Biomedical subjects

T Ogihara

Publications and source records attributed to T Ogihara.

At least 523 records · Page 29Linked to original sources

PubMed1994

A novel gene-transfer technique mediated by HVJ (Sendai virus), nuclear protein, and liposomes.

There have been many reports of in vivo direct gene transfer methods, but there are problems with these methods. Recently, we developed a novel, nontoxic and efficient in vivo direct gene transfer method mediated by Sendai virus (HVJ) and liposomes. In our system, foreign genes and nuclear proteins were encapsulated into the same liposomes, which were then treated with inactivated HVJ. The properties of our system are that HVJ enables foreign genes to be introduced directly into the cytoplasm by membrane fusion and that nuclear proteins transport the foreign genes rapidly into the nuclei. In the present study, we succeeded in introducing and expressing the functional gene for human insulin, and we observed the expression of this gene in mouse plasma and the reduction of plasma glucose. Our system will provide a new method of gene transfer aimed at postnatal gene therapy in various diseases.

Analysis of Variance↗

PubMed1994

Open clinical studies on a new angiotensin II receptor antagonist, TCV 116.

OBJECTIVES: The goals of these preliminary studies were to evaluate the effects of a new angiotensin II receptor antagonist, TCV 116, on the daytime blood pressure profile in hospital inpatients with essential hypertension, and to evaluate the clinical efficacy and safety of this agent in outpatients with essential hypertension. SUBJECTS: In study 1, daytime blood pressure changes were studied in 28 inpatients with mild to moderate essential hypertension (systolic blood pressure > or = 150 mmHg, diastolic blood pressure > or = 90 mmHg). In study 2, 55 outpatients with essential hypertension (systolic blood pressure > or = 160 mmHg, diastolic blood pressure > or = 95 mmHg) were enrolled in a dose-finding study. METHODS: In study 1, after a 1-week placebo run-in period, blood pressure and the pulse rate were measured every 2 h except at night. TCV 116 monotherapy was started at 1 mg/day and increased stepwise at 3- to 5-day intervals to 2, 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The daytime profiles of blood pressure and the pulse rate were again monitored at the end of the treatment period. In study 2, after a 4-week placebo run-in period, TCV 116 alone was administered for 2 weeks at 1 mg/day. The dose was then increased to 2 mg/day and stepwise at 2-week intervals to 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The total treatment period was 8-12 weeks. RESULTS: In study 1, a sufficient reduction in blood pressure was achieved in 19 of 28 patients (68%), with blood pressure significantly reduced at all measurement points, compared with the placebo run-in period. No differences were seen in the pulse rate. The only adverse reaction reported was a rash in one patient. In study 2, a sufficient reduction in blood pressure was achieved in 42 out of 55 patients (76%). The cumulative efficacy rate increased dose-dependently (15% at 1 mg/day, 38% at 2 mg/day, 60% at 4 mg/day and 76% at 8 mg/day). No differences were seen in the pulse rate. Adverse reactions were reported in three out of 55 patients (5.5%). No dry cough was reported by any of the patients. CONCLUSIONS: TCV 116, an angiotensin II receptor antagonist, has potential as an antihypertensive agent. A dose of 4-8 mg once per day appears to be appropriate for the treatment of patients with mild to moderate essential hypertension.

Benzimidazoles↗

PubMed1994

Role of the renin-angiotensin system in hypertension in the elderly.

Although the activity of the renin-angiotensin system is known to decrease with age, the antihypertensive efficacy of angiotensin-converting enzyme (ACE) inhibitors has been demonstrated in the elderly. To examine the role of the renin-angiotensin system in hypertension in the elderly, we evaluated the antihypertensive response to enalapril and to TCV-116, an angiotensin II type-1 receptor antagonist, in elderly patients with essential hypertension. A single oral dose of enalapril (10 mg) increased plasma renin activity (PRA) and reduced the angiotensin II concentration, whereas a single oral dose of TCV-116 (4 mg) increased both PRA and the angiotensin II concentration. Blood pressure was significantly reduced by these drugs from 4 h after administration. Basal levels of PRA and angiotensin II declined with age. However, the changes in blood pressure produced by either TCV-116 or enalapril did not correlate with age. These results suggest that the activity of the renin-angiotensin system in plasma declines with age, and that the extrarenal renin-angiotensin system may play a role in hypertension in the elderly.

Adult↗

PubMed1994

Activated angiotensin II generation and regulation in rat mesenteric arteries following nephrectomy.

The objectives of the present study were to test the hypothesis that vascular angiotensin II (AII) generation may be negatively regulated by circulating AII in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and to clarify the role of this vascular AII in the sustained hypertension seen in SHR following nephrectomy. The mesenteric arteries from kidney-intact and nephrectomised WKY and SHR were perfused, and the level of AII released into the perfusate were measured. The effects of CV-11974, a newly developed nonpeptide AII receptor antagonist, on AII release were examined to investigate the existence of a local feedback system in the blood vessels. Nephrectomy augmented vascular AII release both in WKY and SHR despite the reduction in circulating AII. CV-11974 significantly increased AII release from the mesenteric arteries of kidney-intact rats. There were no significant differences in these responses between WKY and SHR. These results suggest that WKY and SHR share a potent pathway for producing vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension seen in SHR after nephrectomy.

Angiotensin II↗

PubMed1994

Long-term therapy with terazosin may improve glucose and lipid metabolism in hypertensives: a multicenter prospective study.

The effects of long-term monotherapy with terazosin, an alpha-1 blocker, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 53 hypertensive patients: 19 with normal glucose tolerance (NGT) and 34 with impaired glucose tolerance (IGT). The plasma glucose, serum lipids, fructosamine, and glycosylated hemoglobin A1c (HbA1c) levels were determined before and during long-term (6 months) therapy with terazosin. A 75-g oral glucose tolerance test was performed before and during long-term terazosin therapy. Significant falls in both systolic and diastolic blood pressure in both patient groups were maintained during the long-term therapy with terazosin. Neither fasting nor postglucose-load venous plasma glucose levels were altered in either group of patients, and diabetes mellitus did not develop in any patient with NGT during the study. There was no significant change in the insulinogenic index (delta IRI/delta BS at 30 minutes after glucose load) in either patient group. In patients with IGT, glucose intolerance was slightly improved with significant reductions in HbA1c and fructosamine during terazosin therapy. Serum total cholesterol (TC) and triglyceride levels were significantly decreased in patients with IGT. In addition, TC and low density lipoprotein (LDL) cholesterol were significantly decreased in patients with hypercholesterolemia (TC > 220 mg/dL). These results suggest that long-term therapy with terazosin may improve glucose and lipid metabolism in hypertensive patients and terazosin seems to be an antihypertensive agent with beneficial effects for hypertensive patients with either dyslipidemia or impaired glucose metabolism.

Adrenergic alpha-Antagonists↗

PubMed1994

Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese.

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.

Angiotensinogen↗

PubMed1994

[A case of adrenal pheochromocytoma with normotention and normal levels of urinary excretion of catecholamines].

A 62-year-old man was admitted to our hospital for further examination of right adrenal mass accidentally pointed out by ultrasonogram. He had no symptoms and no physiological abnormalities. Endcrinological examinations revealed normal adrenocortical function, excluding the possibility of functioning adrenocortical adenoma. Pheochromocytoma seemed to be also unlikely since 24-hr urinary excretion of catecholamines were within normal limits. The tumor was surgically removed and histopathologically diagnosed as pheochromocytoma. This case of adrenal incidentaloma is unique in that little sign of pheochromocytoma was presented before operation. The reasons were discussed especially in respect of tissue contents of catecholamines and opioid peptide in comparison with other cases with pheochromocytoma we had experienced.

Adrenal Gland Neoplasms↗

PubMed1994

Glomerular nodular lesions in non-amyloid immunoglobulin deposition disease: their pathogenetic relationship to mesangiolysis.

Renal biopsy of a 70-year-old woman with clinical features of rapidly progressive glomerulonephritis revealed nodular glomerulosclerosis with conspicuous crescent formation. Other peculiar findings were the presence of many mesangiolytic cystic lesions and multinucleated giant cells in the cystic lesions. By immunofluorescent microscopic study, lambda light and gamma heavy chains were found in mesangial nodules, Bowman's capsule and the tubular basement membrane. Multiple myeloma was diagnosed by bone marrow examination. Autopsy performed two months later revealed systemic deposition of lambda light and gamma heavy chains, and fairly advanced nodular glomerulosclerosis. Most of the glomerular nodular lesions had a lamellar structure. Amyloid was not found. The high incidence of both mesangiolytic lesions in the biopsy specimen and laminated glomerular nodules in the autopsy material supports the previously proposed pathogenetic relationship of these two findings.

Aged↗

PubMed1994

Linkage disequilibrium and haplotype studies of chromosome 8p 11.1-21.1 markers and Werner syndrome.

Werner syndrome (WS) is an autosomal recessive disorder, characterized as a progeroid syndrome, previously mapped to the 8p 11.1-21.1 region. Because WS is so rare, and because many patients are from consanguineous marriages, fine localization of the gene by traditional meiotic mapping methods is unlikely to succeed. Here we present the results of a search for a region that exhibits linkage disequilibrium with the disorder, under the assumption that identification of such a region may provide an alternative method of narrowing down the location of WRN, the gene responsible for WS. We present allele frequencies in Japanese and Caucasian cases and controls for D8S137, D8S131, D8S87, D8S278, D8S259, D8S283, fibroblast growth factor receptor 1, ankyrin 1, D8S339, and two polymorphisms in glutathione reductase (GSR), covering approximately 16.5 cM in total. We show that three of the markers examined--D8S339 and both polymorphisms in the GSR locus--show strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, we show that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as eight or nine independent WRN mutations in these two populations.

Ankyrins↗

PubMed1994

FS2. a mamba venom toxin, is a specific blocker of the L-type calcium channels.

The peptide FS2 is a mamba venom toxin, consisting of 60 amino acids, three residues of which are different from those of calciseptine (CaS), a natural L-type Ca2+ channel blocker. The biological activities of synthetic FS2 for L-type Ca2+ channels were determined under comparisons to those of CaS and nitrendipine, a 1,4-dihydropyridine derivative. Similar to CaS, FS2 competitively inhibited the binding of [3H]nitrendipine to rat brain synaptosomal membranes on Lineweaver-Bulk plot, with Kd value of 210 nM, which was similar to that of CaS being 290 nM, but did not affect binding of an N-type Ca2+ channel ligand omega-[125I]-conotoxin GVIA to the membranes. Pretreatment of A7r5 cells with either FS2 or CaS at concentrations of 10(-8) M and greater for 5 min significantly and dose-dependently reduced 10(-6) M Bay K8644-induced increase in the cytosolic free Ca2+ concentration ([Ca2+]i) of the cells determined by the fluorescent Ca2+ indicator fura-2, with the half inhibitory concentrations (IC50) of 2.3 x 10(-8) and 2.7 x 10(-8) M, being similar to that of the IC50 value of nitrendipine (4.4 x 10(-8) M). These observations indicate that FS2, similar to CaS, is an active natural L-type Ca2+ blocker sharing the binding site on the channels with the 1,4-dihydropyridines.

Amino Acid Sequence↗

PubMed1993

Cellular mechanism of glyburide-induced insulin gene expression in isolated rat islets.

The cellular mechanism for the effects of glyburide on the synthesis and release of insulin and insulin gene expression in isolated islets was investigated. On incubation for 1 h, glyburide increased insulin release without affecting either the insulin content or the PPI mRNA level. H-7, an inhibitor of PKC, inhibited the glyburide-induced insulin release, while H-8, an inhibitor of cyclic nucleotide-dependent protein kinases, did not affect the glyburide-induced insulin release. On incubation for 20 h, glyburide increased insulin release and the PPI mRNA level, without affecting the insulin content. H-7 inhibited glyburide-induced insulin release and increased the PPI mRNA level. H-8 significantly inhibited both the glyburide-induced increase in insulin release and increase in PPI mRNA level. In conclusion, glyburide stimulated insulin release via a PKC-mediated pathway and increased the PPI mRNA level via cyclic nucleotide-dependent protein kinase(s).

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1993

Single intraluminal delivery of antisense cdc2 kinase and proliferating-cell nuclear antigen oligonucleotides results in chronic inhibition of neointimal hyperplasia.

To develop an effective strategy to prevent neointima formation after angioplasty injury, we have identified cell-cycle regulatory proteins as targets for inhibition by using antisense oligonucleotides (ODNs). We utilized an intraluminal molecular delivery method that employs the protein coat of a Sendai virus complexed with liposomes that enhances markedly the efficiency of ODNs uptake. First, we examined the effect of antisense cdc2 kinase and proliferating-cell nuclear antigen (PCNA) ODNs in vitro. Cotransfection of antisense cdc2 kinase and PCNA ODNs inhibited serum-stimulated vascular smooth muscle cell growth, whereas antisense cdc2 kinase ODNs alone or PCNA ODNs alone failed to show any inhibitory effect. Transfection of the combination of antisense cdc2 kinase and PCNA ODNs into balloon-injured arteries in vivo provided a marked decrease in cdc2 and PCNA mRNA expression as determined by reverse transcription-PCR, compared to sense controls. Antisense ODN treatment significantly inhibited the increase in DNA synthesis induced by balloon injury. Moreover, antisense ODN administration inhibited completely neointima formation at 2 weeks after angioplasty in an apparent dose-dependent manner. Moreover, the inhibitory effect of antisense ODN on neointima formation persisted up to 8 weeks after a single transfection. The present study documents that a single intraluminal molecular delivery of combined cdc2 kinase and PCNA antisense ODNs results in a sustained inhibition of neointima formation in the rat carotid balloon-injury model.

Animals↗

PubMed1993

Calciseptine binding to a 1,4-dihydropyridine recognition site of the L-type calcium channel of rat synaptosomal membranes.

Calciseptine (CaS) is a natural peptidic L-type Ca2+ channel blocker consisting of 60 amino acids with four disulfide bonds. The effects of synthetic CaS on the binding of various ligands to Ca2+ channels of rat brain synaptosomal membranes were studied. The membranes possessed specific binding sites for L-type Ca2+ channel ligands [3H]nitrendipine, [3H]diltiazem and [3H]verapamil, derivatives of 1,4-dihydropyridine, benzothiazepine and papaverine, respectively, and also for N-type Ca2+ channel ligand omega-[125I]-conotoxin GVIA (omega-[125I]CTX). Lineweaver-Bulk plot analysis disclosed that CaS competitively inhibited the binding of [3H]nitrendipine, with maximal binding capacity of 0.19 pmol/mg protein and dissociation constant (Kd) of 290 nM, being about 10(3) times the Kd value of [3H]nitrendipine. Similar to nitrendipine, CaS noncompetitively enhanced the binding of [3H]diltiazem, but did not affect the binding of [3']verapamil. CaS at up to 10.0 microM did not affect the binding of omega-[125I]CTX. These observations indicate that CaS shares the properties of 1,4-dihydropyridine derivatives, and allosterically modulates the binding of other L-type Ca2+ channel ligands.

Animals↗

PubMed1993

Nitric oxide mediates interleukin-1-induced prostaglandin E2 production by vascular smooth muscle cells.

We examined the possible participation of nitric oxide (NO) in the activation of cyclooxygenase, a heme-containing enzyme, induced by interleukin-1 (IL-1) in vascular smooth muscle cells (VSMC). IL-1 induced a delayed and prolonged release of both NO and prostaglandin E2 (PGE2) from VSMC. NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, partially but significantly inhibited the PGE2 release induced by IL-1, whereas it completely inhibited the IL-1-induced NO production. The inhibitory effects of L-NMMA on IL-1-induced production of both NO and PGE2 were partially reversed by a 10-fold excess of L-arginine. In addition, coincubation with superoxide dismutase enhanced the IL-1-induced PGE2 release from VSMC. In contrast, 8-bromo-cyclic GMP did not stimulate PGE2 release. Furthermore, 0.2 mM sodium nitroprusside directly stimulated PGE2 release from VSMC. These findings suggest that NO at least in part mediates the IL-1-induced PGE2 production, and that NO may be one of the important signals for the activation of cyclooxygenase to produce PGE2 in VSMC.

Animals↗

PubMed1993

[The renin-angiotensin system and blood pressure].

The renin-angiotensin system plays an important role in the regulation of blood pressure. Recent progress in molecular biology enables us to investigate the molecular mechanism of essential hypertension. Accumulating data suggest that the disorder of the renin-angiotensin system is not essentially a primary factor of hypertension, but it apparently plays an indispensable role in the pathogenesis of hypertension. Many researchers including us have shown that the renin-angiotensin system also contributes the development of various hypertension-related organ damages by its hypertrophic, vasculotoxic or unknown mechanisms. Gene diagnosis and newly developed antihypertensive drug therapy including gene therapeutics will open the new era of individualized and etiology-based hypertension treatment.

Animals↗

PubMed1993

MHC-linked diabetogenic gene of the NOD mouse: molecular mapping of the 3' boundary of the diabetogenic region.

To localize and characterize the MHC-linked diabetogenic gene of the NOD mouse, we studied the class III region of the MHC in the NOD mouse and related strains. Hsp70, Bat5, Tnfa and Tnfb loci were studied by microsatellite polymorphism analysis and/or restriction mapping. The CTS mouse had the same allele as the NOD mouse at the Hsp70 locus, but different alleles at the Bat5, Tnfa and Tnfb loci from those of the NOD mouse. Our previous studies indicated that in the CTS mouse, class II MHC was the same as that of the NOD mouse, but that class I MHC was different at both K and D loci, and that CTS MHC was diabetogenic in the presence of NOD background genes. These data map major genetic susceptibility to type 1 diabetes to the segment flanked by class I K and class III Bat5 loci. Moreover, since the diabetogenic effect of the CTS MHC is weaker than that of the NOD MHC, these data suggest the presence of a second MHC-linked gene or gene complexes that modulate susceptibility to type 1 diabetes outside this segment.

Animals↗

PubMed1993

Dahl's salt-resistant normotensive rat has mutations in cytochrome P450(11 beta), but the salt-sensitive hypertensive rat does not.

Molecular cloning of cytochrome P450(11 beta) cDNAs from the adrenal glands of Dahl's salt-sensitive hypertensive (DS) and salt-resistant normotensive (DR) rats was performed using a combined technique of the first strand cDNA synthesis by reverse transcriptase followed by polymerase chain reaction. The cDNA sequence of P450(11 beta)-DS was identical to that of wild type P450(11 beta). In contrast, the clone obtained from the DR rat contained six nucleotide substitutions causing five amino acid alterations (Arg-127-->Cys, Val-351-->Ala, Val-381-->Leu, Ile-384-->Leu, and Val-443-->Met). When the two cDNAs were expressed in COS-7 cells and steroid conversion rates of the transformed cells were determined, a ratio of 18-hydroxylation to 11 beta-hydroxylation of 11-deoxycorticosterone by P450(11 beta)-DS-expressed cells was 0.58, whereas that by P450(11 beta)-DR-expressed cells was 0.23. Plasma levels of 18-hydroxy-11-deoxycorticosterone and corticosterone (the 11 beta-hydroxylation product of 11-deoxycorticosterone) in DS and DR rats well reflected the steroidogenic activities of the two P450s. These results suggest that the characteristic plasma steroid level of the DR rat is caused by the mutations in P450(11 beta) gene and may act to maintain the normotensive blood pressure in this rat strain during sodium loading.

Amino Acid Sequence↗

PubMed1993

A neuropeptide Y locus on chromosome 4 cosegregates with blood pressure in the spontaneously hypertensive rat.

Recent advances in molecular biology have allowed the study of the candidate genes for essential hypertension. To identify the genes responsible for basal blood pressure in the spontaneously hypertensive rat strain, the rat model of genetic hypertension, we performed a cosegregation analysis between the genotype and blood pressure in a set of male F2 progeny obtained from SHR and Wistar-Kyoto rats, a reference normotensive strain. Our investigation revealed that a locus on the chromosome 4 cosegregates with the blood pressure in SHR, especially at neuropeptide Y locus. The degree of cosegregation with all values of blood pressure without sodium loading was moderate but consistent. We propose that neuropeptide Y locus on chromosome 4 is a new candidate for the hypertensive effect in original SHR.

Animals↗