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T Saruta

Publications and source records attributed to T Saruta.

At least 181 records · Page 10Linked to original sources
PubMed1997

Improvement in baroreflex function by an oral angiotensin receptor antagonist in rats with myocardial infarction.

Impaired baroreflex function is a factor responsible for poor prognosis in myocardial infarction patients. Using logistic function curves, we calculated the maximal gain of the baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate in conscious Wistar-Kyoto and spontaneously hypertensive rats whose left anterior descending artery had been ligated 4 weeks earlier. We further investigated whether 3-week oral treatment with the angiotensin II type 1 receptor antagonist TCV-116 would improve the baroreflex in rats with myocardial infarction. The maximal gain of the mean arterial pressure-RSNA relation in spontaneously hypertensive rats with myocardial infarction and treated with vehicle (1.7 +/- 0.1% control per mm Hg) was smaller than the gain in sham-operated hypertensive rats (2.3 +/- 0.1% control per mm Hg). After 3-week oral treatment with TCV-116, the maximal gain of the arterial pressure-RSNA relation in hypertensive rats with myocardial infarction was 2.3 +/- 0.1% control per mm Hg and significantly greater than the gain in infarcted and vehicle-treated hypertensive rats. In hypertensive rats, the maximal gain of the arterial pressure-heart rate relation of infarcted and TCV-116-treated rats was larger than in infarcted and vehicle-treated rats but significantly smaller than in sham-operated rats. These results demonstrate that oral treatment with an angiotensin receptor antagonist is effective in restoring the impaired baroreflex caused by myocardial infarction and that endogenous angiotensin II is one of the critical factors involved in the impaired baroreflex in myocardial infarction.

Administration, Oral↗
PubMed1997

Regulation of vascular type 1 angiotensin receptors by cytokines.

Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1 alpha (220 U/mL [10 ng/mL]), tumor necrosis factor-alpha (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT1) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1 alpha caused a 1.4- to 1.7-fold increase in AT1 binding after 24 hours (P<.01) and a 2.3-fold increase in AT1 mRNA (P<.05). Tumor necrosis factor-alpha and interferon gamma did not cause a significant change in AT1 binding when administered alone but caused a 30% reduction in binding when administered together (P<.05). The maximal decrease in AT1 binding (60%, P<.01) was seen with the combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma. Although the upregulation of AT1 by interleukin-1 alpha was unaffected by pretreatment of cells with N-monomethyl-L-arginine or indomethacin, downregulation of AT1 by interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma was inhibited by N-monomethyl-L-arginine (P<.01). Interleukin-1 alpha treatment enhanced Ang II-induced [3H]uridine incorporation, whereas treatment with interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma attenuated Ang II-induced [3H]uridine and [3H]leucine incorporation. These results demonstrate that interleukin-1 alpha upregulates AT1 receptors and enhances Ang II-stimulated hypertrophic responses. However, a combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma downregulates AT1 receptors by a nitric oxide-dependent mechanism and reduces Ang II-stimulated trophic responses in vascular smooth muscle cells.

Angiotensin II↗
PubMed1997

Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

The present study was undertaken to determine whether the non-peptide V2 arginine vasopressin (AVP) antagonist 5-dimethylamino- 1[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepi ne hydrochloride (OPC-31260) produces water diuresis and improves hyponatremia in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Eleven patients (9 males and 2 females, 64 +/- 3.5 yr) with SIADH were included in the present protocol, which was comprised of 3 successive days. Day 1 was a control day, and on days 2 and 3 OPC-31260 was administered intravenously. Five blood and urine collections were made at 1-2 h intervals during the 6 h observation period each day. A single administration of 0.25 and 0.5 mg/kg OPC-31260 increased the 4 h cumulative urine volume and decreased urinary osmolality to below 225 mOsm/kg H2O. Such a diuretic effect was independent of an increase in urinary solute excretions. This aquaresis by 0.5 mg/kg OPC-31260 caused a significant increase in serum sodium level by approximately 3 mEq/L. The antagonistic effect of OPC-31260 lasted for 4 h when it was given intravenously. These results indicate that OPC-31260 is an effective therapeutic agent for hyponatremia in patients with SIADH.

Aged↗
PubMed1997

Evidence for internalization of both type 1 angiotensin receptor subtypes (AT1a, AT1b) by a protein kinase C independent mechanism.

We and others have demonstrated the existence of two isoforms or subtypes of the angiotensin type 1 (AT1) receptor, named the AT1a and AT1b receptors. In this study we examined if both types of mouse AT1 receptors are internalized after agonist stimulation and whether protein kinase C (PKC) is involved in this process. To directly visualize the cellular localization of the receptors, an antigenic epitope was engineered onto the amino-terminal of the receptors, and stable cell lines specifically expressing each receptor subtype were isolated. Treatment of these cells with angiotensin II (Ang II) resulted in translocation of surface receptors to intracellular vesicles, together with a reduction in surface binding of Sar1Ile8-Ang II. The agonist-induced internalization of AT1a and AT1b receptors was not inhibited by the PKC inhibitor staurosporine, nor mimicked by the phorbol ester phorbol 12-myristate 13-acetate. Similar results were obtained with cultured rat vascular smooth muscle cells expressing predominantly wild-type AT1a receptors. These results suggest that both AT1a and AT1b receptors are internalized after agonist stimulation by a PKC-independent mechanism.

Angiotensin II↗
PubMed1997

Interaction between endothelin and nitric oxide in sympathetic nerve modulation in hypertensive rats.

To test the hypothesis that endothelin (ET) and nitric oxide (NO) interact in modulating the sympathetic nervous system in conscious rats, as they do in the endothelium, mean arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) were recorded in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) given losartan and compared before and during intravenous infusion of an NO synthase inhibitor, L-NMMA (0.25 mg/kg/min). The slope of the relation between RSNA and MAP to blood pressure reduction was increased in the presence of L-NMMA (from 0.6 +/- 0.1 to 2.8 +/- 0.2), suggesting that endogenous NO suppresses the reflex increase in RSNA. Since NO inhibits ET production in the endothelium, we speculated that the increase in MAP-RSNA slope was due partly to an unmasking of ET, and thus recorded MAP, heart rate, and RSNA during intravenous infusions of both L-NMMA and the ET-type-A-receptor antagonist BQ-485 (0.10 mg/kg/min). The slope decreased significantly in SHR when BQ-485 was added (1.5 +/- 0.2), but not in WKY, implying that unmasked ET enhanced the sympathetic increase via ETA receptors in hypertensive rats. An ETB-receptor antagonist potentiated the sympathetic response only in WKY rats. These results suggest that NO suppressed the reflex increase in RSNA to blood pressure reduction, while ET uncovered by L-NMMA enhanced the sympatho-activation, indicating an interaction between ET and NO in modulating the sympathetic nervous system in conscious hypertensive animals in vivo. In contrast, the interaction was not observed in normotensive rats.

Animals↗
PubMed1997

Glutamic acid decarboxylase65 (GAD65) antibodies and insulin auto-antibodies in Japanese patients with non-insulin-dependent diabetes mellitus.

To clarify whether glutamic acid decarboxylase65 antibodies (GAD65 Ab) and insulin autoantibodies (IAA) are good predictive markers for insulin-dependency in NIDDM, we studied GAD65 Ab and IAA in NIDDM patients treated with diet alone or in combination with oral hypoglycemic agents. GAD65 Ab were found in 12 or 29 (5.2%, P = 0.079 vs. control) NIDDM patients and IAA in 8 of 229 (3.5%). The frequency of GAD65 Ab and IAA positivity in NIDDM did not differ significantly from those of healthy controls (2/150, 1.3%, 2/150, 1.3%, respectively), but the frequency of patients who were positive for either GAD65 Ab or IAA, or both, was significantly higher than that of normal controls (17/229, 7.4% and 4/150, 2.7%, respectively, P < 0.05). In addition, the prevalences of GAD65 Ab and of IAA in those patients whose disease durations, since the diagnosis of diabetes, were less than one year were significantly higher than those of controls (4/30, 13.3%, P < 0.05, 4/30, 13.3%, P < 0.05, respectively). We found no differences between GAD65 Ab positive- and negative-patients in either BMI or serum C-peptide levels. Over a one to five year follow-up period (mean 2.0 yrs), serum C-peptide levels gradually decreased necessitating insulin treatment in three of the patients positive for GAD65 Ab and/or IAA (3/17, 17.6%; two were positive for both GAD65 Ab and IAA and one was positive for GAD65 Ab only). In contrast, only five patients negative for the two antibodies developed insulin requirement (5/212, 2.4%, P < 0.01). These results suggest that GAD65 Ab and IAA are good markers for predicting the development of insulin dependency in NIDDM patients and that the predictive value for insulin-dependency in NIDDM is enhanced by measuring both antibodies.

Adolescent↗
PubMed1997

Autoantibody against IA-2 improves the test sensitivity for insulin-dependent diabetes mellitus in Japanese patients of child onset.

We previously reported that IA-2 autoantibodies (Ab) facilitated the diagnosis of Japanese insulin-dependent diabetes mellitus (IDDM), but the number tested was not large enough to investigate whether IA-2Ab can improve the diagnostic accuracy. In this report, sera from 78 patients with less than 2 year-disease duration (the mean (range) ages were 19.2 (6-52) years old) were tested in order to clarify that the combination of IA-2Ab and glutamic acid decarboxylase 65 (GAD65)Ab would improve the test sensitivity for IDDM. Both of the autoantibodies were frequently detected in Japanese abrupt-onset IDDM but the frequency of GAD65Ab was higher than that of IA-2Ab (69% and 47%, respectively, P = 0.024). The two autoantibodies were discordant in respect to both positivity and titer. The positivity for IA-2Ab decreased with the increasing onset-age of the patients (76, 47, 37, 21% for each quartile of age tested), but the frequency of GAD65Ab was unaffected. Among the youngest quartile (< or = 12 years old), IA-2Ab, in combination with GAD65Ab, significantly improved sensitivity (68% to 92%, P < 0.05), but when we tested patients over 12 years old, IA-2Ab caused little, if any, improvement in sensitivity. We confirmed that IA-2 antibody was detected in IDDM among Japanese, as seen in Caucasians, but the test sensitivity was improved only in young IDDM patients among Japanese.

Adolescent↗
PubMed1997

Malignant hypertension in a patient with primary aldosteronism with elevated active renin concentration.

A 40-year-old male, with a past history of hypertension but receiving no medical treatment, was referred. He manifested malignant hypertension (190/130 mmHg; Keith-Wagener III), renal dysfunction (serum creatinine, 3.8 mg/dl), and elevated plasma aldosterone (450 pg/ml) and active renin concentration (ARC, 104 pg/ml). His blood pressure was controlled with multiple antihypertensive agents and ARC thus decreased (4.3 pg/ml), but aldosterone remained elevated. Abdominal magnetic resonance imaging (MRI) revealed a right adrenal adenoma, and aldosterone-producing adenoma was confirmed by adrenal venous sampling. Primary aldosteronism very rarely develops to malignant hypertension, and even in that case ARC is suppressed. Therefore this is a rare case of primary aldosteronism complicated with malignant hypertension and high ARC.

Adrenal Cortex Neoplasms↗
PubMed1997

Na+/H+-exchanger 3 activity and its gene in the spontaneously hypertensive rat kidney.

OBJECTIVE: To examine the mechanisms affecting proximal tubule sodium reabsorption, we studied the gene expression and functional changes of the Na+/H+-exchanger 3 (NHE3) and its gene expression in spontaneously hypertensive rats (SHR). METHODS: The S1 segment of the superficial proximal convoluted tubules (PCT) was microdissected from collagenase-treated kidneys of SHR and Wistar-Kyoto (WKY) rats. The tubules were then superfused in a HEPES-buffered solution. The intracellular pH was measured by monitoring changes in fluorescent dye emission. By measuring the amiloride-sensitive intracellular pH recovery rate after intracellular acid loading with NH4Cl, we estimated the NHE3 activity. Northern blotting was performed to quantitate the NHE3 messenger RNA (mRNA) expression, and the NHE3 complementary DNA sequence was determined both in SHR and in WKY rat strains. RESULTS: NHE3 activity was significantly higher in SHR than it was in WKY rats both at age 4 weeks and at age 7 weeks. Northern blot analysis showed that the mRNA expression did not differ significantly in the two strains at either age. Sequence analysis of complementary DNA of SHR NHE3 revealed five allelic variations compared with the known wild-type sequence in Sprague-Dawley rats. The same variations were also identified in the WKY rats. CONCLUSION: NHE3 activity is increased in SHR compared with WKY rats of the same age. Changes in the NHE3 mRNA expression level and protein structure are not responsible for this difference between SHR and WKY rat strains.

Alleles↗
PubMed1997

Retroviral infection in peripheral mononuclear cells in patients with IgA nephropathy.

An etiologic agent directly linked to the development of IgA nephropathy (IgAN) has not been identified, despite the fact that various causes, including viral infections, have been implicated in the pathogenesis of this disease. Human immunodeficiency virus (HIV) infection has been linked with the development of IgAN in several clinical studies, and retroviral infection may be associated with the pathogenesis of IgAN in some patients. The incidence of IgAN has been found to possess distinct geographical distributions, and familial genetic clustering. To determine if retroviral infection is associated with IgAN in a large population of patients, genomic DNA from peripheral blood mononuclear cells from 90 patients seronegative for HIV and human T-cell leukemia virus type 1 (HTLV-1) (37 IgAN, 33 other glomerulonephritis, and 20 healthy controls) was evaluated by nested PCR using a pan-lentivirus-specific primer set (PLSPS), targeting the consensus sequence of the lentiviral pol gene. In 37.8% (14 of 37) of the patients with IgAN, the PCR products migrated in parallel with bands produced by PCR of simian immunodeficiency virus (SIV) infected cells. No products of the expected size were detected in the other patient groups (p < 0.0001, Chi-square). These results suggest that exposure to retroviral infection is more common in patients with IgAN, compared with patients with other proliferative glomerulonephritides, or patients without renal disease. These data demonstrate a possible association of IgAN with infection with non-HIV, non-HTLV-1 retrovirus.

Adolescent↗
PubMed1997

[Renal function and hemodynamics in hypertension].

Hypertension is one of important causes of impairment in renal function. Glomerular filtration rate (GFR) remains stable while renal blood flow (RBF) declines in patients with long-term essential hypertension, resulting in an increased filtration fraction. Myogenic response of afferent arterioles and tubuloglomerular feedback to maintain RBF and GFR and sodium homeostasis can be impaired in salt-sensitive hypertension, whereas they are relatively normal in essential hypertension and its rat model. Position of pressure-natriuresis curve is shifted to the right without alteration in the slope of the curve in essential (non-salt-sensitive) hypertension, whereas the slope is significantly decreased in salt-sensitive hypertension, such as nephritis-related hypertension and diabetic nephropathy because of decreased ultrafiltration coefficient and increased sodium reabsorption.

Animals↗
PubMed1997

[Large, long-term, randomized trials and meta-analysis of therapy of patients with hypertension].

Over the past few decades, numerous randomized controlled studies of the treatment of hypertension have been conducted in Western countries to determine whether blood pressure reduction reduces the risk of stroke and myocardial infarction. Diuretics and beta blockers, because they have been shown in clinical trials to reduce cardiovascular morbidity and mortality, are the preferred drugs of first choice. No direct evidence yet supports the theoretical advantages of calcium channel blockers and ACE inhibitors over diuretics and beta blockers. Because East Asian nations differ culturally from Western countries, it is very difficult to conduct a randomized trials, thus, there were no reports of large, long-term, randomized placebo-controlled clinical trials of hypertension.

Adrenergic beta-Antagonists↗
PubMed1997

Role of angiotensin II generated by angiotensin converting enzyme-independent pathways in canine kidney.

Recent studies have provided evidence of angiotensin converting enzyme (ACE)-independent angiotensin (Ang) II formation in tissue renin-angiotensin systems. We studied the effects of Ang II generated by ACE-independent pathways on renal hemodynamics. We used a synthetic peptide, [Pro11, D-Ala12]-Ang I (S), which yields Ang II by chymase, but not by ACE. Infusion of Ang I into a renal artery caused a decrease in renal blood flow, and reciprocally an increase in mean arterial pressure. Infusion of S (1 nmol/kg) caused a decrease in renal blood flow (-20%), but a larger dose was needed to increase mean arterial pressure. Studies with an intravital needle-probe CCD camera revealed that the Ang I infusion induced dose-dependent vasoconstriction of afferent and efferent arterioles (49% and 54%, respectively at 1 nmol/kg). In contrast, infusion of S elicited only 30% constriction of these vessels at a dose of 1 nmol/kg and induced no further constriction at higher doses, indicating that different segments of renal vessels responded in different fashions to Ang II formed via ACE-independent pathways. These vasoconstrictions were abolished by an angiotensin II receptor (AT-1) antagonist. Enzymatic assays using reverse-phase HPLC revealed that the ACE-dependent pathway was predominant in the rena1 cortex (approximately 80%). We also determined Ang II concentrations in renal cortex specimens obtained by needle biopsy. Intrarenal S infusion (10 nmol/kg) increased plasma and renal Ang II concentrations to 160% and 710% of the respective baseline levels. This study provides in vivo evidence of ACE-independent Ang II formation in renal tissue and suggests that this locally-formed Ang II influences the renal circulation in a paracrine fashion.

Angiotensin II↗
PubMed1996

Genetic linkage of the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase II gene to intracellular Ca2+ concentration in the spontaneously hypertensive rat.

A cosegregation analysis of sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (SERCA) II genotype, systolic blood pressure and platelet intracellular Ca2+ concentration was performed to dissect polygenic hypertensive traits in spontaneously hypertensive rats. Backcross analysis between spontaneously hypertensive rats and normotensive. Donryu rats demonstrated the existence of an inferred single major gene locus (ht). Thrombin-stimulated intraplatelet Ca2+ concentration was significantly higher in the SERCA II homozygotes than in the heterozygotes. The SERCA II genotype did not cosegregate with the blood pressure level. The SERCA II gene was assigned to rat chromosome 12. These results suggest that the SERCA II gene on rat chromosome 12 contributes to increased thrombin-stimulated intraplatelet Ca2+ concentration and that the SERCA II gene is not identical to ht.

Animals↗