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T Saruta

Publications and source records attributed to T Saruta.

At least 163 records · Page 9Linked to original sources
PubMed1997

Cellular mechanisms mediating rat renal microvascular constriction by angiotensin II.

To assess cellular mechanisms mediating afferent (AA) and efferent arteriolar (EA) constriction by angiotensin II (AngII), experiments were performed using isolated perfused hydronephrotic kidneys. In the first series of studies, AngII (0.3 nM) constricted AAs and EAs by 29+/-3 (n = 8, P < 0.01) and 27+/-3% (n = 8, P < 0.01), respectively. Subsequent addition of nifedipine restored AA but not EA diameter. Manganese (8 mM) reversed EA constriction by 65+/-9% (P < 0.01). In the second group, the addition of N-ethylmaleimide (10 microM), a Gi/Go protein antagonist, abolished AngII- induced EA (n = 6) but not AA constriction (n = 6). In the third series of experiments, treatment with 2-nitro-4-carboxyphenyl-N, N-diphenyl-carbamate (200 microM), a phospholipase C inhibitor, blocked both AA and EA constriction by AngII (n = 6 for each). In the fourth group, thapsigargin (1 microM) prevented AngII-induced AA constriction (n = 8) and attenuated EA constriction (8+/-2% decrease in EA diameter at 0.3 nM AngII, n = 8, P < 0.05). Subsequent addition of manganese (8 mM) reversed EA constriction. Our data provide evidence that in AAs, AngII stimulates phospholipase C with subsequent calcium mobilization that is required to activate voltage-dependent calcium channels. Our results suggest that AngII constricts EAs by activating phospholipase C via the Gi protein family, thereby eliciting both calcium mobilization and calcium entry.

Angiotensin II↗
PubMed1997

Intramuscular injection of expression plasmid DNA is an effective means of long-term systemic delivery of interleukin-5.

It has been demonstrated that intramuscularly injected expression plasmid DNA is taken up by myofibers and subsequently expresses exogenous genes. In the present study, we assessed intramuscular DNA injection as a means of systemically delivering interleukin-5 (IL-5). We constructed an IL-5 expression plasmid, pCAGGS-IL-5, containing murine IL-5 cDNA under the control of the CAG promoter. The soleus muscle of mice was pretreated with bupivacaine. Two days later, mice were injected with pCAGGS-IL-5 or a control pCAGGS plasmid DNA at the same site. At 2 weeks after DNA injection, eosinophils had increased from 2-3% to 8-29% of peripheral white blood cells in 9 of 10 mice injected with pCAGGS-IL-5, while eosinophils never exceeded 3% in control mice injected with pCAGGS. IL-5 mRNA was present in the muscle area injected with pCAGGS-IL-5. IL-5 was also detectable by ELISA in the sera of most mice injected with pCAGGS-IL-5, but in none of the control mice. These results demonstrate that intramuscular plasmid injection serves as a useful method of systemically delivering cytokines by combining the strong CAG promoter and bupivacaine pretreatment.

Animals↗
PubMed1997

Regulation of expression of leptin mRNA and secretion of leptin by thyroid hormone in 3T3-L1 adipocytes.

Leptin, the obese gene product, is secreted exclusively by adipocytes and regulates energy balance. We examined the effects of thyroid hormones on the regulation of leptin in 3T3-L1 adipocytes. Fully differentiated adipocytes were incubated with thyroid hormones, and the expression of leptin mRNA was measured by quantitative reverse transcription-polymerase chain reaction. After a 24-h incubation, triiodothyronine (T3) at 10-1000 nmol/l significantly increased the expression of leptin mRNA (237-337%). These stimulatory effects were not observed in preadipocytes. By contrast, thyroxine (T4) at 1-1000 nmol/l did not affect leptin mRNA expression in adipocytes. We also measured the levels of secreted leptin in conditioned media using radioimmunoassay. T3 at 10 and 1000 nmol/l significantly increased the levels of secreted leptin (132% and 126%, respectively) after a 24-h incubation. Our present data suggest that thyroid hormone is a novel regulator of leptin mRNA expression and protein secretion in 3T3-L1 adipocytes.

3T3 Cells↗
PubMed1997

Thromboxane A2 synthetase inhibition suppresses cough induced by angiotensin converting enzyme inhibitors.

Based on our earlier animal study, we became interested to investigate if thromboxane A2 (TXA2) is involved in angiotensin converting enzyme (ACE) induced cough in man. To 11 patients with hypertension, who had developed cough induced by ACE inhibitors, a TXA2 synthetase inhibitor, ozagrel was given for 1 to 2 months together with the ACE inhibitors. One patient developed headache induced by ozagrel and was eliminated from the study after 3 weeks. In other 10 patients, no obvious drug attributable abnormality was observed in subjective and objective symptoms or laboratory tests. In ten patients, cough scores were taken just before and after the administration of a combination of an ACE inhibitor with ozagrel. Median values of cough scores after the combination was significantly (p=0.012) lower than before the combination. Ozagrel reduced cough scores in 5 patients, completely suppressed cough in 3 patients and in 2 of 10 patients, ozagrel did not affect cough scores. Our observations suggest that TXA2 may somehow, mediate coughing induced by the ACE inhibitors. Further, patients on ACE inhibitors who develop cough may benefit from TXA2 synthetase inhibitors.

Adult↗
PubMed1997

Effects of alpha 2-adrenergic agonism, imidazolines, and G-protein on insulin secretion in beta cells.

It is well known that alpha 2-adrenergic agonism inhibits insulin secretion and stimulates glucagon secretion in both animal and human studies. Recently, alpha 2-adrenergic blockers (DG-5128, MK-912, and SL 84.0418) have been studied as antihyperglycemic agents in human subjects. To clarify the action mechanism(s) of these agents, we investigated the effects of alpha 2 agonists and antagonists (10(-10) to 10(-4) mol/L) and pretreatment by pertussis toxin (PTX) on glucose-stimulated insulin secretion using the hamster insulinoma cell line HIT-T15. The imidazoline-derivative alpha 2-adrenoceptor agonists clonidine and oxymetazoline at concentrations as low as 10(-8) mol/L significantly inhibited glucose-stimulated insulin secretion by 63% and 65%, respectively (P < .01 for both). These inhibitory effects were abolished by 20-hour preincubation of these cells with PTX 100 ng/mL. The imidazoline-derivative alpha 2-adrenoceptor antagonist DG-5128 at a concentration of 10(-4) mol/L doubled insulin secretion with or without pretreatment by PTX (P < .01 for both). Furthermore, both clonidine and oxymetazoline at a high concentration of 10(-4) mol/L stimulated insulin secretion with pretreatment of the cells by PTX (P < .05 for both). These results indicate that glucose-stimulated insulin secretion is inhibited by alpha 2-adrenoceptor agonists through PTX-sensitive G-protein in HIT-T15 cells. It is also suggested that imidazoline compounds at high concentrations directly stimulate insulin secretion.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1997

Effects of aminoguanidine on serum advanced glycation endproducts, urinary albilmin excretion, mesangial expansion, and glomerular basement membrane thickening in Otsuka Long-Evans Tokushima fatty rats.

This study evaluated the effects of treatment with an inhibitor of advanced glycation endproducts, aminoguanidine, on the development of albuminuria, mesangial expansion and glomerular basement membrane (GBM) thickening in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which we found to be an excellent model of non insulin-dependent diabetes mellitus (NIDDM), for its very close similarity to human NIDDM. OLETF rats were randomized into a non-treatment diabetic group (D-group, n = 5) and an aminoguanidine-treated group (AG-group, n = 5). The AG-group was given 100 mg/dl aminoguanidine HCl in free drinking water. Treatment was started at 16 weeks of age. We measured body weight, plasma glucose, total cholesterol, triglycerides and the urinary albumin excretion (UAE) rate before and after treatment at regular intervals. At 56 weeks of age, we measured serum advanced glycation endproducts (AGE), mesangial expansion and glomerular basement membrane. There were no significant differences in pre-treatment body weight, plasma glucose and UAE between the D-group and the AG-group. Likewise, after treatment there were no significant differences in body weight, plasma glucose, total cholesterol, triglycerides and immunoreactive insulin. Significant differences were, however, noted in serum AGE (63.2 +/- 3.5 and 51.8 +/- 3.0 U AGE/ml, P < 0.05), UAE (203.6 +/- 37.7 and 89.8 +/- 18.6 mg/day, P < 0.05), fractional mesangial volume (21.3 +/- 1.7 and 16.7 +/- 0.8%, P < 0.05) and GBM thickness (453 +/- 17 and 366 +/- 50 nm, P < 0.05) between the D-group and the AG-group. Our results suggest that aminoguanidine inhibits the AGE formation and the development of diabetic nephropathy in OLETF rats.

Albuminuria↗
PubMed1997

Increased intracellular Ca2+ is not coinherited with an inferred major gene locus for hypertension (ht) in the spontaneously hypertensive rat.

Hypertension is characterized by a complex mode of inheritance, consisting of the accumulation and interaction of major and minor genes. The existence of a single major gene locus (ht) has been demonstrated in the backcross analysis of spontaneously hypertensive rats (SHR) and normotensive Donryu rats. Intracellular Ca2+ concentration ([Ca2+]i) determines the tonus of vascular smooth muscle. It has been hypothesized that abnormal Ca2+ transport is an inheritable trait with profound influence on the development of hypertension. Backcross analysis between SHR and Donryu rats was performed to demonstrate ht and to dissect polygenic hypertensive traits through ht and abnormal intracellular Ca2+ metabolism. Among the parental strains, systolic blood pressure and thrombin-stimulated [Ca2+]i in platelets were significantly greater in SHR than in Donryu and F1 rats. The backcrossed rats were distributed into two clusters on a scattergram of blood pressure versus [Ca2+]i, demonstrating the existence of ht. The blood pressure level was correlated with thrombin-stimulated [Ca2+]i in each cluster. Increased [Ca2+]i in platelets was not coinherited with ht and was considered to be a minor inheritable hypertensive trait discriminated from ht. Therefore, [Ca2+]i in platelets is an inadequate marker for searching ht.

Animals↗
PubMed1997

Ovariectomy aggravated sodium induced hypertension associated with altered platelet intracellular Ca2+ in Dahl rats.

Our purpose was to determine the effect of ovariectomy on intracellular Ca2+ mobilization and platelet aggregation in sodium induced hypertension. At the age of 12 weeks ovariectomy or sham operation was performed in female Dahl-Iwai salt sensitive rats on a 0.3% NaCl diet. Four weeks later we assessed the effects of ovariectomy and an 8% NaCl diet on agonist induced intracellular Ca2+ mobilization in fura-2 loaded platelets and platelet aggregation. Ovariectomy enhanced the increase of systolic blood pressure and heart to body weight ratio on an 8% NaCl diet. However, thrombin evoked intracellular Ca2+ was not correlated with systolic blood pressure (r = -0.338, P = .17), and was lowered by sodium loading and ovariectomy (360+/-23 to 285+/-9, 296+/-10 nmol/L, P < .05). Furthermore, the ionomycin induced intracellular calcium fraction in the absence of external Ca2+ that reflected internal Ca2+ discharge capacity was reduced in ovariectomized rats compared with sham operated rats on an 8% NaCl diet (648+/-15 v 768+/-35 nmol/L, P < .05). The internal Ca2+ discharge capacity was inversely correlated with systolic blood pressure (r = -0.506, P = .03). In addition to the decreased internal Ca2+ discharge capacity, intracellular Ca2+-independent platelet aggregation by phorbol 12-myristate 13-acetate, a protein kinase C activator, was significantly enhanced in hypertensive rats. We concluded that ovariectomy enhanced sodium induced hypertension associated with the decreased internal Ca2+ discharge capacity and increased platelet aggregation in Dahl-Iwai salt-sensitive rats.

Animals↗
PubMed1997

Effects of insulin on rat renal microvessels: studies in the isolated perfused hydronephrotic kidney.

Although insulin is demonstrated to decrease vascular tone, the role of insulin in renal microcirculation has not been fully determined. In the present study, the effect of insulin on renal microvascular tone was assessed using the isolated perfused hydronephrotic rat kidney. Insulin (300 microU/ml) had no effect on the basal renal microvessel diameter. In addition, insulin did not alter myogenic (that is, pressure-induced) constriction of preglomerular microvessels, with similar magnitude of constriction of preglomerular microvessels, with similar magnitude of constriction observed in response to elevated renal perfusion pressure from 80 to 180 mm Hg (interlobular artery, -23 +/- 3% vs. -19 +/- 4%; afferent arteriole, -22 +/- 3% vs. -21 +/- 4%, for control and insulin, respectively). In striking contrast, insulin dose-dependently reversed the norepinephrine (NE)-induced tone of interlobular arteries, afferent arterioles, and efferent arterioles, with 94 +/- 9%, 104 +/- 6%, and 86 +/- 10% reversal at 300 microU/ml, respectively. These vasodilator actions were markedly inhibited by N-Arg; in the presence of N-Arg, insulin (300 microU/ml) exerted only a modest dilator action on interlobular arteries (24 +/- 9% reversal), afferent arterioles (23 +/- 10% reversal), and efferent arterioles (14 +/- 9% reversal). A similar renal microvascular responsiveness to insulin was also observed during angiotensin II (Ang II)-induced constriction. In conclusion, the ability of insulin to dilate the renal microvasculature differs, with marked inhibitory action during NE/Ang II-induced constriction and almost no inhibition during myogenic constriction. Furthermore, the present study suggests that the insulin-induced renal vasodilation is mediated by nitric oxide.

Angiotensin II↗
PubMed1997

Blood pressure, insulin, and haematocrit values in Japanese subjects over 60 years of age.

Many studies have suggested an association between blood pressure (BP) and both insulinaemia and haematocrit values in Western populations. However, relatively few data regarding such associations for the Japanese population are available. We investigated the relationship between BP and various parameters, including insulin and haematocrit, in 269 healthy Japanese individuals (113 men and 156 women) over 60 years of age. The data were analysed by stepwise multiple regression analysis. In men, the most important determinant of systolic BP (SBP) and diastolic BP (DBP) was the plasma insulin concentration (beta = 0.32, F = 12.4, P < 0.001 and beta = 0.32, F = 13, P < 0.001, respectively), and haematocrit was found to be associated with DBP (beta = 0.21, F = 5.3, P < 0.05). In women, fasting insulins were unrelated to BP, but fasting plasma glucose and triglyceride concentrations and age were associated with SBP (beta = 0.29, F = 15.5, P < 0.001, beta = 0.27, F = 14.3, P < 0.001, and beta = 0.2, F = 7.8, P < 0.01, respectively), and haematocrit, fasting plasma glucose concentration and age were associated with DBP (beta = 0.29, F = 14, P < 0.001, beta = 0.2, F = 6.9, P < 0.01 and beta = 0.2, F = 6.3, P < 0.05, respectively). These results suggest that the insulin-BP associations in healthy Japanese subjects over 60 years of age differ according to sex, and that haematocrit is an important determinant of DBP in both sexes in our population.

Aged↗
PubMed1997

Bone mineral density after surgical treatment for Graves' disease.

Restoration of bone loss associated with thyrotoxicosis follows normalization of thyroid function. However, the extent of bone loss and restoration remain controversial. To clarify whether bone recovery is complete, we examined lumbar and femoral bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) in 14 thyrotoxic premenopausal women with Graves' disease and 31 premenopausal women treated for Graves' disease by subtotal thyroidectomy who had been in remission for at least 3 years. In the remission group, to exclude the influence of subclinical hyperthyroidism, thyrotropin (TSH) levels were followed and subjects with low levels excluded. Thus, all 31 subjects had normal thyroid hormone levels with transiently or persistently elevated TSH levels post-thyroidectomy. Data from the two study groups were compared with those from healthy premenopausal controls matched for age, height and weight. Mean lumbar (anterior-posterior and lateral), femoral neck, and trochanter BMDs were significantly lower in the thyrotoxic group than in controls (p < .05, all four BMDs). Mean lumbar (anterior-posterior), femoral neck and trochanter BMDs were significantly higher in the remission group than in controls (p < 0.05, all three BMDs). At the time of DXA, the 31 remission subjects showed a significant positive correlation between lumbar BMD and TSH (p < 0.05) and a significant negative correlation between femoral neck BMD and free triiodothyronine (FT3) (p < 0.05). These observations suggest: (1) in premenopausal women, bone loss associated with thyrotoxicosis due to Graves' disease is present but is fully restored when remission is reached after subtotal thyroidectomy; (2) subclinical hypothyroidism after subtotal thyroidectomy may result in higher BMD than that of controls.

Absorptiometry, Photon↗
PubMed1997

CTLA4 gene polymorphism confers susceptibility to Graves' disease in Japanese.

Susceptibility to Graves' disease (GD) is determined by environmental and genetic factors. The genetic susceptibility to GD is conferred by genes in the human leukocyte antigen (HLA), and several other genes unlinked to HLA are thought to contribute to the development of GD. Three recent papers described the association of GD with the CTLA-4 gene. CTLA-4 is a candidate gene for T-cell mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. As CTLA-4 association with GD may be influenced by the racial composition of the population, it is important to study it in other ethnic groups. We investigated the distribution of CTLA-4 gene polymorphism in 153 Japanese patients with GD (35 males and 118 females) and 200 controls (96 males and 104 females). An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The distribution of genotype frequencies differs between GD and controls (chi2 = 9.46, 2 degrees of freedom, p < 0.01). The presence of at least one G allele (GG or AG) conferred an odds ratio of 2.64 (95% CI = 1.92-3.36). The present study supported the association of the CTLA-4 gene with GD in Japanese and showed that the CTLA4 gene could be one of the non-HLA linked susceptibility genes for GD.

Abatacept↗
PubMed1997

Thyroid hormone stimulates renin synthesis in rats without involving the sympathetic nervous system.

The present study was performed to examine whether renal expression of the renin gene is regulated by thyroid hormone. Thirty male Sprague-Dawley rats were divided into hypothyroid, control, and hyperthyroid groups by use of daily intraperitoneal administration of methimazole, saline vehicle, or thyroxine, respectively. Each group was further subdivided into sympathetic innervated and sympathetic denervated subgroups by use of intraperitoneal administration of saline vehicle or 6-hydroxydopamine. Plasma renin activity and renal levels of renin were measured by radioimmunoassays after 8 wk. Renal expression of renin mRNA was evaluated by a semiquantitative reverse transcriptase-polymerase chain reaction. Compared with control animals, plasma renin activity, renal level of renin, and renal expression of renin mRNA were reduced (82, 94, and 71%, respectively) in hypothyroid animals and elevated (155, 1,182, and 152%, respectively) in hyperthyroid animals. Sympathetic denervation had no independent effect on these renin values. Our results indicate that thyroid hormone stimulates renin synthesis without involving the sympathetic nervous system.

Animals↗
PubMed1997

Role of kinin and renal ANG II blockade in acute effects of ACE inhibitors in low-renin hypertension.

In conscious deoxycorticosterone acetate (DOCA) salt-hypertensive dogs, the angiotensin-converting enzyme (ACE) inhibitors captopril and imidaprilat significantly decreased mean arterial pressure (MAP) and significantly increased urine flow rate, effective renal plasma flow (ERPF), glomerular filtration rate, and urinary sodium excretion. However, the angiotensin type 1 (AT1) receptor antagonist losartan caused a significant increase only in urinary sodium excretion without significant changes in MAP, urine flow rate, ERPF, and glomerular filtration rate. Simultaneous infusion of a bradykinin receptor antagonist inhibited the ACE inhibitor-induced reduction in MAP and increase in ERPF. DOCA salt treatment markedly suppressed plasma angiotensin II (ANG II) concentration (P < 0.001), although it decreased renal ANG II content only slightly (P < 0.05). Comparison of the expression of renal AT1 receptor mRNA in control kidneys with that in DOCA salt-hypertensive kidneys revealed no significant change. These results suggest that, in low-renin hypertension, inhibition of the relatively maintained ANG II production in the kidney participates in the natriuretic action of ACE inhibitors. However, hypotensive and other renal effects are mainly due to the action of bradykinin.

Angiotensin II↗
PubMed1997

Role of the renin-angiotensin system in cardiac hypertrophy induced in rats by hyperthyroidism.

This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism.

Animals↗
PubMed1997

Expression and localization of the water channels in human autosomal dominant polycystic kidney disease.

To characterize the cyst-lining cells in human autosomal dominant polycystic kidney disease (ADPKD), we performed immunohistological studies with specific antibodies against human aquaporin-2 (AQP-2, the vasopressin-regulated water channel) and aquaporin-3 (AQP-3), which are expressed only in collecting duct cells in the normal kidney. The polycystic kidney samples were obtained from 2 hemodialysis patient at uninephrectomy. Immunohistochemical studies revealed two types of staining of cyst-lining cells. Approximately 30% of all the cysts were simultaneously immunostained by both antibodies. Among these AQP-positive cysts, more than 90% of the cysts were intensely stained, with well-polarized localization of AQP-2 and AQP-3. In fewer than 10% of AQP-positive cysts, by contrast, immunostaining for AQP-2 and AQP-3 was faint and no clearly polarized localization of the channels was observed. We examined the immunostaining in further detail by electron microscopy. Staining specific for AQP-2 was mainly observed in the apical membrane of cyst-lining cells. Moreover, staining specific for AQP-3 was observed in all of the AQP-2-positive cysts. It appeared unlikely that the variations in immunostaining observed under the light microscope had been induced by total disruption of water-channel polarity. The present study suggests that about 30% of the cysts in our cases of ADPKD were derived from the collecting duct cells and that the cyst-lining cells were well differentiated in terms of AQP expression.

Aquaporin 2↗