate the afferent arteriole. Unlike the effects on the afferent arteriole, efferent arteriolar responsiveness to calcium antagonists differ, depending on the type of calcium antagonist. The efonidipine-induced efferent arteriolar vasodilation is probably not related to voltageoperated calcium channels, and may act, in concert with blood pressure lowering effect, to ameliorate glomerular capillary hypertension.

Angiotensin II↗
PubMed1996

Insulin resistance syndrome in adolescents and adults.

This study was designed to investigate the possibility of sex and age differences in the insulin-blood pressure relationship in a general Japanese population with a wide age range. Fasting serum insulin, lipids, plasma glucose, blood pressure and anthropometric measurements were made on 1,537 men and 843 women aged 16 to 65 years. Of the 2,380 subjects in the present analysis, 290 (184 men, 106 women) were hypertensive. When divided into four age groups (16 to 17, 21 to 22, 30 to 49 and 50 to 65 years), the male hypertensive subjects were found to have significantly higher fasting insulin levels, triglycerides levels and body mass index and lower glucose/insulin ratios than normotensive male subjects in all age groups. In the women, there was no significant difference in serum insulin levels or glucose insulin ratios between the hypertensive and normotensive groups in any age group. Simple correlation analysis showed that blood pressure was statistically significantly correlated with serum insulin levels and body mass index in the men in all age groups. In women, the correlation between blood pressure and serum insulin was insignificant in the 21- to 22-year-old age group. In men but not women, multivariate analysis showed that blood pressure was significantly and independently correlated with fasting serum insulin levels. The results of this study suggests the existence of sex and age differences in the insulin-blood pressure relationship in a Japanese population.

Adolescent↗
PubMed1996

Hyperglycemia decreases dehydroepiandrosterone in Japanese male with impaired glucose tolerance and low insulin response.

Recent studies indicate that experimentally induced hyperinsulinemia may reduce serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S). Serum DHEA and DHEA-S decrease in diabetic patients, but the mechanism by which hyperglycemia decreases DHEA and DHEA-S is unknown. In this study, we investigated the effect of hyperglycemia on DHEA and DHEA-S in impaired glucose tolerance (IGT) by means of the 75g-oral glucose tolerance test (OGTT). We selected 30 male IGT patients receiving diet therapy only, whose insulinogenic Index was under 0.3. Oral glucose challenge significantly reduced DHEA (P = 0.0001) and DHEA-S (P < 0.05) at 60 and 120 min after OGTT. Setting the value of DHEA and DHEA-S at time zero as 100%, we calculated the DHEA and DHEA-S values at 60 and 120 min after OGTT as %DHEA(-S) 60 min and %DHEA(-S) 120 min, respectively. DHEA and DHEA-S at time zero showed no correlation with BMI, HbA1c, the sum of insulin values (sigma IRI) or the area under the curve of plasma glucose (AUC). We found decreases in %DHEA 60 min (r = -0.411, P < 0.05), %DHEA-S 60 min (r = -0.508, P < 0.01) and %DHEA-S 120 min (r = -0.393, P < 0.05) as AUC increased, but sigma IRI showed no correlation with %DHEA(-S) 60 min or %DHEA(-S)120 min. We conclude that the depression of DHEA and DHEA-S after OGTT is attributable to hyperglycemia in male Japanese IGT with low insulin response.

Dehydroepiandrosterone↗
PubMed1996

Antibodies to the 37,000-Mr tryptic fragment of islet antigen were detected in Japanese insulin-dependent diabetes mellitus patients.

Sera from 30 Japanese insulin-dependent diabetes mellitus (IDDM) patients of short duration were examined to determine whether they had antibodies to proteolytic fragments of islet antigen, the molecular weights of which were 37,000 and/or 40,000 Mr (37KAb). The median age and disease duration of the patients were 13 (range 6-22) years old and 12 (range; 0-24) months, respectively. Twelve out of the 30 IDDM patients (40%) had 37KAb, while none of the 16 control subjects was positive for 37KAb. The frequency of the 37KAb was not correlated with disease duration tested. We further investigated the antibodies to ICA512, by radioligand binding assay, which has been proposed to be a target antigen for the 37 KAb. Twenty-two (73.3%) patients had antibodies to ICA512 (ICA512AA), but none of the control subjects did. The levels of ICA512AA, which were described as indexes using standard sera, were significantly higher in the patients than in the control subjects (1.436 +/- 2.674 and 0.001 +/- 0.002, respectively, P < 0.05). The frequency of antibodies to glutamic acid decarboxylase 65 (GAD65Ab) was also higher in the patients than in the control subjects (70% and 0%, respectively), but 7 out of 9 GAD65Ab-negative patients had ICA512AA and/or 37KAb. Since 93% of the IDDM patients had at least one of these antibodies, combined analysis with 37KAb, ICA512AA, and GAD65Ab facilitates diagnosis of Japanese IDDM.

Adolescent↗
PubMed1996

Depression of dehydroepiandrosterone in Japanese diabetic men--comparison between non-insulin-dependent diabetes mellitus and impaired glucose tolerance.

Hyperglycemia is known to reduce dehydroepiandrosterone (DHEA) circulating levels; however, the mechanism by which hyperglycemia decreases DHEA is not elucidated. In this study, serum DHEA and DHEA sulfate (DHEA-S) levels were compared in 50 men with non-insulin-dependent diabetes mellitus (NIDDM) and 50 age-matched men with impaired glucose tolerance (IGT) receiving only diet therapy. Serum concentrations of DHEA and DHEA-S in the NIDDM group were significantly lower than in the IGT group (7.8 and 9.7 nmol/l vs 3.4 and 4.9 mumol/l, respectively; p < 0.01) but there was no significant difference in immunoreactive insulin between the two groups. When the results from both groups were combined, HbA1C was significantly inversely related to DHEA (r = -0.243, p < 0.01) and DHEA-S (r = -0.305, p < 0.01). Immunoreactive insulin showed no correlation with DHEA and DHEA-S. Multiple regression analysis showed that HbA1C was independently negatively related to both DHEA and DHEA-S. We conclude that hyperglycemia may decrease serum DHEA and DHEA-S in Japanese men with NIDDM, but the depression of DHEA(-S) is independent of serum insulin level.

Dehydroepiandrosterone↗
PubMed1996

Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes.

The obese (ob) gene has been cloned recently and its protein product is called "leptin". Leptin is an adipocyte-derived satiety factor that regulates body weight homeostasis. Several hormonal factors have been reported to regulate ob mRNA expression. To determine which factors are most important for regulation of ob mRNA expression, we examined the effects of insulin, dexamethasone, a beta3-adrenergic agonist (CGP12177A), 8-bromo-cAMP, 8-bromo-cGMP and 1-methyl-3-isobutylxanthine (MIX) on primary cultured adipocytes. Rat adipocytes obtained from epididymal fat were cultured using the ceiling method. Total RNA was extracted and the expression of ob mRNA was measured by quantitative reverse transcription-polymerase chain reaction. After 24 h of incubation, 100 nmol/l insulin significantly increased the expression of ob mRNA (21.4-fold compared to control). Moreover, insulin increased ob mRNA expression in a dose-dependent manner over a range of 1-100 nmol/l. The effect of 100 nmol/l insulin was similar to that seen with 20% newborn calf serum. Dexamethasone (25-1000 nmol/l) also increased ob mRNA expression (2.5-2.9-fold). The effect of dexamethasone occurred more rapidly than insulin. CGP12177A (1-10 micromol/l) and 0.5 mmol/l 8-bromo-cAMP had no effects, whereas 0.5 mmol/l 8-bromo-cGMP and 0.5 mmol/l MIX had stimulatory effects (2.8- and 2.4-fold increase in ob mRNA, respectively). The combination of 250 nmol/l dexamethasone and 0.5 mmol/l MIX did not have an additive effect on ob mRNA levels. Our present data suggest that, of these agents, insulin is the most important factor regulating ob mRNA expression.

Adipocytes↗
PubMed1996

McArdle's disease with non-insulin-dependent diabetes mellitus: the beneficial effects of hyperglycemia and hyperinsulinemia for exercise intolerance.

A 64-year-old female with McArdle's disease and non-insulin-dependent diabetes mellitus (NIDDM) is reported. She had none of the characteristic symptoms of McArdle's disease such as muscle cramps but her serum creatine kinase level was elevated. Muscle biopsy with negative muscle phosphorylase staining showed McArdle's disease. Modified forearm ischemic exercise test was done at two conditions; fasting and two hours after a meal. When fasting, the level of lactic acid did not elevate after exercise. After a meal, however, the serum lactic acid level rose with the elevation of plasma glucose and IRI. Thus, we suggested that high plasma glucose and insulin due to NIDDM may induce blood-borne glucose uptake with exercise.

Biopsy↗
PubMed1996

Myasthenia-like syndrome induced by overdosage of cibenzoline.

A case of cibenzoline-induced myasthenia-like syndrome is reported. A 67-year-old woman with renal failure and no previous disorder of neuromuscular junction complained of fatigue during climbing up a flight of stairs and experiencing heavy eyelids after administration of 100 mg/day of cibenzoline. Repetitive nerve stimulation tests revealed decrement at 5-10 Hz. After reduction of the dosage, myasthenia-like signs and symptoms disappeared. The peak cibenzoline concentration was still high even after the dose reduction (666.4 ng/ml). In conclusion, cibenzoline, at a high plasma level, may induce myasthenia-like syndrome without any disorder of the neuromuscular junction.

Aged↗
PubMed1996

Immune response to heat-shock protein correlates with induction of insulitis in I-E alpha d transgenic NOD mice.

To evaluate the correlation between heat-shock protein (HSP) and insulitis, we compared lymphocyte proliferative response to Mycobacterium leprae HSP65 of NOD mice with that of I-E alpha d transgenic NOD (I-E+NOD) mice, which show no insulitis. We found that splenocytes from 15-week-old NOD mice showed a more marked proliferative response to HSP than did those from age-matched I-E+NOD mice (P < 0.05). We then transferred splenocytes from 12-week-old NOD mice into I-E+NOD mice to induce insulitis in the recipients and examined antibody levels against HSP. By 6 weeks posttransfer, insulitis was successfully transferred to four out of five recipients of NOD splenocytes and antibody levels against HSP were significantly higher in the NOD splenocyte-transferred group than in controls, which showed no insulitis (P < 0.01). These results suggest that immune response to HSP correlates with insulitis in NOD mice. Our results support the assertion that HSP is a useful antigen for investigating the etiology of IDDM.

Animals↗
PubMed1996

Does combined therapy of Ca-channel blocker and angiotensin converting enzyme inhibitor exceed monotherapy in renal protection against hypertensive injury in rats?

Either calcium channel blocker (CCB) or angiotensin converting enzyme inhibitor (ACEi) is used as an antihypertensive agent, and we are recommended to use them in combination to refractory hypertension with evidence dependent on clinical observations. We examined the renal protective effect of the combined therapy with calcium channel blocker (amlodipine) and angiotensin converting enzyme inhibitor (enalapril) against hypertensive renal injury in 5/6 nephrectomized spontaneously hypertensive rats (SHRs) with salt loading, comparing with monotherapy of each drug. Forty males SHRs with 5/6 nephrectomy and salt loading were divided to five groups: group 1 as control (n = 8), group 2 received 0.2 mg/kg/day of amlodipine (n = 8), group 3 received 0.2 mg/kg/day of enalapril (n = 8), group 4 (n = 8) and group 5 (n = 8) that were treated with 0.1 mg/kg/day and 0.2 mg/kg/day of each drug in combination respectively. Either amlodipine or enalapril had remarkable effects on reducing the increases in blood pressure and urinary protein excretion. In histopathological examination, it also suppressed renal injury significantly. Additional significant effect of combined therapy was not observed in blood pressure and urinary protein. There were not remarkable, additional effects of the combination of CCB and ACEi on protecting the remnant kidney in 5/6 nephrectomized SHRs fed a high-salt diet, possibly because sodium retention was not alleviated by the combination.

Amlodipine↗
PubMed1996

Serum cortisol in the white-coat phenomenon.

BACKGROUND: The rise in blood pressure associated with a clinic visit (the white-coat phenomenon) may result from anxiety or an alerting reaction. There is evidence to suggest that glucocorticoids may be involved in the mechanism of stress-related blood pressure elevation, but the relationship between the white-coat phenomenon and glucocorticoids has not been assessed. DESIGN: Forty-eight young subjects with essential hypertension were compared with 12 control normotensive subjects. METHODS: Home blood pressure monitoring for 7 days and serum cortisol at 0900 h and 2 h rest at 1100 h were measured. The white-coat phenomenon was calculated for systolic and diastolic blood pressure and average home blood pressure. RESULTS: The serum cortisol level was significantly greater at 0900 h than that at 1100 h in the hypertensive subjects and was higher in the hypertensive subjects than in the normotensive subjects (21.5 +/- 0.5 versus 14.3 +/- 0.9 µg/dl), but there was no difference between serum cortisol levels at 1100 h in the two groups. The magnitude of the white-coat phenomenon, which was greater in the hypertensive subjects than in the normotensive group (22 +/- 2/12 +/- 1 versus 4 +/- 3/1 +/- 3 mmHg), correlated with serum cortisol at 0900 h, but not at 1100 h. The higher level of serum cortisol at 0900 h was confirmed by another measurement conducted 4 months later in a subsample of the hypertensive subjects ( n = 18). CONCLUSIONS: These results suggest that the white-coat phenomenon is related to the transient increase in serum cortisol or psychological stress, or both, which can trigger arousal of the hypothalamic pituitary adrenocortical axis.

Journal Article↗
PubMed1996

Antihypertensive agents and renal protection: calcium channel blockers.

This study defines the nature of the renal protective effects of calcium channel blockers (Ca blockers) and the effects of the Ca blocker, amlodipine, compared to those of the angiotensin-converting enzyme inhibitor (ACEI), enalapril, on the progression of renal injury in 5/6 nephrectomized spontaneously hypertensive rats (SHR) fed a high-salt diet. Furthermore, we studied the effects of various Ca blockers on the glomerular afferent and efferent arterioles using the isolated perfused hydronephrotic kidneys of six-week-old male Sprague-Dawley rats. In the first study, forty 6-week-old male SHRs which underwent 5/6 nephrectomy were equally divided into five groups. One group received no therapy. In two groups, therapy was started at four weeks post-nephrectomy, one with amlodipine and the other with enalapril. In the remaining two groups, amlodipine or enalapril therapy was started at eight weeks postnephrectomy. Amlodipine was more effective than enalapril in reducing proteinuria and glomerulosclerosis in the group that was started on drug therapy eight weeks after surgery. In the second study, at concentrations of 10(-6) to 10(-9) M, nifedipine, nicardipine and amlodipine dilated the afferent, but not the efferent, arteriole preconstricted with angiotensin II. On the other hand, efonidipine and manidipine clearly dilated angiotensin II-induced constriction of both the afferent and efferent arterioles. These results indicated that Ca blockers are effective at reducing renal injury in 5/6 nephrectomized SHR, and that they are more effective than ACEI in advanced stages of renal injury. The observation that only certain Ca blockers can dilate the efferent arteriole suggests that the renal protective effect of Ca blockers is not necessarily dependent on the dilation of the efferent arterioles.

Amlodipine↗
PubMed1996

Sodium balance and hypertension in obese and fatty rats.

To investigate the role of sodium in obesity induced hypertension, Wistar fatty rats (WFR) were employed. This rat has the following characteristics: (1) hyperglycemia, (2) hyperinsulinemia, and (3) hypertriglycemia. Four percent sodium chloride with constant amount of food intake was administered to these rats from 8 to 16 weeks. During this period, body wt, food intake, water consumption, urine volume, systolic blood pressure, urinary excretion of sodium and potassium, urinary albumin excretion, plasma sodium and potassium, and plasma glucose and immunoreactive insulin (IRI) were measured before, and twice more during eight weeks. No remarkable changes were observed in plasma glucose level during these periods between the two groups. On the other hand, in group 1 IRI significantly increased compared with group 2. Mean blood pressure was increased from 110 +/- 5 to 130 +/- 8 mm Hg (P < 0.01). To ascertain whether this salt sensitivity relates to the abnormalities in pressure-natriuresis responses, the pressure-natriuresis (P-N) was characterized. The P-N curve in WFR was shifted to the right and its slope was flattened compared to its control Wistar lean rats. In conclusion, an excess of dietary sodium intake may contribute to an elevation of blood pressure in Wistar fatty rat with hyperglycemia and hyperinsulinemia. This salt sensitivity may change the abnormal pressure-natriuresis responses.

Animals↗
PubMed1995

Tranilast inhibits the effects of platelet-derived growth factor on cell proliferation and induction of nitric oxide.

The effects of tranilast on DNA synthesis and cell proliferation in cultured rat mesangial cells, treated with platelet-derived growth factor (PDGF), were investigated. Tranilast significantly inhibited PDGF-stimulated DNA synthesis and cell proliferation in a dose-dependent manner. In the absence of PDGF, it also enhanced cytokine-induced nitric oxide (NO) production, PDGF significantly inhibited cytokine-induced NO production, but tranilast completely abolished this inhibitory effect of PDGF. These results show that tranilast inhibits PDGF-induced proliferation of mesangial cells under both normal and inflammatory conditions.

Animals↗
PubMed1995

Effect of dietary chloride on aldosterone synthase induction and angiotensin II receptors in rat adrenals.

Effects of dietary chloride ions on the levels of both cytochrome P-450aldo (CYP11B2) and angiotensin II receptors were examined in rat adrenals. Capsular adrenal CYP11B2 protein levels significantly increased in previously chloride-depleted animals treated with either ammonium- or choline chloride. No changes in CYP11B2 protein levels were detected in previously chloride-depleted rats replenished with either ammonium acetate or choline bromide. The induction of CYP11B2 by chloride-repletion was not concurrent with either increased plasma renin activity or elevated serum potassium levels. None of the above dietary manipulations affected angiotensin II receptor number and affinity, respectively. Treatment of chloride-repleted animals with an angiotensin II receptor antagonist (TCV116) significantly attenuated the increase of CYP11B2 protein levels. In addition, chloride-repletion of previously chloride-depleted animals increased mRNA levels encoding angiotensin II type 1B receptor, but decreased mRNA levels encoding the type 1A form of the receptor. Thus, the presented data are supportive of the notion that the regulation of CYP11B2 expression in the capsular portion of the rat adrenal is, in part, mediated via induction of the angiotensin II type 1B receptor.

Adrenal Glands↗
PubMed1995

Heterotetrameric complex formation of inositol 1,4,5-trisphosphate receptor subunits.

The inositol 1,4,5-trisphosphate receptor (IP3R) exists as a tetrameric complex to form a functional inositol 1,4,5-trisphosphate-gated Ca2+ channel. Molecular cloning studies have shown that there are at least three types of IP3R subunits, designated type 1, type 2, and type 3. The levels of expression of IP3R subunits in various cell lines were investigated by Western blot analysis using type-specific antibodies against 15 C-terminal amino acids of each IP3R subunit. We found that all the three types of IP3R subunits were expressed in each cell line examined, but their levels of expression varied. To determine whether IP3Rs form heterotetramers, we employed immunoprecipitation experiments using Chinese hamster ovary cells (CHO-K1 cells), in which all three types are abundantly expressed. Each type-specific antibody immunoprecipitated not only the respective cognate type but also the other two types. This result suggests that distinct types of IP3R subunits assemble to form heterotetramers in CHO-K1 cells. We also detected heterotetramers in rat liver, in which IP3R type 1 and type 2 are expressed abundantly. Previous studies have shown some functional differences among IP3R types, suggesting the possibility that various compositions of subunits show distinct channel properties. The diversity of IP3R channels may be further increased by the co-assembly of different IP3R subunits to form homo- or heterotetramers.

Amino Acid Sequence↗