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Biomedical subjects

J Higaki

Publications and source records attributed to J Higaki.

At least 163 records · Page 9Linked to original sources
PubMed1996

A vascular modulator, hepatocyte growth factor, is associated with systolic pressure.

Endothelial cells are known to secrete various antiproliferative and vasodilating factors, such as nitric oxide and natriuretic peptides. The presence of endothelial dysfunction, well known in hypertensive individuals, potentially results in the development and progression of atherosclerosis. Therefore, it is important to know the factors that might influence endothelial cell growth. We examined the mitogenic actions of hepatocyte growth factor (HGF) on human endothelial and vascular smooth muscle cells. Exogenously added human recombinant HGF stimulated endothelial but not vascular smooth muscle cell growth in a dose-dependent manner. We also compared the mitogenic action of HGF with that of basic fibroblast growth factor and vascular endothelial growth factor. Interestingly, the mitogenic action of HGF on endothelial cells was greater than the actions of basic fibroblast growth factor and vascular endothelial growth factor, whereas basic fibroblast growth factor but not HGF and vascular endothelial growth factor stimulated vascular smooth muscle cell growth. Given the characteristics of HGF as an endothelium-specific growth factor, we evaluated the relationship of circulating HGF and blood pressure in normotensive and hypertensive subjects. Serum HGF concentration has been reported to be elevated in response to organ damage, such as in hepatitis and nephritis, and recent findings show that HGF may play an important role in tissue regeneration. We hypothesized that HGF might contribute to the protection or repair of vascular endothelial cells. If so, serum HGF level might be elevated in response to endothelial cell damage induced by hypertension. To test this hypothesis, we measured serum levels of HGF, lipoprotein(a), plasminogen activator inhibitor-1, tissue plasminogen activator, total cholesterol, and blood pressure in 41 normotensive and hypertensive subjects without liver, kidney, or lung damage. Serum HGF concentration was significantly correlated with systolic pressure (P < .01, r = .43) but not diastolic pressure. Serum HGF concentration in hypertensive subjects was significantly higher than in normotensive subjects. None of the other factors showed any correlation with blood pressure. We have demonstrated that HGF is an endothelium-specific growth factor whose serum concentration is significantly associated with systolic pressure. These results suggest that HGF secretion might be elevated in response to high blood pressure as a counterregulatory system against endothelial dysfunction.

Aged↗
PubMed1996

Analysis and comparison of new candidate loci for hypertension between genetic hypertensive rat strains.

To search for the genes that determine the level of blood pressure, we performed linkage analyses using rat microsatellite markers in two sets of F2 rats derived from two hypertensive rat strains and one normotensive rat strain. In the first F2 progeny obtained from spontaneously hypertensive rats and Wistar-Kyoto rats, it was found that two different loci cosegregated with blood pressure. One was gamma-crystallin locus on rat chromosome 9, which has a hypertensive effect, and the other was peroxisomal 3-keto acyl-CoA thiolase locus on rat chromosome 8, which has a hypotensive effect. Then, we studied the same loci in second F2 progeny obtained from Dahl/Iwai salt-sensitive rats and Wistar-Kyoto rats. It was found that the locus located on rat chromosome 8 also had a hypotensive effect, although the others were not cosegregated with blood pressure in this cross. We suggest that a new locus for hypertension is located on rat chromosome 9 and that a locus on rat chromosome 8 has a common effect that makes blood pressure decrease in different hypertensive strains.

Animals↗
PubMed1996

Analysis of candidate genes for insulin resistance in essential hypertension.

To clarify the genetic basis of insulin resistance in hypertension, case-control association studies were performed to examine candidate genes for insulin resistance in hypertension. Since the main site of insulin resistance in hypertension is glycogen synthesis in skeletal muscle, genes that encode molecules involved in this pathway, i.e. insulin receptor (INSR), insulin-responsive glucose transporter (GLUT4) and glycogen synthase (GSY), were studied. In addition, since recent studies suggest the contribution of beta3 adrenergic receptor to the insulin resistance syndrome, the gene encoding beta3 adrenergic receptor (ADRB3) was also studied. Frequency of homozygotes for common C allele of a microsatellite polymorphism in the INSR gene was higher in the hyperinsulinemia group, but not in the normoinsulinemia group of hypertensive patients than in normotensive control subjects. Insulin sensitivity, however, was not significantly different between hypertensive patients with C/C genotype and those without this genotype. No significant differences were observed in the distribution of alleles or genotypes of the GLUT4, GSY and ADRB3 genes between hyperinsulinemia and normoinsulinemia groups of hypertensive patients or between these groups and the control group. These data suggest that the INSR polymorphism is associated with hyperinsulinemia, but not with insulin resistance, in hypertension.

Case-Control Studies↗
PubMed1996

Links between hypertension and myocardial infarction.

The mechanisms through which hypertension contributes to the occurrence of myocardial infarction should be discussed from two points of view: (1) common risk factors for the two diseases, such as genetic risk, insulin resistance, sympathetic hyperactivity, and vasoactive substances such as angiotensin K, and (2) linking factors that are induced by hypertension and contribute to the development of atherosclerosis and myocardial infarction, such as atherosclerosis and left ventricular hypertrophy. Mechanical stress on blood vessels because of high blood pressure is an especially important factor in endothelial dysfunction, the progression of atherosclerosis, and plaque rupture. This article concentrates on these factors from the perspective of their relationship with the renin-angiotensin system, because recent multicenter trials have demonstrated that angiotensin-converting enzyme inhibitors are effective for preventing recurrence of myocardial infarction.

Arteriosclerosis↗
PubMed1996

In vivo gene transfer of insulin gene into neonatal rats by the HVJ-liposome method resulted in sustained transgene expression.

In Many areas of disease such as homozygous familial hypercholesterolemia, no known effective therapy exists. The time is ripe for the introduction of gene therapy for the management of incurable disorders. However, for clinical gene therapy it is necessary to establish an efficient and non toxic gene delivery system. Recently, we have developed a gene delivery system mediated by Sendai virus as a potential means of gene therapy. However, this HVJ-liposome method has some disadvantages: (1) transient transgene expression; and (2) no integration. In gene therapy, it is desirable for transgenes to be expressed for as long as possible. To deal with this issue, we hypothesized that gene transfer into newborn animals would result in sustained expression of transgene. Our results demonstrated that transgene expression in liver was subsequently sustained for at least up to 8 weeks, as detected by reverse transcriptase PCR and radioimmunoassay, while our previous studies documented that transgene expression in adult animals disappeared within 2 weeks. Interestingly, we detected the presence of transgene in the host genomic DNA extracted from the nuclei of hepatic cells assessed by PCR. These findings provide new important information for gene therapy, although the mechanisms of sustained transgene expression are not clear.

Aging↗
PubMed1996

[Bartter syndrome].

The characteristic clinical features of Bartter syndrome consist of hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism. Some are constantly present, such as juxtaglomelular hyperplasia, decrease of the pressor response for angiotensin II infusion, impairment of concentrating ability, and elevated prostaglandin E2 and I2, while others such as hypomagnesemia are observed in some cases. The primary cause remains unknown, but the most likely candidate is reduced sodium chloride reabsorption in the thick ascending limb of Henle's loop. Exclusion of pseudo-Bartter syndrome, mainly of surreptitious vomiting and diuretic abuse, is necessary to diagnose the syndrome. The current therapy focuses on multiple agents to reduce massive potassium loss and to inhibit the syntheses of prostaglandin.

Bartter Syndrome↗
PubMed1996

In vivo transfer of gene and oligodeoxynucleotides into skin of fetal rats by incubation in amniotic fluid.

One of the tools to test an in vitro hypothesis in vivo is transgenic/gene targeting technology. Transgenic technology provides many advantages such as: (1) the study of specific gene function as systemic and developmental effects; and (2) testing of specific gene function chronically. nevertheless, one disadvantage of this technology is the difficulty in tissue-specific targeting of the transgenic expression. Another useful tool is the in vivo gene transfer approach. Therefore, we tested a potential novel model for the study of transgene expression and knock-out using antisense technology. Here, we have demonstrated that incubation of hemagglutinating virus of Japan (HVJ)-liposome complex containing FITC-labeled oligonucleotides in the amniotic fluid of fetal rats resulted in the nuclear localization of fluorescence in the skin (epidermis and dermis). Similarly, transfection of beta-galactosidase gene resulted in positive staining in several surface layers of the skin. Thus, local gene or antisense oligonucleotide transfer approach into the skin may be useful for studying the role of autocrine/paracrine mediators and treating diseases.

Amniotic Fluid↗
PubMed1995

Expression of local hepatocyte growth factor system in vascular tissues.

Since endothelial cells (EC) are known to secrete various anti-proliferative and vasodilating factors, an agent that promotes seeding or regeneration of EC may have potential therapeutic value against vascular smooth muscle cell (VSMC) proliferation. For the above purpose, we have found that hepatocyte growth factor (HGF) fulfills such conditions. However, the local HGF system has not yet clarified. Therefore, we investigated endogenous HGF production and its specific receptor (c-met) in vascular tissues. Our results revealed the expressions of HGF and its receptor (c-met) mRNA in endothelial cells, VSMC and neointimal VSMC of rat assessed by RT-PCR. HGF and c-met mRNA were also detected in human aortic endothelial cells and VSMC. Endothelial cells and VSMC of both rat and human produce and secrete immunoreactive HGF as assessed by ELISA. Of importance, the existence of local HGF system (HGF and c-met) was also observed in vivo in intact abdominal aorta of SD and Wistar rats. Overall, this study demonstrated that HGF is expressed and secreted from endothelial cells and VSMC of both rat and human in vitro as well as in vivo. Since HGF has characteristics of an endothelium-specific growth factor, locally synthesized HGF in endothelial cells and VSMC may have a role in vascular functions in autocrine-paracrine manner.

Animals↗
PubMed1995

Pancreatitis associated with choledochal cyst and other anomalies in childhood.

Fifty-one children with anatomical anomalies of the pancreatic duct developed pancreatitis associated with either congenital dilatation of the bile duct (choledochal cyst; n = 48) or other rare causes (n = 3). Among those with choledochal cyst, 41 underwent primary surgical resection of the dilated bile duct, while five of the remaining seven patients receiving cystenterostomy underwent secondary resection of the cyst.

Adolescent↗
PubMed1995

Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism.

Cerebral deposition of beta-amyloid protein is a pathological feature central to Alzheimer's disease. Production of beta-amyloid by proteolytic processing of the beta-amyloid precursor protein (beta APP) is a critical initial step in beta-amyloidogenesis. We use an inhibitor of beta APP processing to block beta-amyloid peptide formation. Application of the inhibitor to cultured cells results in an accumulation of proteolytic intermediates of beta APP, enabling a precursor-product relationship between beta APP carboxy-terminal fragments and beta-amyloid peptides to be demonstrated directly. In the presence of inhibitor, these amyloidogenic carboxy-terminal fragments can be degraded to nonamyloidogenic products. The catabolism of beta APP carboxy-terminal intermediates and the formation of beta-amyloid peptides are likely to involve an early endosomal compartment as the subcellular site of processing.

Alzheimer Disease↗
PubMed1995

Persistent inhibition of the pressor and aldosterone responses to angiotensin-II by TCV-116 in normotensive subjects.

TCV-116 is an orally active, nonpeptide antagonist of angiotensin-II type-1 receptor. The angiotensin-II antagonistic potency of TCV-116 was evaluated in normal volunteers. TCV-116 was administered at single doses of 1, 2.5, and 5 mg orally on separated days. Before, and 4, 8, and 24 h after the drug administration, angiotensin-II was infused intravenously at the rate of 2.5 to 40 ng/kg/min for 5 min each. At 2.5 mg of TCV-116, the pressor response to angiotensin-II was significantly suppressed at 4 and 8 hours after drug administration. TCV-116 at 5 mg produced a reduction of basal blood pressure and a suppression of pressor response to angiotensin-II, which persisted for 24 h. Aldosterone response to exogenous angiotensin-II was suppressed to 10% at 8 h after 5 mg of TCV-116 administration and remained suppressed to 48% until 24 h. These results suggest that TCV-116 is a highly potent and long-lasting antagonist of angiotensin-II receptor in man. The renin-angiotensin system may play a role in the regulation of blood pressure even in normotensive subjects.

Administration, Oral↗
PubMed1995

Effect of an antihypertensive drug on brain angiotensin II levels in renal and spontaneously hypertensive rats.

1. Although numerous studies suggest that brain angiotensin (AII) may play an important role in the regulation of blood pressure, it is still unclear what factors may influence brain AII. In this study, we hypothesized that brain AII is influenced by circulating factors. To investigate the role of blood pressure and plasma AII in brain AII level, we studied the effect of an antihypertensive drug on brain AII in two-kidney, one-clip (2K1C) and spontaneously hypertensive (SHR) rats. 2. Hydralazine (20 mg/kg per day) and vehicle (water) were given to 2K1C rats between 2 and 6 weeks after operation and SHR for 4 weeks. In addition, vehicle was applied to sham operated rats and Wistar-Kyoto (WKY) rats. Brain and plasma AII was measured by a highly sensitive radioimmunoassay coupled with high performance liquid chromatography. 3. Hydralazine treatment effectively lowered blood pressure to the same level of sham-operated and WKY rats. 2K1C rats showed significantly higher plasma AII than sham rats, but hydralazine treatment did not show any change in plasma AII. Brain AII in the hypothalamus region of 2K1C rats showed a significantly higher level than sham rats. Interestingly, hydralazine treatment diminished this increase in brain AII. In contrast, SHR showed higher brain AII levels in the hypothalamus, brainstem and cerebellum than in WKY rats, whereas there was no significant change in plasma AII concentration between SHR and WKY rats. In contrast to the results found in 2K1C rat experiments, hydralazine treatment failed to decrease brain AII levels despite lowered blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1995

Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis.

To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n = 103) and control subjects (n = 103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P < .05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P < .0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.

Angioplasty, Balloon, Coronary↗
PubMed1995

Transient decrease in high blood pressure by in vivo transfer of antisense oligodeoxynucleotides against rat angiotensinogen.

The renin-angiotensin system plays an important role in blood pressure regulation. Angiotensinogen, which is mainly produced in the liver, is a unique component of the renin-angiotensin system, because angiotensinogen is only known as a substrate for angiotensin I generation. It is unclear whether circulating angiotensinogen is a rate-limiting step in blood pressure regulation. Recent findings of genetic studies and analyses suggest that the angiotensinogen gene may be a candidate as a determinant of hypertension. To test the hypothesis that angiotensinogen may modulate blood pressure, we transfected antisense oligonucleotides against rat angiotensinogen into the rat liver via the portal vein using liposomes that contain viral agglutinins to promote fusion with target cells, a technique that has been reported to be highly efficient. Transfection of antisense oligonucleotides resulted in a transient decrease in plasma angiotensinogen levels in spontaneously hypertensive rats from day 1 to day 7 after the injection, consistent with the reduction of hepatic angiotensinogen mRNA. Plasma angiotensin II concentration was also decreased in rats transfected with antisense oligonucleotides. Moreover, a transient decrease in blood pressure from day 1 to day 4 was observed, whereas transfection of sense and scrambled oligonucleotides did not result in any changes in plasma angiotensinogen level, blood pressure, or angiotensinogen mRNA level. Overall, our results demonstrate that transfection of antisense oligonucleotides against rat angiotensinogen resulted in a transient decrease in the high blood pressure of spontaneously hypertensive rats, accompanied by a decrease in angiotensinogen and angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Gap junction protein locus on chromosome 18 cosegregates with body weight in the spontaneously hypertensive rat.

To detect genetic predisposing factors for hypertension, we screened the genome of the spontaneously hypertensive rat (SHR). We determined the genotypes of all F2 rats at polymorphic sites between the two strains, using the DNA of F2 rats derived from mating of SHR and Wistar-Kyoto rats (WKY). Cosegregation analysis was conducted to assess whether the genotypes of polymorphic markers associate with any phenotypic parameters such as directly measured blood pressure, heart rate or body weight. All measurements in F2 rats were performed at 15 weeks of age. Two polymorphic markers on chromosome 18 cosegregated with body weight. Gap junction protein (heart connexin 43) gene showed the most significant association with body weight as a recessive trait, but no association was noted with other parameters. We conclude that the gap junction protein locus is a new candidate for the determinant gene of body weight in SHR.

Analysis of Variance↗
PubMed1995

Angiotensin I-converting enzyme gene polymorphism is associated with myocardial infarction, but not with retinopathy or nephropathy, in NIDDM.

OBJECTIVE: To clarify the relationship between the angiotensin I-converting enzyme (ACE) gene polymorphism and diabetic micro- and macroangiopathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: We examined 267 NIDDM patients with various stages of diabetic retinopathy, 61 patients with myocardial infarction (MI), and 136 patients without MI. An insertion/deletion polymorphism of the ACE gene was typed by polymerase chain reaction. RESULTS: Although no association was found between ACE gene polymorphism and diabetic retinopathy or nephropathy, this polymorphism was associated with MI in the patients with NIDDM. Homozygotes for the deletion polymorphism (DD genotype) were found more frequently in diabetic patients with MI (31.1%) than in diabetic patients without ischemic heart disease (16.9%), with a relative risk of 2.22 (95% confidence interval 1.11-4.46, P = 0.024). CONCLUSION: These data indicate that ACE gene polymorphism is associated with MI, but not with retinopathy or nephropathy, in patients with NIDDM and suggest that the ACE gene confers susceptibility to diabetic macroangiopathy but not to microangiopathy.

Alleles↗
PubMed1995

The effect of central amino acid neurotransmitters on the antihypertensive response to angiotensin blockade in spontaneous hypertension.

OBJECTIVE: To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974. MATERIALS AND METHODS: We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and gamma-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle. RESULTS: In SHR, CV 11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 +/- 83%) and gamma-aminobutyric acid (363 +/- 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35 +/- 4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, -18 +/- 5 mmHg; nitroglycerin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or gamma-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the gamma-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR. CONCLUSION: The present results suggest that the release of the inhibitory amino acids glycine and gamma-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.

Angiotensin Receptor Antagonists↗