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Biomedical subjects

M Nagasaka

Publications and source records attributed to M Nagasaka.

At least 37 records · Page 2Linked to original sources
PubMed1997

Comparison of resting beta-methyl-iodophenyl pentadecanoic acid (BMIPP) and thallium-201 tomography using quantitative polar maps in patients with unstable angina.

We compared resting beta-methyl-iodophenyl pentadecanoic acid (BMIPP) tomography with resting thallium-201 tomography in 28 patients with unstable angina. Tracer distribution was displayed on a polar map and compared with a normal standard deviation map obtained from a group of 12 normal subjects. The extent scores and severity scores obtained by BMIPP were significantly greater than those obtained by thallium-201. Confirmation by coronary angiography revealed the sensitivity of the methods in identifying patients to be 89% for BMIPP and 54% for thallium-201. There were significant differences between BMIPP and thallium-201 in the sensitivities of detecting postischemic jeopardized myocardium in the area supplied by the right coronary artery (RCA; 53% vs 18%, p < 0.05), left circumflex artery (LCX; 78% vs 39%, p < 0.025) and all 3 vessels combined (71% vs 35%, p < 0.001) but no significant differences in specificity (RCA: 82% vs 64%; LCX: 70% vs 90%; and total 3 vessels combined: 75% vs 79%). In conclusion, resting BMIPP tomography is more sensitive than resting thallium-201 tomography in detecting postischemic myocardial damage in patients with unstable angina.

Angina, Unstable↗
PubMed1996

Occurrence of a novel L-2,4-diaminobutyrate decarboxylase activity in some species of Enterobacteriaceae, and purification and characterization of the enzymes of Enterobacter aerogenes and Serratia marcescens.

L-2,4-Diaminobutyrate decarboxylase (DABA DC) is a novel enzyme yielding 1,3-diaminopropane (DAP) from DABA, which has previously been purified from strains of the genera Vibrio and Acinetobacter. In this study, we also detected DABA DC activity in the species of Enterobacteriaceae: E. aerogenes, E. cloacae, E. agglomerans, Serratia marcescens, S. liquefaciens, Klebsiella pneumoniace, K. oxytoca and Citrobacter freundii, all of which produced DAP in sufficient amounts. Subsequently, the DABA DCs of E. aerogenes and S. marcescens were purified to homogeneity and characterized. Two separate enzymes had similar properties with respect to chromatographic behaviors, and were a dimer with subunits of identical molecular mass of about 51 kDa. The maximal activity of each enzyme was obtained at pH 8.0-8.25. Both enzymes required pyridoxal 5'-phosphate and Mg2+ for full activity, and were highly specific for L-DABA. There was immunological similarity, but not identity between these proteins, as determined by Ouchterlony double diffusion analysis with antiserum against the E. aerogenes DABA DC. They showed the same N-terminal amino acid sequence up to the 8th residue (S-K-L-N-P-I-L-A-). These enzymes were different in molecular mass, N-terminal amino acid sequence and antigenicity from DABA DCs of Acientobacter and Vibrio species.

Carboxy-Lyases↗
PubMed1996

Modulation of transforming growth factor-beta secretion from malignant glioma cells by interleukin-1 beta.

Malignant glioma cells secrete transforming growth factor-beta (TGF-beta) which has potent immunosuppressive properties. We investigated the effect of interleukin-1 beta (IL-1 beta) on TGF-beta secretion from malignant glioma cells in vitro. T98G glioblastoma cells were treated with various doses of IL-1 beta and the TGF-beta activity in the supernatant was determined using a specific bioassay. Six other human malignant glioma cell lines were also treated with 1000 U/ml of IL-1 beta, and the TGF-beta activity in the supernatants was determined. The effect of IL-1 beta on the growth of tumor cells was also assessed by a bioassay using crystal violet which reflects the actual cell number in the plate wells. IL-1 beta treatment resulted in inhibition of TGF-beta secretion in two malignant glioma cell lines. TGF-beta secretion from T98G cells was suppressed by IL-1 beta in a dose-related manner. However, IL-1 beta treatment resulted in an obvious increase (> 20%) of TGF-beta secretion in two tumor lines, and a slight increase (< 20%) in three tumor lines. IL-1 beta did not affect the growth of four malignant glioma cell lines, and only slightly affected the growth of the other three cell lines. IL-1 beta modulates TGF-beta secretion from malignant glioma cells, but not in a consistent way.

Cell Division↗
PubMed1996

Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated with tumor cells.

The effect of transforming growth factor-beta (TGF-beta) secreted by glioblastoma (T98G) cells on the secretion of interferon-gamma (IFN-gamma) by lymphokine-activated killer (LAK) cells stimulated with tumor cells was investigated in cocultures of LAK and Daudi cells supplemented with T98G culture supernatant, T98G culture supernatant preincubated with anti-TGF-beta 1 and anti-TGF-beta 2 neutralizing antibodies, anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, or natural human TGF-beta 1 or recombinant human TGF-beta 2. LAK cells were incubated with anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, and with T98G cells of which the supernatant contained both active and latent forms of TGF-beta 1 and TGF-beta 2, with or without neutralizing antibodies. Addition of the supernatant from T98G cells to LAK/Daudi culture caused inhibition of IFN-gamma secretion by LAK cells. The inhibition was abolished by pretreatment of the supernatants with anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to the LAK/Daudi culture inhibited IFN-gamma secretion by LAK cells in a dose-dependent manner. Addition of anti-TGF-beta antibodies to the LAK culture resulted in increased IFN-gamma secretion. T98G cells failed to stimulate LAK cells to secrete more IFN-gamma. Addition of anti-TGF-beta antibodies to the LAK-T98G culture resulted in increased IFN-gamma secretion by LAK cells. These results suggest that most malignant glioma cells which secrete high levels of TGF-beta can inhibit IFN-gamma secretion by LAK cells even after tumor cell stimulation.

Brain Neoplasms↗
PubMed1995

Dopamine tonically modulates natriuresis in the saline-expanded dogs.

Dopamine (DA) has been shown to be an endogenous catecholamine that promotes natriuresis by activating tubular DA receptors, but its role on natriuresis appears to be equivocal, and the precise mechanisms and signaling pathway of multiple DA's receptor subtypes are not yet clarified. We used low dose of DA intravenously in saline (S) volume-expanded dogs to see the alterations in natriuresis. The results showed that there is a critical dose that induces no enhancement of natriuresis of volume expansion, and that the lower and higher doses of DA produced relatively larger natriuresis. Pretreatment of metoclopramide (MCP) in this settings caused even higher and significant increases of natriuresis. In conclusion, DA seems to determine tonically the level of natriuresis in saline-expanded dogs. DA may exert a dual effect on signal transduction pathways such that one leading to antinatriuresis with high affinity and the other to natriuresis with low affinity signaling cascades for DA. MCP may block the antinatriuretic limb of the signaling pathway.

Animals↗
PubMed1995

Secretion of transforming growth factor-beta 1 and -beta 2 by malignant glioma cells.

The secretion of transforming growth factor-beta (TGF-beta), a growth inhibitory factor with immunosuppressive properties, was investigated in one glioblastoma cell line and seven surgically resected malignant glioma cells. Cultured cells from surgically resected tumors were examined immunohistochemically for glial fibrillary acidic protein (GFAP) and S-100 protein. The levels of TGF-beta 1 and TGF-beta 2 in culture supernatants from malignant glioma cells were determined by a specific bioassay using anti-TGF-beta 1 and anti-TGF-beta 2 antibodies. Two glioblastoma cell lines were cultured in the presence of TGF-beta 1 or TGF-beta 2 to assess the effect of TGF-beta on the growth of glioblastoma cells. Cultured cells from surgically resected tumors were positive for both GFAP and S-100 protein. Both active and latent forms of TGF-beta 1 and TGF-beta 2 were detected in the culture supernatants from malignant gliomas, except in one patient with anaplastic astrocytoma which secreted only latent forms of TGF-beta 1 and TGF-beta 2. There was no statistical difference in the levels of TGF-beta 1 and TGF-beta 2 in glioblastomas and anaplastic astrocytomas. Neither TGF-beta 1 nor TGF-beta 2 affected the growth of glioblastoma cells. These findings suggest that most malignant glioma cells secrete both TGF-beta 1 and TGF-beta 2, can convert TGF-beta from a latent to active form, and may suppress cytokine secretion by activated lymphocytes in vivo as well as in vitro.

Astrocytoma↗
PubMed1994

Progression of kaolin-induced hydrocephalus and changes in performance of operant tasks by rats.

The behavior of rats with progressive hydrocephalus was examined to detect early neurological deterioration. Kaolin solution was injected into the cisterna magna of 10 of 17 anesthetized 8-week-old male rats (day 0), and saline in the other 7 rats (control group). Reaction time (RT, sec) and error ratio (ER, %) of unanesthetized rats escaping from electrical stimuli toward a nonstimulated sheet within a box were recorded daily from day 4 until autopsy after 4 weeks. Three rats in the kaolin group died in acute stage. Rats were assigned to either severe (S) (n = 4) or moderate (M) (n = 4) group according to the degree of ventricular dilatation at autopsy. The RTs prolonged and ERs increased in the kaolin group and they reached their minimum values. Values after the minimum RT value on day 12 in the M-group and 22 in the S-group during the chronic stage were compared with those in the controls, which decreased throughout the experiments (P < 0.03). In all animals in the S-group RT was prolonged each day with a linear regression (P < 0.005), although ER was decreased (0.69 > P > 0.23). In 3 rats and in another rat in the M-group RT was prolonged (P < 0.04 and P = 0.19) and ER was decreased in 3 rats (two: P = 0.41; one: P = 0.01) and increased in one (P = 0.55). In conclusion, deteriorated motor function is more important for early diagnosis in progressive hydrocephalus than behavioral symptoms.

Animals↗
PubMed1994

Inhibition of tumor necrosis factor-alpha and -beta secretion by lymphokine activated killer cells by transforming growth factor-beta.

Transforming growth factor-beta (TGF-beta) has a variety of immunosuppressive properties. We investigated the effect of TGF-beta secreted by glioblastoma (T98G) cells on the secretion of tumor necrosis factor-alpha and -beta (TNFs) by lymphokine activated killer (LAK) cells stimulated with tumor cells. The supernatant from T98G cells was preincubated with anti-TGF-beta 1 and -beta 2 neutralizing antibodies or untreated, and added to a coculture of LAK and Daudi cells. The neutralizing antibodies were added to LAK/Daudi and LAK culture, and natural human TGF-beta 1 and recombinant human TGF-beta 2 were also added to the LAK/Daudi culture. LAK cells were also cultured with T98G cells, of which the supernatant contained both active and latent forms of TGF-beta 1 and TGF-beta 2, and the neutralizing antibodies were added to the coculture. TNFs activity in the supernatants from LAK/Daudi cultures was examined by a specific bioassay. Addition of the supernatant from T98G cells to LAK/Daudi culture resulted in the inhibition of TNFs secretion by LAK cells. The inhibition was abrogated by the pretreatment of the supernatants with the anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to LAK/Daudi culture inhibited TNFs secretion by LAK cells in a dose-dependent manner. Addition of anti-TGF-beta antibodies to LAK culture resulted in an increase of TNFs secretion. These results suggest that, if tumor cells have the capacity to convert TGF-beta from a latent to an active form, the active TGF-beta suppresses TNFs secretion by LAK cells stimulated with the tumor cells, and that TGF-beta secreted and activated by glioblastoma cells suppresses the propagation of immune reaction by inhibiting TNFs secretion by activated lymphocytes adjacent to tumor cells.

Glioblastoma↗
PubMed1994

Synthesis and structure-activity relationships of new (5R,8R,10R)-ergoline derivatives with antihypertensive or dopaminergic activity.

A series of new (5R,8R,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were tested in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra. (5R,8R,10R)-6-Alkyl-8-ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R,8R,10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-methylergoline (4s, maleate: BAM-1110) exhibited potent dopaminergic activity, about 18-fold greater than that of bromocriptine mesylate. (5R,8R,10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-propylergoline (8b, fumarate: BAM-1602) showed extremely potent dopaminergic activity, being about 220 and 1.15 times more active than bromocriptine mesylate and pergolide mesylate, respectively. Several compounds exhibited potent antihypertensive activity. Structure-activity relationships for antihypertensive and dopaminergic activities are discussed.

Animals↗
PubMed1994

Synthesis and structure-activity relationships of new (5R,8S,10R)-ergoline derivatives with antihypertensive or dopaminergic activity.

A series of new (5R,8S,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were evaluated in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra, respectively. (5R,8S,10R)-6-Methyl-8- ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R,8S,10R)-8-(1-Imidazolylmethyl)-6-methylergoline (5a, BAM-2101) and (5R,8S,10R)-2-bromo-6-methyl-8-(1,2,4-triazol-1-ylmethyl) ergoline (7c, BAM-2202) exhibited potent antihypertensive activities. The maximum falls of systolic blood pressure after oral administration of 5a and 7c at 3 mg/kg were 95 and 132 mmHg, respectively, while those of cianergoline, bromocriptine mesylate, hydralazine, and nifedipine at the same dose were 40, 37, 47, and 49 mmHg, respectively. The durations of significant antihypertensive effects of these compounds except nifedipine were more than 7 h. None of the ergolines exhibited potent dopaminergic activity. Structure-activity relationships are discussed.

Animals↗
PubMed1993

MPC-1304, another type of dihydropyridine, possessing highly potent vasodilating action.

We investigated the vasodilating action of MPC-1304, one of the most potent dihydropyridines causing hypotension, in anesthetized dogs and compared this with its binding properties. After intraarterial injection, MPC-1304 was 3 times less potent than other dihydropyridines (nitrendipine, nifedipine, nicardipine and nisoldipine) in increasing femoral blood flow. After infusion of these drugs, however, MPC-1304 was the most potent in increasing femoral blood flow. The onset and recovery of the effect of MPC-1304 on femoral blood flow were slower than for nifedipine. Higher doses of Bay K 8644 were needed to antagonize the stimulating activity of MPC-1304 than for nifedipine. In a competition assay of [3H]nitrendipine binding, MPC-1304 and its metabolites bound to the dihydropyridine receptor with lower affinity than the other dihydropyridines. The binding affinity of [3H]MPC-1304 was lower than that of [3H]nitrendipine, consistent with the potency of this drug to increase femoral blood flow by bolus injection. The association and dissociation of [3H]MPC-1304 was slower than those of [3H]nitrendipine, which is consistent with the slow onset and long-lasting vasodilating effects of MPC-1304 on femoral blood flow. Moreover, diltiazem reduced a part of [3H]MPC-1304 binding in a competitive manner. In ex vivo binding assays with serum and aorta obtained after oral administration of the drug in spontaneously hypertensive rats, MPC-1304 inhibited [3H]nitrendipine binding to membrane preparations less potently than nifedipine. From these results, we conclude that MPC-1304 is a different type of dihydropyridine possessing the most potent vasodilating action of the representative dihydropyridines tested. Its activity cannot be explained solely by a slow interaction with voltage-dependent Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Effects of MPC-1304, a novel Ca2+ entry blocker, on alpha-adrenoceptor-mediated pressor responses in pithed rats.

MPC-1304 is a novel Ca2+ entry blocker of the 1,4-dihydropyridine type. In the present study, the effect of oral administration of MPC-1304 on alpha-adrenoceptor-mediated pressor responses was examined in pithed rats and compared with that of nifedipine. Drugs were administered orally to conscious animals before pithing. MPC-1304 (0.3-3 mg/kg) and nifedipine (1-10 mg/kg) inhibited pressor responses to norepinephrine, phenylephrine (alpha 1-adrenoceptor agonist), UK-14304 (alpha 2-adrenoceptor agonist), and sympathetic nerve (spinal cord segments) stimulation. MPC-1304 was roughly 3 times more potent than nifedipine in inhibiting these responses. The inhibitory effect of MPC-1304 (3 mg/kg) on the pressor response to UK-14304 lasted longer than that of nifedipine (3 mg/kg). At the same time, plasma concentrations of MPC-1304 were lower than those of nifedipine. These results suggest that MPC-1304 has a great ability to inhibit pressor responses to norepinephrine and peripheral sympathetic stimulation after its oral administration, and that this effect of MPC-1304 is closely correlated with its potent antihypertensive activity.

Administration, Oral↗
PubMed1993

Calcium entry blocking activities of MPC-1304 and of its enantiomers and metabolites.

The Ca2+ entry blocking effects of MPC-1304, a new Ca2+ entry blocker of the 1,4-dihydropyridine type, and of its (S) and (R) enantiomers and metabolites were examined on Ca(2+)-induced contractions in isolated rabbit arteries. The Ca2+ entry blocking activity of the (S) enantiomer of MPC-1304 was approximately 150 times greater than that of its (R) enantiomer. Likewise, the antihypertensive effect of the (S) enantiomer was twice as great as that of MPC-1304 (racemate) in conscious spontaneously hypertensive rats, while the (R) enantiomer was ineffective. Thus, most of the pharmacological activity of MPC-1304 resides in its (S) configuration. The main metabolic products of MPC-1304 also inhibited the Ca(2+)-induced contraction in the isolated vascular smooth muscles. These active metabolites showed a stereoselectivity similar to that of MPC-1304 for Ca2+ entry blocking activity, and may contribute to the potent antihypertensive action of MPC-1304.

Animals↗
PubMed1993

Estimation of anterior infarct size with body surface QRST integral maps in the presence of abnormal ventricular activation sequence in dogs.

The possibility of estimating infarct size with body surface QRST integral (IQRST) maps was investigated in dogs. IQRST maps were constructed from 87-lead body surface ECGs, which were recorded 1 week after the production of anterior myocardial infarction during artificial pacing that simulated normal conduction, left bundle branch block, and Wolff-Parkinson-White syndrome in 11 dogs. Small differences were observed between the IQRST maps of the normal conduction and left bundle branch block models (r = 0.93, root mean square difference = 8.71 mVmsec) and between the normal conduction and Wolff-Parkinson-White models (r = 0.96, root mean square difference = 6.03 mVmsec). Summation of the QRST integral values over the body surface leads (QRST index) inversely correlated with infarct size in all three conductions models: r = 0.91 (p < 0.001) in the normal conduction model; r = -0.81 (p < 0.001) in the left bundle branch block model; and r = -0.86 (p < 0.001) in the Wolff-Parkinson-White model. These results show that IQRST maps permit noninvasive estimation of infarct size, even in the presence of abnormal activation sequences.

Animals↗
PubMed1993

Cardiovascular profile of MPC-1304, a novel dihydropyridine calcium antagonist: comparison with other calcium antagonists.

The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris.

Animals↗
PubMed1992

Effects of imidazoline-related compounds on the mechanical response to nicorandil in the rat portal vein.

The purpose of this study was to investigate the interactions of compounds structurally related to imidazoline at K+ channels located in the rat portal vein. Nicorandil, a K+ channel activator, dose dependently inhibited spontaneous contractions of the isolated rat portal vein. Glibenclamide (0.1-1 microM), an ATP-sensitive K+ channel blocker, competitively antagonized the response to nicorandil, whereas methylene blue (10 microM), a guanylate cyclase inhibitor, did not. Phentolamine, antazoline, tolazoline, and midaglizole also shifted the dose-response curve for nicorandil to the right in the dose range of 1-100 microM. The rank order of potency was glibenclamide much greater than phentolamine = antazoline = midaglizole greater than tolazoline. In contrast, clonidine, idazoxan, imidazole, 1-benzylimidazole, and yohimbine were ineffective. In addition, cromakalim (1-100 nM), a selective K+ channel activator, also inhibited spontaneous contractions of the rat portal vein, and this effect was antagonized by phentolamine in a similar way to that found with nicorandil. These results suggest that some 2-substituted imidazolines, including phentolamine, possibly act as K+ channel blockers, like glibenclamide, in vascular smooth muscle.

Animals↗
PubMed1992

Small differences among body surface and epicardial QRST integral maps recorded during normal activation and experimentally simulated left bundle branch block or preexcitation in canine hearts.

QRST integral maps were constructed from 87-lead body surface electrocardiograms (ECGs) and from 45-lead epicardial electrograms during artificial pacing, which simulated left bundle branch block (LBBB) and Wolff-Parkinson-White syndrome in 12 dogs. Although the ECGs and electrograms differed in configuration for each conduction model, the body surface and the epicardial QRST integral maps showed only small differences. Correlation coefficients (r) and root mean square differences (rms) were calculated to assess quantitatively the similarities in the QRST integral maps among the different conduction models. Mean r values between the normal conduction and the left bundle branch block models were 0.95 in the body surface maps and 0.89 in the epicardial maps. Mean r values between the normal conduction and the Wolff-Parkinson-White ECG models were 0.97 in the body surface maps and 0.91 in the epicardial maps, and rms values were small enough. The small differences were also verified by the difference maps and by paired t tests. QRST integral maps on the epicardium and on the body surface were largely independent of altered activation sequences in both the left bundle branch block and the Wolff-Parkinson-White ECG models.

Animals↗