Biomedical subjects

I Takasaki

Publications and source records attributed to I Takasaki.

At least 19 recordsLinked to original sources

PubMed1999

Renin-angiotensin system and fibronectin gene expression in Dahl Iwai salt-sensitive and salt-resistant rats.

OBJECTIVE: The tissue renin-angiotensin system and extracellular matrix are involved in the cardiovascular hypertrophy and remodeling induced by hypertension. In this study, we examined the gene expression of the tissue renin-angiotensin system and fibronectin in inbred Dahl Iwai salt-sensitive and salt-resistant rats. MATERIALS AND METHODS: Eight pairs of 6-week-old male Dahl Iwai salt-sensitive and salt-resistant rats were fed either a low- or high-salt diet (0.3% or 8% NaCl, respectively) for 4 weeks. Activities of the circulating renin-angiotensin system were measured by radioimmunoassay and the gene expression of tissue angiotensinogen, the angiotensin II type 1 receptor (AT1) and fibronectin were analyzed by Northern blot analysis. RESULTS: Salt loading significantly increased blood pressure and produced cardiovascular hypertrophy and nephrosclerosis in the salt-sensitive rats. Activities of the circulating renin-angiotensin system were lower in salt-sensitive rats than in salt-resistant rats fed the low-salt diet, and salt loading lowered these activities in salt-resistant rats but not in salt-sensitive rats. In salt-resistant rats, salt loading increased renal, cardiac and aortic angiotensinogen, AT1 and fibronectin messenger (m)RNA expression except for aortic fibronectin mRNA expression. In contrast, in the salt-sensitive rats, salt loading stimulated the expression of cardiac fibronectin and aortic angiotensinogen, AT1 and fibronectin mRNAs. Furthermore, the cardiac and aortic fibronectin mRNA levels in salt-sensitive rats were higher than those in salt-resistant rats when both strains were fed the high-salt diet. CONCLUSIONS: These results demonstrate that the expression of tissue angiotensinogen, AT1 and fibronectin mRNAs is regulated differently in Dahl Iwai salt-sensitive and salt-resistant rats, and indicate that salt-mediated hypertension activates the cardiac fibronectin gene independently of the tissue renin-angiotensin system and stimulates the aortic fibronectin gene with activation of the tissue renin-angiotensin system.

Angiotensin I↗

PubMed1999

Thrombin receptor mediated signals induce expressions of interleukin 6 and granulocyte colony stimulating factor via NF-kappa B activation in synovial fibroblasts.

OBJECTIVE: To clarify the mechanism of thrombin receptor mediated signal transduction and the induction of cytokines by thrombin stimulation in rheumatoid synovial fibroblasts. METHODS: Cytokines were measured by enzyme linked immunosorbent assay (ELISA) in the supernatants of cultured rheumatoid synovial fibroblasts stimulated by thrombin. To assess the mechanism of thrombin receptor mediated signal transduction in the rheumatoid synovial fibroblasts, electrophoretic mobility gel shift assay (EMSA), immunoglobulin kappa-chloramphenicol acetyltransferase (CAT) assay, and immunostaining for NF-kappa B subunit molecule was performed. RESULTS: Thrombin stimulation activated the inducible transcription factor NF-kappa B, and then induced subsequent expressions of interleukin 6 (IL6) and granulocyte colony stimulating factor (G-CSF) in the cells. CONCLUSION: Thrombin receptor mediated signal transduction could induce the expressions of IL6 and G-CSF, and increase inflammatory events in the cavum articulare via NF-kappa B activation.

Arthritis, Rheumatoid↗

PubMed1999

Severe hyperparathyroidism with hypercalcemia associated with chronic renal failure at pre-dialysis stage.

We report a case of a 23-year-old Japanese woman who had severe hyperparathyroidism associated with chronic renal failure before the start of dialysis treatment. Her chief complaints were swelling and pain in both shoulders. Laboratory examination revealed renal failure (BUN 134 mg/dl, serum Cr 7.3 mg/dl), severe normocytic normochromic anemia (hemoglobin 4.3 g/dl), hypercalcemia (11.8 mg/dl), and hyperphosphatemia (9.7 mg/dl). Serum PTH levels were extremely increased (intact PTH >1,000 pg/ml: normal range 10-50 pg/ml). X-ray examination of the skull and shoulders showed a salt and pepper appearance, and cauliflower-like deformity of the distal end of both clavicles, respectively. Accelerated ectopic calcification was observed in the costal cartilages, internal carotid arteries, and splenic arteries. Ultrasonographic examination revealed enlargement of the four parathyroid glands. Thallium-technetium subtraction scintigraphy of the parathyroid glands showed increased uptake into the upper two. Renal needle biopsy revealed severe impairment of the interstitium and tubules with much milder changes in glomeruli. The etiology of the renal failure could not be identified. Hemodialysis, total parathyroidectomy and auto-transplantation into the forearm were immediately performed. The pathological diagnosis was chief cell hyperplasia of the parathyroid glands. Based on the presence of chronic renal failure, remarkable hyperphosphatemia with mild hypercalcemia, an unusually high level of serum PTH, and accelerated ectopic calcification, the patient was diagnosed to have severe secondary hyperparathyroidism caused by chronic renal failure with major impairment of the renal interstitium and tubules.

Adult↗

PubMed1998

Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells.

This study was performed to investigate a mechanism of angiotensin II (Ang II)-mediated activation of the fibronectin (FN) gene in rat vascular smooth muscle cells. Actinomycin D and CV11974 completely inhibited Ang II-mediated increase in FN mRNA levels. Inhibitors of protein kinase C (PKC), protein-tyrosine kinase (PTK), phosphatidylinositol-specific phospholipase C, Ras, phosphatidylinositol 3-kinase, p70 S6 kinase, and Ca2+/calmodulin kinase also decreased Ang II-induced activation of FN mRNA. In contrast, cycloheximide; PD123319; or inhibitors of Gi, protein kinase A, or mitogen-activated protein kinase kinase did not affect the induction. FN promoter contained a putative AP-1 binding site (rFN/AP-1; -463 to -437), and the results of a transient transfection and electrophoretic mobility shift assay showed that Ang II enhanced rFN/AP-1 activity. CV11974 and inhibitors of PKC or PTK suppressed Ang II-mediated increases in rFN/AP-1 activity, although neither PD123319 nor a protein kinase A inhibitor affected the induction. Furthermore, mutation of rFN/AP-1 that disrupted nuclear binding suppressed Ang II-induced transcription in the native FN promoter (-1908 to +136) context. Thus, Ang II activates transcription of the FN gene through the Ang II type 1 receptor in vascular smooth muscle cells, at least in part, via the activation of AP-1 by a signaling mechanism dependent on PKC and PTK.

Angiotensin II↗

PubMed1998

Cough-challenge trial with a new angiotensin-converting enzyme inhibitor, imidapril.

This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin-converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor-induced dry cough were enrolled in a randomized, open-labeled, crossover trial with two 6-week periods to be treated with imidapril or amlodipine, a calcium-channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough-challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/ 60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I- and bradykinin-degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Intravascular ultrasound imaging of atherosclerotic renal arteries: comparison between in vitro and in vivo studies.

BACKGROUND: Intravascular ultrasound (IVUS) imaging, a new modality, may be feasible and useful for the assessment of atherosclerotic renal arteries. However, comparison between in vivo and in vitro studies to confirm pathological changes corresponding with IVUS findings obtained from renal arteries was not fully evaluated. METHODS: We evaluated ultrasound images of 18 post-mortem human renal arteries and cross-sectional IVUS images of main renal arteries in five patients with renal artery stenosis (RAS) or essential hypertension. RESULTS: In vitro studies have shown that renal-artery images had three layers when the arteries had fibrous intimal thickening and medial hypertrophy. Renal arteries, in which the fibrous intima was not well developed, showed circumferentially homogeneous bright echoes. In patients with atherosclerotic RAS and essential hypertension, IVUS images showed hyperechoic areas in the renal arterial walls, probably due to atherosclerosis. Typical three-layered ultrasound appearance was not easily seen during in vivo studies. CONCLUSION: Our findings suggest that hyperechoic images can be a diagnostic clue of atherosclerosis However, in vitro results do not always correspond exactly to in vivo findings, and caution is needed when findings from in vitro IVUS imaging studies are applied to in vivo studies.

Adolescent↗

PubMed1998

Effects of renin-angiotensin system blockade and dietary salt intake on left ventricular hypertrophy in Dahl salt-sensitive rats.

We studied the effects of chronic blockade of the renin-angiotensin system on hypertension and cardiac left ventricular hypertrophy (LVH) in Dahl salt-sensitive (DS) rats given a high-salt or low-salt diet. [Experiment 1] Twelve-week-old male DS rats were fed an 8% NaCl diet and received the angiotensin II receptor (AT1) antagonist, candesartan (3 mg/kg/d), the angiotensin converting enzyme inhibitor enalapril (30 mg/kg/d), or vehicle for 6 wk after 3 wk of 8% salt-loading. Neither candesartan nor enalapril with concomitant high salt-loading attenuated the blood pressure (BP) elevation. LVH was also not attenuated significantly by these treatments. [Experiment 2] After 8 wk of 8% salt-loading, the rats were given a 0.3% NaCl diet and concurrently received candesartan, enalapril, or vehicle for 5 wk. Switching from the high-salt to low-salt diet significantly decreased BP and left ventricular mass in the vehicle-treated animals. Both candesartan and enalapril normalized BP during salt-depletion; the blockade of the renin-angiotensin system produced an additive reduction in LVH. These findings suggest that sodium intake and hemodynamic load, but not the renin-angiotensin system, may be major determinants of the development of LVH in DS rats.

Angiotensin II↗

PubMed1998

Long-term therapy with an ACE inhibitor, temocapril, reduces microalbuminuria in essential hypertension.

The present study was conducted to prospectively evaluate whether a new ACE inhibitor, temocapril, could modify urinary microalbumin excretion rate (UAE) in a group of hypertensive outpatients who had no evidence of renal impairment. Sixty-three outpatients (32 men and 31 women; mean age, 59.9 +/- 1.5 yr) with essential hypertension entered the study, all having been treated for at least 6 mo with dihydropyridine calcium-channel blockers (CCBs: nitrendipine, nisoldipine, or amlodipine). Their blood pressures (BPs) had been controlled to adequate levels with the CCBs. None had overt proteinuria (determined by Albustix) or abnormal serum creatinine levels. After 3 mo of baseline observation under the previous treatment, the subjects were randomly divided into two groups. In group A (n = 31), the previously used CCBs were switched to temocapril, 2 to 4 mg once daily for 12 mo, and BP was controlled at a level equivalent to that during CCB treatment. In group B (n = 32), the subjects were maintained on their previous treatment for a further 12 mo. The effect of temocapril on BP appeared to be clinically similar to that of the previously used CCBs, but it significantly decreased UAE as compared with the previous therapy. In group A, UAE decreased significantly (p < 0.01) from the baseline value of 38.9 +/- 5.1 mg/g creatinine (Cr) to 22.2 +/- 4.2 and 25.3 +/- 5.6 mg/g Cr at the 6th and 12th months of temocapril therapy, respectively. In contrast, in group B UAE was unchanged (baseline 39.8 +/- 6.6 mg/g Cr; 6 mo, 44.6 +/- 6.8; 12 mo, 45.9 +/- 7.7). In group A, 17 of 31 patients (54.8%) had abnormal UAE levels (> or = 29.5 mg/g Cr) during previous therapy with CCBs, but 6 mo after switching to temocapril 25 of these patients (80.6%) had normal UAE (< 29.5 mg/g Cr). In group B, 15 of 32 patients (46.9%) had abnormal UAE levels during the observation period, and these abnormal UAE levels remained unchanged; 17 of the 32 patients (53.1%) had abnormal UAE levels after a further 6 mo of continued CCBs therapy. We conclude that long-term therapy with temocapril may provide renal protection by reducing UAE even in hypertensive patients with no evidence of renal impairment.

Albuminuria↗

PubMed1997

Progression of glomerulosclerosis, renal hypertrophy, and an increased expression of fibronectin in the renal cortex associated with aging and salt-induced hypertension in Dahl salt-sensitive rats.

Aging and hypertension are known to be closely related with the pathogenesis and development of glomerulosclerosis. In this study, we examined the time course changes in the glomerulus associated with salt-induced hypertension using the inbred Dahl salt-sensitive rats. For this purpose, 5-week-old Dahl salt-sensitive rats (n=36) were fed either 4% NaCl diet (n=18) or 0.3% NaCl diet (n=18) up to 17 weeks of age. The high salt diet caused a dramatic increase in systolic blood pressure and also a dramatic renal hypertrophy as shown by a significant increase in the kidney weight. Histological examination revealed an age-dependent progression of glomerulosclerosis as documented by a quantitative scoring. This age-dependent progression was further accelerated by the co-existence of salt-induced hypertension in the high salt diet group. Northern blot analysis revealed an increase in the steady state mRNA levels of fibronectin, an important component of mesangial matrices, in the renal cortex, but not in the renal medulla, only in salt-loaded Dahl salt-sensitive rats. These findings indicate that salt-induced hypertension accelerates the age-dependent progression of glomerulosclerosis in Dahl salt-sensitive rats, and fibronectin may play a role in the pathogenesis, development, and progression of glomerulosclerosis associated with salt-induced hypertension.

Aging↗

PubMed1997

Fosinopril. Clinical pharmacokinetics and clinical potential.

Fosinopril is a phosphorus-containing ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It is hydrolysed mainly in the gastrointestinal mucosa and liver to the active diacid, fosinoprilat, which has unique pharmacological properties. The majority of the active moieties of other ACE inhibitors are excreted in the urine. This means that an adjustment in either the dosage and/or the administration interval is needed in patients with moderate to severe renal dysfunction, in order to reduce drug accumulation and the possibility of an excessive decrease in blood pressure or other adverse effects. On the other hand, fosinoprilat is excreted both in urine and bile (as with temocaprilat, zofenoprilat and spiraprilat), and thus an adjustment of dosage and/or administration interval may be unnecessary in patients with moderate to severe renal dysfunction, as impaired renal function influences little of the pharmacokinetics of fosinoprilat. Furthermore, the available evidence suggests that the pharmacokinetic variables of fosinoprilat in patients receiving haemodialysis were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dose administration following dialysis may be unnecessary. The hypotensive effect of the combination of fosinopril and a diuretic is synergistic. Pharmacokinetic interactions with fosinopril are unlikely in patients receiving thiazide or loop diuretics. Fosinopril has beneficial effects for patients with hypertension and left ventricular hypertrophy because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy. There are a large number of studies of the pharmacokinetics of fosinopril. However studies of its pharmacokinetic drug interactions with other drugs are far fewer. Further investigations are needed in several clinical settings.

Absorption↗

PubMed1997

[Regitine test].

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Adrenal Gland Neoplasms↗

PubMed1997

[Angiotensin-converting enzyme inhibitors: recent therapeutic aspect].

Angiotensin-converting enzyme (ACE) inhibitors now have an accepted place in the treatment of hypertension and congestive heart failure. With the discovery and development of captopril, several other ACE inhibitors have been synthesized and introduced for clinical use. All ACE inhibitors bind to zinc ions located in the active site of the ACE molecule. ACE inhibitors can be classified according to the ligand of the zinc ion of ACE, into 3 different structural types: (1) the first type such as captopril has a sulphhydryl moiety as the ligand; (2) the second type such as enalapril uses a carboxyl moiety as the ligand; (3) the third type such as fosinopril uses neither a sulphhydryl nor carboxyl group, but a phosphinic acid as the zinc binding moiety. ACE inhibitors can also be classified according to the excretion route of their active moiety, into 2 different excretion route types:(1) excreated mainly through the kidney such as captopril, enalaprilat, lisinopril, benazeprilat, imdaprilat, trandraprilat, etc.; (2) excreated both in the bile and urine such as fosinoprilat, temocaprilat, zofenoprilat etc. ACE inhibitors have clinically beneficial effects not only for patients with either hypertension or congestive heart failure, but also can be used to prevent the progression of renal dysfunction induced by hypertension and diabetes mellitus.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

[Case of renovascular hypertension with pheochromocytoma].

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Adrenal Gland Neoplasms↗

PubMed1996

Induction of apoptosis in murine clonal osteoblasts expressed by human T-cell leukemia virus type I tax by NF-kappa B and TNF-alpha.

We investigated the effects of various cytokines in the presence of human T-cell leukemia virus type I (HTLV-I) tax protein in murine clonal osteoblasts, MC3T3-E1 cells. Skeletal remodeling by osteoclasts and osteoblasts is coordinated by cytokines, which are activated by HTLV-I tax protein via nuclear factor-kappa B (NF-kappa B). MC3T3-E1 cells were cocultured with an irradiated HTLV-I-producing lymphocyte cell line, MT-2. After coculture, the tumor necrosis factor-alpha (TNF-alpha) level in the medium was markedly elevated during the 7 days of culture, and MC3T3-E1 cells underwent apoptotic cell death. Marked apoptosis was also observed in MC3T3-E1 cells treated with MT-2 culture medium and in HTLV-I tax-expressing MC3T3-E1 clones, which both expressed high levels of TNF-alpha. This apoptosis was prevented by treatment with neutralizing anti-TNF-alpha antibody (alpha TNF). HTLV-I tax protein and TNF-alpha induced activation of NF-kappa B in apoptotic MC3T3-E1 cells. Decreased NF-kappa B activation was observed in HTLV-I tax-expressing MC3T3-E1 cells treated with alpha TNF. Our results suggest that HTLV-I tax activated NF-kappa B and subsequently TNF-alpha, leading to apoptosis of osteoblasts.

Animals↗

PubMed1996

Ceramide-induced nuclear translocation of NF-kappa B is a potential mediator of the apoptotic response to TNF-alpha in murine clonal osteoblasts.

Osteoblasts are affected by TNF-alpha overproduction by immune cells during inflammation. We demonstrate that apoptosis is induced in murine osteoblastic MC3T3-E1 cells by exceeding the concentrations 100 units/mL of TNF-alpha and 10 mumol/L of synthetic ceramide. The apoptotic signaling pathway activated by TNF-alpha was examined in MC3T3-E1 cells. Endogenous cellular ceramide concentrations increased within 3 min, and comparable peak levels were observed for 30 min after TNF-alpha treatment. Activation of nuclear factor-kappa B (NF-kappa B) was detected after TNF-alpha or synthetic ceramide stimulation. The concentration of NF-kappa B increased in the perinuclear region after 5 min of treatment and translocation into the nucleus was observed within 15 min of treatment. Degradation of I kappa B alpha/MAD-3 was observed after 60 min of ceramide treatment. These results indicate that nuclear translocation and activation of NF-kappa B through TNF-alpha generated ceramide may be one important apoptotic signaling pathway in MC3T3-E1 cells. The osteoblastic apoptosis triggered by TNF-alpha-generated ceramide may explain the inhibition of bone formation during severe bone inflammation.

Animals↗

PubMed1996

AT1 receptor antagonist, TCV 116, does not prevent cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats.

1. We investigated the effects of direct blockade of angiotensin II (AngII) by a potent, non-peptide angiotensin II toff 1 (AT1) receptor antagonist, TCV 116, on the development of cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats. 2. Six week old male Dahl salt-sensitive rats (n = 44) were fed a 4% salt diet and were simultaneously given various doses of TCV 116 orally for 7 weeks. Each control group received vehicle alone. 3. Dietary high salt intake elevated blood pressure continuously and caused left ventricular hypertrophy in rats treated with vehicle. TCV 116 had a minor effect on the rise in blood pressure. Left ventricular mass (left ventricular weight/body-weight) decreased slightly but not significantly, in rats treated with 3 mg/kg per day of TCV 116 (n = 8). Higher doses of TCV 116 (6 and 10 mg/kg per day; n = 8 each) did not show a decrease in left ventricular mass compared with the vehicle control. 4. These results suggest that AngII blockade has only minor effects on hypertension and on cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats and that the renin-angiotensin system may not contribute to the development of cardiac hypertrophy in Dahl salt-sensitive rats on a moderately high-salt diet.

Angiotensin Receptor Antagonists↗

PubMed1996

Vertebral growth disturbance in rapidly growing rats during 14 days of spaceflight.

The effect of 14 days of spaceflight on the vertebrae of rapidly growing rats was studied. The hardness of the vertebrae was measured with a Knoop microhardness tester, and bone mineral density was measured from X-ray photographs. Histomorphometric examination was performed with a microcomputer-aided system. No significant difference (P > 0.05) was observed between flight rats and ground controls with regard to mechanical hardness or bone mineral density. However, histological examination revealed irregular thickening of the endosteal surface of cortical bone in the flight rats, whereas it was uniform in the ground controls. The relative area of lamellar bone showed a significant reduction (P < 0.001) in the flight rats. These findings suggest that the structural disturbances were due to retardation of endosteal modeling and remodeling. We conclude that delay of vertebral maturation can occur in rapidly growing rats after even short-term exposure to microgravity.

Animals↗

PubMed1996

A case report of angioedema during long-term (66 months) angiotensin converting enzyme inhibition therapy with enalapril.

We describe a rare case of ACE inhibitor-induced angioedema during long-term therapy in a 51-year-old male patient with essential hypertension; and this is the third case reported of this adverse reaction in Japan. The patient received enalapril for 66 months, and complained of a dry cough which was mild and tolerable. Recently, he noted tenderness of his mouth, face, swelling of lips and tongue for 3 to 4 h after taking his morning dose of enalapril. These symptoms abated spontaneously, so he continued taking the drugs. He again noted similar episodes of angioedema 29 days after the first experience. He had no further episodes of angioedema or dry cough after cessation of enalapril. This case of angioedema developed during long-term therapy with enalapril administered as 19,930 mg of enalapril maleate. We emphasize that angioedema may occur at any time during the use of enalapril.

Angioedema↗