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Biomedical subjects

T Ogihara

Publications and source records attributed to T Ogihara.

At least 343 records · Page 19Linked to original sources
PubMed1997

Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions. We have previously reported that HGF is a novel member of endothelium-specific growth factors whose serum concentration is positively associated with blood pressure in humans. Therefore, we speculated that serum HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction. However, it is difficult to elucidate the role of circulating and tissue HGFs in human hypertension. To address this issue, we measured circulating and tissue HGF concentrations in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at different ages. Serum HGF concentration in SHR was significantly higher than that in WKY at 6, 15, and 25 weeks of age (P<.01). Serum HGF concentration was also significantly positively correlated with blood pressure in SHR (P<.02, r=.455). In contrast, tissue HGF concentrations in heart, aorta, and kidney were significantly decreased in SHR as compared with WKY at 25 weeks of age, when these organs showed hypertrophic changes induced by hypertension (P<.01). Cardiac HGF mRNA was also decreased in SHR as compared with WKY at 25 weeks of age. Moreover, cardiac HGF concentration showed a significant negative correlation with left ventricular (LV) weight (P<.01), whereas serum HGF concentration showed a significant positive correlation with LV weight (P<.05). Interestingly, concentrations of cardiac and vascular angiotensin II, a suppressor of HGF, were increased in SHR as compared with WKY at 25 weeks of age (P<.01). Therefore, we examined the effects of angiotensin blockade on circulating and tissue HGF concentrations, to study the role of angiotensin II in HGF regulation. Administration of an angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II type 1 receptor antagonists (losartan and HR 720) for 6 weeks resulted in a significant increase in cardiac HGF concentration, accompanied by increased cardiac HGF mRNA, and a significant decrease in serum HGF concentration, accompanied by lowered blood pressure and reduced LV weight (P<.01). Here, we demonstrated increased circulating HGF and decreased vascular, cardiac, and renal HGF in SHR as compared with WKY at the maintenance stage of hypertension. Decreased tissue HGF in target organs of hypertension may be due to increased tissue angiotensin II. These results suggest that decreased local HGF production may have an important role in the cardiovascular remodeling of target organs in hypertension, since HGF prevented endothelial injury and promoted angiogenesis. Blockade of angiotensin augmented local decreased cardiovascular HGF in hypertension, potentially resulting in the improvement of endothelial dysfunction.

Aging↗
PubMed1997

Molecular Delivery System for Antisense Oligonucleotides: Enhanced Effectiveness of Antisense Oligonucleotides by HVJ-liposome Mediated Transfer.

BACKGROUND: The effectiveness of antisense oligodeoxynucleotides for in vitro and in vivo studies is limited by a low efficiency of cellular uptake and instability due to degradation by nucleases. To overcome some of these problems, we recently developed a transfer method that utilizes inactivated Sendai virus (hemagglutinating virus of Japan [HVJ]) complexed with liposomes to deliver antisense oligodeoxynucleotides. In this study, we compared the effectiveness of the HVJ-liposome method versus a cationic liposome method versus passive uptake to deliver antisense oligodeoxynucleotides against basic fibroblast growth factor on angiotensin (Ang) II-induced rat vascular smooth muscle cell growth. METHODS AND RESULTS: Twenty to twenty-eight hours after transfection, antisense fibroblast growth factor oligodeoxynucleotides introduced by passive uptake and HVJ-liposome method decreased basal DNA synthesis significantly as compared to the sense, control, and scrambled oligodeoxynucleotides groups; however, 60-68 hours after transfection, only antisense fibroblast growth factor oligodeoxynucleotides transduced by the HVJ-liposome method resulted in a significant inhibition of DNA synthesis under basal and Ang II-(10(-;6)M) stimulated conditions. The IC(25) of oligodeoxynucleotides assessed by the inhibition of thymidine incorporation was significantly lower using the HVJ-liposome method than those using the other transfer methods. To clarify the mechanisms of cellular uptake of oligodeoxynucleotides with the HVJ-liposome method, we studied the cellular fate of fluorescein isothiocyanate (FITC)-labeled oligodeoxynucleotides FITC-oligodeoxynucleotides was localized in nuclei at 5 minutes after transfection with the HVJ-liposome method. In contrast, FITC-oligodeoxynucleotides introduced by passive uptake was detected in nonnuclear cellular compartments, possibly endosomes, but not the nuclei. Cellular fluorescence of oligodeoxynucleotides introduced by passive uptake disappeared within 24 hours, while that introduced by the HVJ-liposome method could be observed up to 72 hours. CONCLUSION: These results demonstrate that the HVJ-liposome transfer enhanced the effectiveness of AS-fibroblast growth factor via its specific molecular mechanisms of transfer.

Journal Article↗
PubMed1997

Metabolic fate of ulinastatin (2); Pharmacokinetics in rabbits following intra-articular administration.

The absorption and distribution of ulinastatin following intra-articular administration of [125I]ulinastatin to rabbits were determined and kinetic analysis using a multi-compartment model was performed. At 4 h after administration, the content of radioactivity in the synovial fluid, which was comparable to that of the immunoreactive ulinastatin, was 14.51% of the dose and decreased in a biphasic manner. The highest level of radioactivity was observed in the synovial membrane, followed by the meniscus, ligament, cartilage and patella, the radioactivities of which also declined biphasically. After intra-articular administration, the plasma concentration of total radioactivity increased slowly and reached maximum at 4.3 h, and then declined slowly in a monophasic manner with a half-life of 10.8 h. The radioactivity of the high molecular weight fraction in plasma, which reached maximum at 1.7 h after administration and then declined with a half-life of 11.8 h, was consistent with the time curve for immunoreactive ulinastatin in the plasma through 24 h after the administration. Within 8 and 24 h after administration, respectively, 1.48 and 4.66% of the administered radioactivity were transferred to the lymphatic fluid. The pharmacokinetics of [125I]ulinastatin after an intra-articular administration could be explained using a multi-compartment model in which a portion of the administered ulinastatin was absorbed via the lymphatic system. This finding suggested that ulinastatin was rapidly distributed and retained for a long period of time in the joint tissues. In addition, the pharmacokinetics of ulinastatin following intra-articular administration indicated typical flip-flop kinetics.

Animals↗
PubMed1997

Influence of aging on progression of cardiovascular complications associated with insulin resistance in patients with essential hypertension.

Hyperinsulinemia or insulin resistance is suggested to play a role in the pathogenesis of hypertension and its target organ diseases. It is also well documented that aging is associated with a decline in glucose tolerance and insulin sensitivity, but there are few reports on the relationship between aging and insulin sensitivity or on the effects of aging on the progression of cardiovascular complications in patients with essential hypertension. To clarify these effects of aging in essential hypertension, 44 patients were examined by the euglycemic hyperinsulinemic glucose clamp test and ultrasonography of the heart and carotid arteries. There was a significant negative correlation between aging and insulin sensitivity (r = -0.37, p < 0.05). Significant increases in left ventricular mass index and carotid wall thickening accompanied by insulin resistance were seen in only non-elderly patients but not in elderly patients. These results suggest that aging decreases insulin sensitivity even in essential hypertensive subjects and that insulin resistance does not affect the progression of cardiac hypertrophy and atherosclerosis in elderly patients with essential hypertension.

Aged↗
PubMed1997

Recognition of tissue- and subtype-specific modulation of angiotensin II receptors using antibodies against AT1 and AT2 receptors.

Polyclonal antibodies have been prepared against synthetic peptides of human angiotensin II type-1 (AT1) and type-2 (AT2) receptors. Synthetic peptides corresponded to amino acids 15-24 of AT1 receptor and amino acids 241-253 of AT2 receptor. Western blot analysis of membranes from cell homogenates of COS-7 cells transfected with expression plasmids for mouse AT1b receptor, human vascular smooth muscle cells, and rat peripheral tissue demonstrated a major band of MW 44,000 with AT1 receptor antibody. Cell homogenates of COS-7 cells transfected with expression plasmids for human AT2 receptor showed a band of MW 44,000 with AT2 receptor antibody. Tissue homogenate of rat adrenal medulla and human pheochromocytoma presented a major band of MW 52,000 and a minor band of MW 44,000 with AT2 receptor antibody. AT1 receptor expression was in the following order: rat aorta > > lung, kidney, spleen, adrenal cortex > adrenal medulla, heart. Expression of AT2 receptor was in the following order: rat adrenal medulla > cortex, kidney, heart. Three-day treatment with CS866, an AT1 receptor antagonist, and temocapril, an angiotensin-converting enzyme inhibitor, suppressed AT1 receptor expression in the rat adrenal cortex, but not in the heart or adrenal medulla. AT2 expression was not affected by treatment with these drugs. These results suggest that newly developed antibodies for AT1 and AT2 receptors are useful in elucidating the regulation of subtype-specific receptor expression, and that AT1 but not AT2 receptors in adrenal tissue are regulated by angiotensin II.

Adrenal Glands↗
PubMed1997

Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes.

Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose-induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-beta (TGF-beta) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-beta antibody. As TGF-beta inhibited local HGF production in endothelial cell and VSMC, increased TGF-beta induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-beta production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.

Animals↗
PubMed1997

[Urinary bacteria in elderly patients with urinary incontinence and low levels of daily activity].

The results of bacteria isolated from the urine of inactive elderly patients with urinary incontinence in 1982, 87, 93 and 95 were compared and the chronological changes of urinary bacteria were analyzed. The following results were obtained: (1) The most common bacteria isolated from the patients in 1995 were D-group Enterococcus, followed by Providencia rettgeri, E. coli, Pseudomonas aeruginosa and Proteus mirabilis. It is thought that the main cause of the more frequent isolation of Enterococcus is an abuse of cephems and fecal contamination. (2) The most common bacteriaisolated from the patients who were managed with an indwelling urethral catheter were Proteus and Providencia species, and their incidence tended to decrease from 1982 to 1995. (3) Infection with Pseudomonas species tended to increase, as did that Staphylococcus species, especially Methicillin-resistant Staphylococcus aureus and then decreased. Based on these findings, it is important to assess and treat dysuria before inserting an indwelling urethral catheter, and to select an antibacterial agent that is effective in elderly patients with urinary incontinence and limited activity.

Activities of Daily Living↗
PubMed1997

[Glucose tolerance and insulin resistance in the elderly].

Glucose tolerance is reported to be impaired in the elderly, and this is said to be mainly due to a decrease in insulin sensitivity (insulin resistance). Insulin resistance is known to be associated with atherosclerosis and coronary artery disease. To clarify whether or not age-dependent changes in glucose tolerance and insulin sensitivity are risk factors for coronary artery disease, as they are in the case of the insulin resistance syndrome, we studied age-dependent changes in glucose tolerance, insulin sensitivity, blood pressure, and serum lipids in a large number of subjects who underwent annual health check-ups, and then studied the relationships between coronary artery disease and aging, insulin sensitivity, and other risk factors in subjects who underwent coronary angiography. Aging was associated with an increased prevalence of noninsulin-dependent diabetes mellitus and impaired glucose tolerance; even in subjects with normal glucose tolerance, plasma glucose levels during an oral glucose tolerance test were significantly higher in the elderly. Insulin sensitivity, as assessed by the ratio of the sum of the plasma glucose divided by the sum of the serum insulin during the test (sigma PG/sigma IRI), was significantly lower in subjects over 60 years old than in younger subjects. Age-dependent impairment of insulin sensitivity and glucose tolerance was associated with increased blood pressure and serum cholesterol levels, but not with changes in boy mass index or serum triglyceride levels. As an independent variable, aging, but not insulin sensitivity, was related to the severity of coronary artery disease. These data suggest that aging is associated with glucose intolerance, insulin resistance, and an increased risk of coronary artery disease, but that the effect of aging on coronary artery disease cannot be explained by insulin resistance alone. Other factors, such as glucose intolerance and increased blood pressure, in addition to insulin resistance, appear to be responsible of the increased risk for coronary artery disease in the elderly.

Aged↗
PubMed1997

[Cerebral infarction and asymptomatic arteriosclerosis obliterans in the elderly].

We examined the associations between cerebral infarction (CI), asymptomatic arteriosclerosis obliterans (ASO), and known risk factors for these diseases. The subjects were 67 elderly patients (11 men and 56 women, mean +/- SD age of 79.6 +/- 8.5 years). in 44 patients CI was diagnosed by CT scan; 23 were classified as having cortical infarction and 21 as having lacunar infarction. In 41 patients asymptomatic ASO was diagnosed by an ankle-pressure index (API) of less than 0.9. To identify risk factors for these diseases, we examined the association among these diseases and hypertension (blood pressure > or = 140/90 mmHg), hypercholesterolemia (total cholesterol concentration > or = 220 mg/dl), hypertriglyceridemia (triglyceride concentration > or = 150 mg/dl), low HDL-cholesterolemia (HDL-C concentration < 40 mg/dl), high LDL-cholesterolemia (LDL-C concentration > or = 150 mg/dl), and glucose intolerance (fasting blood sugar concentration > or = 110 mg/dl). The incidence of asymptomatic ASO in the subjects with CI was significantly higher than that in the subjects without CI (chi 2 test; p < 0.05, odds ratio 6.4), including cortical infarction (p < 0.05, odds ratio 8.9) and lacunar infarction (p < 0.05, odds ratio 3.8). Patients with lacunar infarction were more likely to have hypertension than were controls (p < 0.05). Cortical infarction was not associated with these risk factors. Both low HDL-C and high LDL-G were more common in patients with asymptomatic ASO than patients without asymptomatic ASO (p < 0.05). These results indicate that CI and asymptomatic ASO are strongly associated in the elderly, especially in subjects with cortical infarction, and that aging itself contributes to cortical infarction.

Aged↗
PubMed1997

[Evaluation by specialists of the Guidelines on Treatment of Hypertension in the Elderly--the second questionnaire survey].

The Guidelines on Treatment of Hypertension in the Elderly, 1995 was published by the Research Group for Guidelines on Treatment of Hypertension in the Elderly Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare. To assess the guidelines, and to further investigate the changes in the therapeutic policy for hypertension in the elderly, we mailed a questionnaire to 133 Japanese hypertension specialists who had replied to the first mailed questionnaire in 1993. We received 102 replies (77%). Overall, the guidelines were scored 4.3/5.0. More than 95% of the specialists agreed with levels of blood pressure (BP) indicative for treatment, as well as the goal of BP control. The guidelines propose that the rate of increase of the drug dose should be very slow, at least every four weeks, and that the target BP be reached after two months. The majority of the specialists agreed with this. However, 10% of them preferred to follow patients every two weeks. The guidelines propose long-acting Ca antagonists and ACE inhibitors as the first choice of drug for the treatment of uncomplicated hypertension in the elderly. Two-thirds of the specialists agreed. However, 17% of specialists proposed adding diuretics or beta-blockers to the first line therapy. Ten specialists (10%) expressed concerns about Ca antagonists and three (3%) insisted on withdrowing them from the first line of drugs. In the guidelines, alpha and beta blockers are designated as relatively contraindicated in elderly patients with hypertension, but half the specialists answered that these drugs can be used safely in elderly patients. These findings indicate that the therapeutic policy of Japanese specialists in hypertension in the elderly has not changed substantially for three years.

Aged↗
PubMed1997

[Hemorrhagic colon ulcer as a side effect of non-steroidal anti-inflammatory drugs in five aged patients].

A report is presented of five aged patients with hemorrhagic colon ulcer, which was strongly suspected to be a side effect of non steroidal anti-inflammatory drugs (NSAID). All patients were suffering from orthopedic diseases and NSAIDs were administered for pain: Zaltoprofen for one patient and slow-releasing diclofenac for the other four. Four patients had being treated underlying diabetes mellitus and three of them were being treated with sulfonylurea. Appetite loss was the earliest symptom, 1-2 weeks after administration of NSAID began. Diarrhea occurred 1-2 weeks after appetite loss, and finally hemorrhagic stool developed 1-2 weeks after that. Acute gastric mucosal lesion, hemorrhagic colon ulcer and colitis were diagnosed in all patients by emergency gastro-duodenocolonoscopy. NSAID and oral diet were ceased, and intravenous hyperalimentation was instituted when the patients revealed severe anemia due to bleeding. All patients could take an oral diet after a few weeks. In conclusion hemorrhagic colon ulcer must be prevented in patients treated with NSAID especially those who are aged and have a history of diabetes mellitus.

Aged↗
PubMed1997

Potential role of a novel vascular modulator, hepatocyte growth factor (HGF), in cardiovascular disease: characterization and regulation of local HGF system.

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. To seek an endothelium specific growth factor, we have focused on hepatocyte growth factor (HGF). HGF is belonged to a member of endothelium specific growth factors, whose mitogenic action on EC was most potent among growth factors. Moreover, the presence of local HGF system (HGF and its specific receptor, c-met) was observed in EC and VSMC of rat and human in vitro as well as in vivo. Production of local HGF production in vascular cells was regulated by various cytokines including transforming growth factor (TGF)-beta and angiotensin II (Ang II). Furthermore, HGF may be a therapeutic growth factor for the treatment of restenosis after angioplasty and arteriosclerosis obliterance, etc., as gene therapy. From these characteristics of HGF, we hypothesized that HGF might contribute to the protection or repair of vascular endothelial cells. Indeed, serum HGF concentration was significantly correlated with blood pressure, suggesting that HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction. In this review, we discussed that HGF is a member of the endothelium specific growth factors whose serum concentration is significantly associated with blood pressure.

Animals↗
PubMed1997

[Insulin, as a regulating factor of blood pressure].

In patients with hypertension, insulin resistance and hyperinsulinemia are more prevalent than in normal individuals. Furthermore, the prevalence of hypertension in diabetic patients is higher than in nondiabetic individuals. Insulin resistance has been implicated in the common mechanisms underlying diabetes, hypertension, hyperlipidemia and obesity. A number of mechanisms have been proposed to account for the elevation of BP secondary to hyperinsulinemia, such as 1) increased tubular reabsorption of sodium ions, 2) increased intracellular sodium and calcium ions, 3) increased sympathetic nervous activity, and 4) proliferation of vascular smooth muscle cells. Moreover, hypertension was reported to be a possible cause of insulin resistance. The detailed mechanism of insulin leading hypertension are still under investigation.

Animals↗
PubMed1997

[Angiotensin receptor antagonist for therapy of patients with hypertension].

Nonpeptide angiotensin II type 1-receptor antagonists, AT1 receptor antagonists are newly developed and useful drugs for hypertension and congestive heart failure. In Japan, the efficacy and safety of losartan and candesartan cilexetil in patients with essential hypertension have been evaluated by the double-blind, parallel group-comparison study using enalapril as control drug. Both trials revealed that these drugs showed a hypotensive effect comparable to that of enalapril with a high safety since the adverse drug reaction of cough was recognized in very few patients. Furthermore, a recent randomised trial of losartan versus captopril in patients over 65 with heart failure, evaluation of losartan in the elderly study (ELITE), showed that losartan was associated with a lower mortality than that found with captopril. Further studies will clarify differences in protection of cardiovascular system with a long-term treatment between AT1, receptor antagonists and angiotensin-converting enzyme inhibitors.

Aged↗