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Biomedical subjects

I Takasaki

Publications and source records attributed to I Takasaki.

At least 37 records · Page 2Linked to original sources
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

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↗
PubMed1995

Interleukin 6 mediated differentiation and rescue of cell redox in PC12 cells exposed to ionizing radiation.

The differentiation of PC12 cells to a neuron-like morphology was induced by ionizing radiation in the presence of serum. This effect was detectable at 5 grays (Gy) and reached a maximum at 10-20 Gy. Increases in the DNA binding activity of nuclear factor kappa B (NF-kappa B) and increased Interleukin 6 (IL-6) mRNA levels were observed at a dose of 15 Gy. Neutralization of supernatant IL-6 by the addition of anti-IL-6 antibody inhibited the neuronal differentiation and decreased cellular redox. Ionizing radiation and serum may act synergistically as neurotropic factors.

Animals↗
PubMed1995

Pharmacokinetics and pharmacodynamics of nisoldipine in hypertensive patients with normal and mild to moderate impaired renal function.

The pharmacokinetics and pharmacodynamics of nisoldipine (CAS 63675-72-9, isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate, Bay k 5552), a calcium antagonist, were investigated after administration of a single oral 10 mg dose and after 7 same doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with mild to moderate renal dysfunction (impaired renal function, IRF). A significant decrease in blood pressure was observed after consecutive dosing of nisoldipine compared to baseline values over 24 h in both groups. There were no significant differences in plasma profiles of nisoldipine in both groups after either single or consecutive dosing. The plasma concentration-time profiles of the active metabolite, Bay r 9425, were similar to those of nisoldipine in both groups. The pharmacokinetic parameters of nisoldipine and its active metabolite in the NRF and IRF groups did not differ after the single and the consecutive dosing. In addition, there were neither prolongation of apparent elimination half-life (t1/2), nor increases in peak plasma levels (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) after consecutive dosing in both groups. Cumulative urinary excretion rates of the major metabolites, Bay s 4755 and Bay s 1869, did not differ significantly between the NRF and IRF groups in both single and consecutive studies. In the present study, mild flushing was observed in one patient with IRF. There was no deterioration in renal function during the study. These results suggest that nisoldipine may have a long-lasting antihypertensive effect during consecutive dosing and that it can be used in hypertensive patients regardless of presence of renal dysfunction.

Blood Pressure↗
PubMed1994

Involvement of NF-kappa B activation in thrombin-induced human vascular smooth muscle cell proliferation.

A thrombin receptor has been cloned and is thought to mediate a variety of thrombin-induced responses. However, the transcription factors important for postreceptor signaling have been little clarified. The post-receptor signals are mediated by several protein kinases responsible for NF-kappa B activation, and most thrombin-inducible genes have the kappa B sequence in the regulatory elements. The possibility that NF-kappa B may participate in thrombin signaling was therefore investigated in cultured human vascular smooth muscle cells (VSMCs). Thrombin receptor stimulation resulted in activation of NF-kappa B. Furthermore, treatment of cells with antisense p65 ODNs of NF-kappa B inhibited thrombin-stimulated growth of VSMC in vitro. Results indicate that the activation of NF-kappa B is involved in thrombin signaling and that this pathway causes the proliferation of VSMC induced by thrombin. Therapeutic potential of antisense NF-kappa B ODNs for the treatment with atherosclerosis and restenosis is also indicated.

Acid Phosphatase↗
PubMed1994

Effects of hypertension and aging on fibronectin expression in aorta of Dahl salt-sensitive rats.

Effects of hypertension and aging on aortic fibronectin expression were investigated in male Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats fed either a low- or high-salt diet from 5 to 37 wk of age. In comparison to low-salt controls, the steady-state mRNA levels for aortic fibronectin in salt-loaded Dahl-S rats were dramatically increased at 37 wk of age, corresponding to a severe stage of hypertension with high mortality, whereas at earlier ages representing early to established phases of hypertension, no significant changes were observed. Salt loading affected neither blood pressure nor aortic fibronectin expression in Dahl-R rats. Aging without coexisting hypertension did not cause significant changes in aortic fibronectin mRNA levels all through the study period in either strain of rats. These results suggest that aortic fibronectin may be strongly regulated by factors associated with severe hypertensive organ damages caused by long-standing hypertension in salt-loaded Dahl-S rats. Also suggested was that aortic fibronectin may not play a major role in the pathogenesis of early aortic changes occurring in response to hypertension or as a process of aging.

Aging↗
PubMed1994

Association analysis of restriction fragment length polymorphism for alpha 2-adrenergic receptor genes in essential hypertension in Japan.

Recently, restriction fragment length polymorphism (RFLP) of alpha 2-adrenergic receptor gene (alpha 2-C10) digested with Bsu36I restriction enzyme has been reported in US populations. Therefore, we examined the association of this RFLP with essential hypertension by comparing the frequency of specific alleles for this gene in Japanese populations. The distribution of this RFLP was compared with that in US populations. Subjects were hypertensive patients with a family history of essential hypertension (n = 56) and normotensive subjects whose parents had no history of essential hypertension (n = 46). DNA was prepared from leukocytes. RFLP was determined by use of Southern blot analysis with an alpha 2-C10 probe and Bsu36I. The frequencies of the major (12-kb) and minor (5.8-kb) alleles were 0.30 and 0.70 in hypertensive patients and 0.38 and 0.62 in normotensive subjects, respectively. The difference between observed alleles in all subjects in each group was not significant (chi 2 = 1.33, P > .1). The difference between the overall allelic frequency in Japan and that reported in US populations was significant. This study found no evidence for an association between alpha 2-adrenergic receptor gene/Bsu36I RFLP and essential hypertension in Japan. However, the findings showed that the allele frequency in Japan differed from that reported in US populations.

Adult↗
PubMed1994

Exaggerated blood pressure response to angiotensin II in patients with Cushing's syndrome due to adrenocortical adenoma.

We studied the roles played by the renin-angiotensin system in inducing hypertension in nine patients with Cushing's syndrome (CS) resulting from adrenocortical adenoma, and compared them with those in patients with primary aldosteronism (PA), renovascular hypertension (RVH) and essential hypertension (EH). In the CS group, each parameter, including serum potassium, plasma renin activity, plasma aldosterone, deoxycorticosterone and corticosterone concentrations, is within the normal range. However, plasma renin activity in the CS group was lower than that in the RVH group but higher than that in the PA group, and plasma aldosterone concentration was lower than that in each RVH or PA group. These findings indicated that the CS group had a different type of hypertension from that in either RVH or PA, in which the renin angiotensin system or mineralocorticoids play an important role in hypertension. Meanwhile, captopril (50 mg) administration either with or without indomethacin pretreatment decreased the mean blood pressure in the CS group, although captopril failed to change it in the PA group or in normal subjects. Furthermore, the pressor response to exogenous angiotensin II in the CS group was higher than that in the RVH or EH group, but was not different from that in the PA group. Thus, the hypertension in patients with CS due to adrenocortical adenoma appears to be mediated through a change in the renin-angiotensin system in the form of exaggerated pressor responses to angiotensin II.

Adenoma↗