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Biomedical subjects

T Saruta

Publications and source records attributed to T Saruta.

At least 127 records · Page 7Linked to original sources
PubMed1999

Zonal heterogeneity in action of angiotensin-converting enzyme inhibitor on renal microcirculation: role of intrarenal bradykinin.

The present study examined the role of intrarenal bradykinin in angiotensin-converting enzyme inhibitor (ACEI)-induced dilation of renal afferent (AFF) and efferent arterioles (EFF) in vivo, and further evaluated whether ACEI-stimulated bradykinin activity differed in superficial (SP) and juxtamedullary nephrons (JM). Arterioles of canine kidneys were visualized with an intravital charge-coupled device camera microscope. E4177 (an angiotensin receptor antagonist, 30 microg/kg) dilated AFF and EFF in SP (15 +/- 3% and 19 +/- 5%) and JM (15 +/- 3% and 18 +/- 4%). Subsequently, cilazaprilat (30 microg/kg) caused further dilation of both AFF (29 +/- 4%) and EFF (36 +/- 4%) in JM, whereas in SP it dilated only EFF (29 +/-3%). Similarly, in the presence of E4177, cilazaprilat caused further increases in sodium excretion. This cilazaprilat-induced vasodilation and natriuresis was abolished by a bradykinin antagonist (N(alpha)-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]b radykinin). In parallel with these results, cilazaprilat increased renal bradykinin content, more greatly in the medulla than in the cortex (5.7 +/- 0.4 versus 4.6 +/- 0.1 ng/g). Similarly, cilazaprilat elicited greater bradykinin-dependent increases of nitrite/nitrate in the medulla. In conclusion, zonal heterogeneity in renal bradykinin/nitric oxide levels and segmental differences in reactivity to bradykinin contribute to the diverse responsiveness of renal AFF and EFF to ACEI. ACEI-enhanced kinin action would participate in the amelioration of glomerular hemodynamics and renal sodium excretion by ACEI.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Calcitonin induces 25-hydroxyvitamin D3 1alpha-hydroxylase mRNA expression via protein kinase C pathway in LLC-PK1 cells.

The biosynthesis of 1alpha, 25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 is catalyzed by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in renal proximal tubules. It was recently demonstrated that LLC-PK1 cells express CYP27B1 mRNA, which is regulated by intracellular cAMP but not vitamin D3. To clarify the effect of calcitonin on vitamin D3 metabolism in vitro, LLC-PK1 cells were incubated with hormonal factors, and expression of CYP27B1 mRNA was measured by quantitative reverse transcription-PCR. Calcitonin at 100 nmol/L significantly increased CYP27B1 mRNA expression by 24 h (271 +/- 21% of control). Incubation with calcitonin over a range of 1 micromol/L to 1 pmol/L resulted in a concentration-dependent increase in CYP27B1 mRNA levels. It is known that the calcitonin receptor has dual intracellular signaling pathways, via protein kinases A and C. Both 500 micromol/L 8-bromo-cAMP, a protein kinase A activator, and 100 nmol/L phorbol 12-myristate 13-acetate, a protein kinase C activator, increased CYP27B1 mRNA levels at 24 h (207 +/- 54 and 246 +/- 58% of control, respectively). However, calcitonin-induced CYP27B1 mRNA expression was only inhibited by the protein kinase C inhibitors staurosporine and calphostin C. The protein kinase A inhibitors Rp-cAMPS at 10 and 100 micromol/L and H-89 at 10 micromol/L had no effect on the action of calcitonin, in spite of cAMP-activation by calcitonin. The present data suggest that calcitonin upregulates CYP27B1 mRNA expression via the protein kinase C pathway in LLC-PK1 cells.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1999

Cloning of porcine 25-hydroxyvitamin D3 1alpha-hydroxylase and its regulation by cAMP in LLC-PK1 cells.

The 25-hydroxyvitamin D3 1alpha-hydroxylase, also referred to as CYP27B1, is a mitochondrial cytochrome P450 enzyme that catalyzes the biosynthesis of 1alpha, 25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) from 25-hydroxyvitamin D3 in renal proximal tubular cells. Recently, human, mouse, and rat CYP27B1 cDNA have been cloned, however the gene regulation has not been fully elucidated. In the present study, porcine CYP27B cDNA was cloned, and the effects of cAMP and vitamin D3 on the regulation of CYP27B1 mRNA expression in LLC-PK1 cells were examined. PCR cloning revealed that porcine CYP27B1 cDNA consisted of 2316 bp, encoding a protein of 504 amino acids. The deduced amino acid sequence showed over 80% identity to the human, mouse, and rat enzyme. LLC-PK1 cells were incubated with humoral factors, and expression of CYP27B1 mRNA was measured by a quantitative reverse transcription-PCR. At the completion of 3-, 6-, 12-, and 24-h incubations, 500 micromol/L 8-bromo-cAMP had significantly increased CYP27B1 mRNA expression (260 to 340%). The adenylate cyclase activator forskolin at 50 micromol/L also had a stimulatory effect at 6 h (190%). Moreover, the protein kinase A inhibitor H-89 reduced the cAMP effect. On the other hand, 1alpha,25(OH)2D3 had no effect on CYP27B1 mRNA expression at 10 and 100 nmol/L, whereas expression of 25-hydroxyvitamin D3 24-hydroxylase (CYP24) mRNA was markedly increased by 1alpha,25(OH)2D3. These findings suggest that LLC-PK1 cells express CYP27B1 mRNA, and that cAMP is an upregulating factor of the CYP27B1 gene in vitro.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1999

Lack of association between CTLA-4 gene polymorphism and IDDM in Japanese subjects.

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both environmental and genetic factors. The main gene associated with predisposition to IDDM is HLA. Recent studies have described linkage and association of IDDM to the CTLA-4 gene (IDDM12) in Caucasians. CTLA-4 is a candidate gene for T-cell-mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. We investigated the distribution of a CTLA-4 gene polymorphism in 110 Japanese patients with IDDM and 200 control subjects. In 84 patients, we also investigated associations between this CTLA-4 gene polymorphism and GAD65 antibody positivity. An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction-restriction fragment length polymorphism method. GAD65 antibody was detected using a radioligand binding assay. There was no significant difference in the distribution of CTLA-4 alleles in patients and controls and no difference was observed in prevalence of CTLA-4 alleles when GAD65 antibody-positive and -negative individuals in the IDDM groups were compared. The present study did not support an association between the CTLA-4 gene and IDDM in the Japanese population.

Abatacept↗
PubMed1999

The effect of pravastatin on renal function and lipid metabolism in patients with renal dysfunction with hypertension and hyperlipidemia. Pravastatin and Renal Function Research Group.

The effect of pravastatin on renal function in hypertensive patients with mild renal dysfunction and hyperlipidemia was examined. A total of 57 subjects given dihydropyridine calcium blockers were randomly assigned to placebo (n = 25) and pravastatin groups (n = 32). The period of study was 6 months. In the placebo group, lipid metabolism did not change throughout the study period, but the serum creatinine concentration (Scr) increased from a baseline of 1.6+/-0.07 mg/dl to 2.1+/-0.2 mg/dl in the 6th month of study and blood urea nitrogen (BUN) increased from 26.2+/-1.1 mg/dl to 32.4+/-30.1 mg/dl. In the pravastatin group, the serum total cholesterol decreased from a baseline of 251.4+/-7.3 mg/dl to 218.2+/-6.5 mg/dl in the 6th month of study, while Scr (1.3+/-0.07 mg/dl vs. 1.3 +/-0.09 mg/dl) and BNU (20.5+/-1.2 mg/dl vs. 21.0+/-1.4 mg/dl) did not change. The change in Scr in the placebo group was significantly different from that in the pravastatin group (F = 3.75, p = 0.05). The slope of the change in 1/Scr was 0.02+/-0.07 dl x mg(-1) x month(-1) in placebo group and -0.01+/-0.03 dl x mg(-1) month(-1) in pravastatin group (P<0.05). The results indicate that pravastatin attenuates the deterioration of renal function in patients with mild renal dysfunction, together with an improvement of lipid metabolism.

Blood Urea Nitrogen↗
PubMed1999

[Angiotensin II receptor antagonists: a review of the development and future perspective].

Pharmacological blockade of the renin-angiotensin system has been found to be a safe and efficacious way to treat hypertension and congestive heart failure. The success of the angiotensin converting enzyme inhibitors has led to interest in alternative ways to block the renin-angiotensin system. Angiotensin II receptor antagonists are a new class of anti-hypertensive drugs that provide a specific blockade of the effects of angiotensin II. Losartan potassium, the first compound of this class, has recently been approved in Japan. It seems likely that the angiotensin receptor antagonists will be suitable to first-line therapy and use of this class for treatment of hypertension will dramatically increase in Japan because of the excellent clinical and laboratory safety profiles.

Angiotensin Receptor Antagonists↗
PubMed1999

[Potential role of angiotensin receptor antagonists in renal protection].

Recent clinical studies have established an important role of angiotensin converting enzyme inhibitors (ACE-I) as a tool for renal protection. Although angiotensin receptor antagonists (AII-A) share the common property with ACE-I with regard to blockade of angiotensin activity via angiotensin type 1 receptors (AT1), AII-A is also reported to stimulate AT2 that plausibly activates nitric oxide production within renal medulla and augments synthesis of vasodilatory P450-metabolites in renal afferent arterioles. In contrast, AII-A is reported to have no effect on bradykinin activity. Results obtained in experimental animals indicate that AII-A effectively prevents the progression of renal injury. Several clinical studies are in progress, and the preliminary results suggest that AII-A has potent renal protective action in a variety of renal disorders.

Angiotensin Receptor Antagonists↗
PubMed1998

Effects of ACTH on adrenal angiotensin II receptor subtype expression in vivo.

Control of adrenal aldosterone secretion is an important endocrine mechanism mediated by angiotensin II (Ang. II). Recently three subtypes of angiotensin receptors have been demonstrated in the rat adrenal. Our aim was to examine if these receptors are affected by hormone treatment in vivo. Treatment of rats with ACTH resulted in a decrease in AT2 receptor binding from 766 +/- 95 to 310 +/- 51 fmol/mg protein (P < 0.05), without significant changes in AT1 receptors. AT2 receptor mRNA was also decreased (18 +/- 2%, of control, P < 0.05; 25+/-7% of control, P < 0.05) after both 2 and 7 day treatment with ACTH. Changes in AT1a receptor mRNA or total AT1 mRNA did not reach statistical significance. Moreover, treatment with dexamethasone or aldosterone did not affect AT1a, AT1b, or AT2 mRNA. These results demonstrate that ACTH treatment results in subtype-specific changes in adrenal AT receptor gene expression in vivo.

Adrenal Glands↗
PubMed1998

Current status of calcium antagonists in Japan.

Calcium antagonists comprise the most popular drug class for treatment of hypertension in Japan. More than half of Japanese clinicians use calcium antagonists as initial drug treatment for mild-to-moderate hypertension and, despite recent controversies, their use continues to increase. Nearly a fourth of clinicians use angiotensin-converting enzyme (ACE) inhibitors, and 9% use beta-receptor blockers. There are 12 dihydropyridine calcium antagonists and 1 benzothiazepine agent in clinical use. Amlodipine is the most widely used agent in the class. Efonidipine and cilnidipine, recently developed in Japan, both have a slow onset of action and long-lasting hypertensive effect and possess characteristics unique to the class. Efonidipine dilates the efferent as well as the afferent arterioles of the glomerulus; therefore, it appears to have a more pronounced renoprotective effect than other calcium antagonists. Cilnidipine is a dual-channel antagonist, acting on both the peripheral neuronal N-type and vascular L-type calcium channels. It depresses the pressor response to acute cold stress but does not induce tachycardia by hypotensive baroreflex.

Antihypertensive Agents↗
PubMed1998

Adrenal angiotensin II type 1 and type 2 receptors in Cushing's and Conn's syndromes.

Cushing's and Conn's syndromes are well recognised endocrine diseases, but the pathobiology of the tumors causing these disorders is unclear. In this study we examined AT1 and AT2 gene expression in adrenal adenomas of Cushing's and Conn's syndromes. AT1 and AT2 receptor mRNA, as well as alternatively spliced AT1 transcripts, were detected by RT-PCR using adjacent adrenal cortex tissue as controls. Whereas no consistent differences in AT1 mRNA were seen compared to control adrenal cortex, AT2 mRNA levels were significantly decreased in the adenomas of Cushing's and Conn's syndromes. No changes in alternative splicing of AT1 mRNA were observed in the adrenal tumors. The fact that no consistent changes were seen in AT1 mRNA or its splicing, whereas AT2 mRNA were reduced in both forms of hormone producing adrenal tumor suggests that the AT2 receptor, rather than the AT1 subtype, may be correlated with adrenal tumorigenesis.

Adrenal Cortex↗
PubMed1998

Mechanosensitive cation channels mediate afferent arteriolar myogenic constriction in the isolated rat kidney.

1. In order to assess ionic mechanisms mediating renal afferent arteriolar myogenic constriction, experiments were performed using isolated perfused hydronephrotic rat kidneys. 2. Increasing pressure progressively constricted the afferent arteriole (-0.26 +/- 0.02% mmHg-1, n = 21, r = 0.97). Gadolinium (10 microM), a mechanosensitive cation channel blocker, abolished this myogenic constriction. However, high potassium media (30 mM) constricted the afferent arteriole in the presence of gadolinium. 3. Lowering extracellular sodium concentration gradually attenuated afferent arteriolar myogenic constriction. In the perfusate containing 50 mM sodium, the myogenic response was arrested. 4. Afferent arteriolar myogenic constriction was prevented in calcium-free perfusate or by the L-type calcium channel blocker diltiazem (10 microM). 5. Our present findings provide evidence that increasing pressure gates mechanosensitive cation channels on the afferent arteriole, thereby eliciting membrane depolarization and activating voltage-dependent calcium channels.

Animals↗
PubMed1998

Effect of insulin therapy on body fat distribution in NIDDM patients with secondary sulfonylurea failure: a preliminary report.

OBJECTIVE: To clarify the influence of insulin therapy on body weight and fat distribution, we compared these parameters in five non-insulin dependent diabetes mellitus (NIDDM) patients, with secondary sulfonylurea failure, before and after insulin therapy. Body weight increased significantly after instituting insulin treatment. However, the visceral to subcutaneous fat (V/S) ratio decreased significantly due to a marked increase in S-fat without a change in V-fat. Insulin therapy necessitated by sulfonylurea failure does not appear to accelerate the atherogenic process in NIDDM patients as there is no increase in visceral fat.

Adipose Tissue↗
PubMed1998

Serum leptin level: possible association with haematopoiesis in adolescents, independent of body mass index and serum insulin.

1. The obese gene product leptin, secreted exclusively from adipocytes, was discovered to serve as a satiety factor and to play an important role in regulating body weight. In adults, the serum leptin level reportedly increases with the degree of obesity. Leptin receptors are expressed in various tissues, and recent in vitro studies suggest a role for leptin in haematopoiesis. 2. The present study was designed to clarify the relationship between serum leptin and body mass index, peripheral blood cell counts, serum cholesterol, high-density lipoprotein-cholesterol, insulin and cortisol levels in 299 Japanese male adolescents aged 15-16 years. 3. With simple linear correlation, log [serum leptin] showed a strong correlation with body mass index (r = 0.56), log [insulin] (r = 0.36) and leucocyte count (r = 0.22) (P < 0.001 for all). There were also correlations with systolic blood pressure, erythrocyte count, haematocrit and high-density lipoprotein-cholesterol (P < 0.01 for all). Even after adjustment for body mass index and log [insulin], log [leptin] correlated with leucocyte (P = 0.004) and erythrocyte (P = 0.057) counts. Stepwise multiple regression analyses revealed log [leptin] to correlate significantly with body mass index, log [insulin] and the leucocyte count (P < 0.005 for all, r2 = 0.399). 4. To our knowledge, this is the first clinical study to show the possible association of serum leptin level with blood cell counts, independent of body mass index and serum insulin. We conclude that these data further support a role for leptin in haematopoiesis.

Adolescent↗