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Biomedical subjects

K Matsuda

Publications and source records attributed to K Matsuda.

At least 379 records · Page 21Linked to original sources
PubMed1995

Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists.

2,8-Dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one (17), designed by incorporating the tetrahydrofuran ring moiety of muscarone into an 8-azaspiro[4,5]decane skeleton, and related 1-oxa-8-azaspiro[4.5]decanes were synthesized and assessed as M1 muscarinic agonists for the symptomatic treatment of dementia of Alzheimer's type. The compounds were tested for central muscarinic M1 and M2 receptor affinity and in vivo muscarinic activities: namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks, and induction of hypothermia, tremor, and salivary secretion. Compound 17 exhibited potent muscarinic activities in vitro and in vivo with no selectivity. Systematic modifications of 17 were conducted, and a number of compounds, including the 2-ethyl analogue (18), 3-methylene analogue (29), 3-dithioketal analogues (26, 28), and 3-oxime analogue (37) were found to display preferential affinity for M1 receptors over M2 receptors and, in addition, to exhibit potent antiamnesic activity sufficiently separated from hypothermia-inducing activity, taken as an index of cholinergic side effects, compared with the reference compound RS86 (1). Structure-activity relationships are discussed in comparison with those for muscarone analogues. Of these compounds only two, 2-ethyl-8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one (18) and 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (29), stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M1 muscarinic receptors. The optical resolution of 18 and 29 was performed. Eudismic ratios of both compounds in binding affinity were low, but M1 agonist activity resided preferentially in the (-)-isomers. The absolute configuration of (-)-29 was determined by X-ray crystal structure analysis to be S, being the same as that of muscarone. Based on the in vivo selectivity, (-)-29 was selected for clinical studies.

Alkanes↗
PubMed1995

[Effect of efonidipine hydrochloride (NZ-105) on modification of low density lipoprotein induced by rat cultured endothelial cells].

We studied the effects of efonidipine hydrochloride [NZ-105: (+/-)-2-[benzyl (phenyl) amino] ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2- yl)-4-(3-nitro-phenyl)-3-pyridinecarboxylate hydrochloride ethanol] and nisoldipine on endothelial cell-induced low density lipoprotein (LDL) modification. The modification of LDL by cultured rat endothelial cells was performed by incubating 3 micrograms protein/well LDL with 5 microM CuSO4 for 24 hr at 37 degrees C in the presence of confluent cells. The extent of modification was assayed by measuring the thiobarbituric acid-reactive substances (TBARS). Efonidipine hydrochloride reduced the TBARS level in a dose-dependent manner. At 3 x 10(-7) M, efonidipine hydrochloride showed a significant effect. On the other hand, the significant effect of nisoldipine was observed only at 10(-5) M. Thus the action of efonidipine hydrochloride on the inhibition of LDL-modification was much more potent than that of nisoldipine. As the modification of LDL was thought to play a key role in the initiation and progression of atherosclerosis, efonidipine hydrochloride may be useful against atherosclerosis.

Animals↗
PubMed1995

Effects of NG-nitro-L-arginine on alpha-agonists-induced contraction of aortae from Wistar Kyoto rats and stroke-prone spontaneously hypertensive rats.

Differences in the influences of endothelium-derived nitric oxside (NO) on alpha-agonists-induced contraction in the aortae of spontaneously hypertensive and normotensive rats were studied by blocking NO synthesis with NG-nitro-L-arginine (L-NNA). L-NNA potentiated the contraction induced by noradrenaline. The potentiation was smaller in the preparation from stroke-prone spontaneously hypertensive rats (SHRSP) than in the preparation from Wistar Kyoto rats (WKY). Similar potentiation was observed in the contraction induced by phenylephrine; the potentiation was also smaller in the preparation from SHRSP. alpha 2-agonists, clonidine and UK-14304 induced dose-dependent contraction only in the presence of L-NNA. The dose-response curves for alpha 2-agonists in SHRSP aorta were different from those in WKY aorta; the maximum tension was observed at the concentration of 10(-6) M in the preparation from WKY, while the contraction further increased up to 10(-4) M in the preparation from WKY. Noradrenaline, clonidine and UK-14304 but not phenylephrine induced relaxation which was blocked by L-NNA. The relaxation was impaired in the preparation from SHRSP in greater extent than that by acetylcholine. It is suggested that basic or noradrenaline-stimulated NO release from endothelium decreased in the preparation from SHRSP and that alpha 2-adrenoceptor of both the endothelium and smooth muscle may be altered in the preparation from SHRSP.

Adrenergic alpha-Agonists↗
PubMed1995

Physical fitness and cardiopulmonary baroreflex to passive head-up tilt.

The relationship between physical fitness and cardiopulmonary (CP) baroreflex induced by the decrease in venous return was investigated. Maximal oxygen uptake/lean body mass (VO2max/LBM) was used as a measure of physical fitness. CP baroreflex was examined in 8 subjects [22.0 +/- 2.0 (SD) yr] ranging from low (47.3 ml.kg-1.min-1) to highly (72.6 ml.kg-1.min-1) fit subjects who were exposed to the orthostatic load using passive head-up tilt. Tilting from 0 degrees to 70 degrees in 10 degrees increments was applied. Each tilting was preceded by measurements at the basal position of 0 degrees. Heart rate, systolic and diastolic pressure, stroke volume, and forearm blood flow were measured before and during tilting; Cardiac output, mean arterial pressure, and forearm vascular resistance (FVR) were calculated. FVR was increased with the raising in tilt angle in each subject, but the onset of increase in FVR tended to be earlier in proportion to the higher level of physical fitness. There is a negative and significant correlation between the onset of increase in FVR and VO2max/LBM. The physically fit subject exhibited a more rapid onset of an increase in FVR to orthostatic stress than the unfit subject. Thus the higher the physical fitness, the lower the threshold in CP baroreflex response.

Adult↗
PubMed1995

[Surgical treatment of congenital aortic stenosis by aortoseptal approach].

Between 1975 and 1994, six patients under 15 years old with congenital aortic stenosis underwent relief of left ventricular outflow tract obstruction (LVOTO) by aortoseptal approach. Although we got satisfactory relief of LVOTO in all patients, there were two late deaths. In one patient with residual ventricular septal defect (VSD), intractable ventricular arrhythmia developed 12 years postoperatively. Although the residual VSD closure was performed, the patient died of the arrhythmia. The another one who was the youngest 4-year-old boy suddenly died 4 months postoperatively. The detail about his death was unknown, but we presumed ischemic heart attack as the cause of his death. In 3 of remaining survived 4 patients, we encountered a few complications. They were right ventricular outflow obstruction, coronary artery injury and conduction system injury. All complications and problems we encountered in this series were related to the incision and the reconstruction of aortoseptal approach. In conclusion, the aortoseptal approach is effective technique for relief of LVOTO, but on the other hand it is invasive and not so safe operation. So we should be cautious about these complications and problems.

Adolescent↗
PubMed1995

[Amygdaloid kindling in variously aged infant rats and rekindling after maturation: epileptogenesis and its persistence].

To study amygdaloid kindling in variously aged infant rats and rekindling development after their maturation, 34 male Wistar rats were subjected to initial kindling 13 days after birth (13-day-old group, 9 rats), 16 days after birth (16-day-old group, 9 rats), 18 days after birth (18-day-old group, 7 rats), or 26 days after birth (26-day-old group, 9 rats). Each group received reoperation on the 70th day, and was subjected to rekindling 5 days after operation. Also, a control group of mature rats was initially kindled at the age of 75 days and rekindled after 2 months (75-day-old group, 11 rats). The obtained results are summarized as follows. I. Results of initial kindling: (1) a significant positive correlation was found between the age of the 4 groups of rats and the after-discharge threshold of infant rats (p < 0.05), (2) significant correlations were not found between the age of the 4 groups of infant rats and the stimulation numbers inducing C0-2 and C0-4 stage symptoms, (3) a significant positive correlation was found between the age of the 4 groups of infant rats and the stimulation number inducing C3-4 symptoms (p < 0.05). II. Results of rekindling: (1) significant negative correlations were found between the age of the 4 groups at initial kindling and the stimulation numbers inducing C0-2, C3-4 and C0-4 symptoms (p < 0.05-0.0001). III. Ratio of initial kindling and rekindling: (1) significant negative correlations were found between the age at initial kindling and the C0-2 and C0-4 stimulation number ratios (p < 0.00001), (2) a negative but not significant correlation was found between the C3-4 stimulation number ratio and age at initial kindling. These results suggest that in infant rats amygdaloid excitability is stronger, when the younger the rat, and that the later in the infant period the epileptogenesis is acquired, the stronger is it preserved even after maturation as high amygdaloid excitability.

Aging↗
PubMed1995

Toxicity of the novel anti-peptic ulcer agent polaprezinc in beagle dogs.

A preliminary dose-range finding study, two 13-week studies and a 52-week study were performed in beagle dogs with polaprezinc (catena-(S)-[mu-[Na-(3-aminopropionyl)histidinato (2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7, Z-103), a novel anti-peptic ulcer agent, as part of a safety evaluation program. In the preliminary single-dose study, treatment-related findings were confined to one animal treated with 200 mg/kg and consisted in emesis and mucosal lesions in the stomach and upper small intestine. Based on these data, dosages were selected for the main 13-week study (0, 50, 120 and 300 mg/kg/day) and additional 13-week study (0, 8 and 20 mg/kg/day). The dosages for the 52-week study were 8, 20 and 50 mg/kg/day. In the 13-week studies, dosages of 50 mg/kg/day and above resulted in emesis, mild diarrhea and salivation; reduced food consumption and associated reduction in body weight gain for high dosed females; increased blood alkaline phosphatase and decreased urinary specific gravity; histopathological changes in the kidney of the high dosed group in males and females. These changes were no longer apparent following the withdrawal period. In the 52-week study, similar but milder and transient results were noted at the high dose of 50 mg/kg/day. From these results, the no-effect dose level was estimated to be 20 mg/kg b.w./day.

Animals↗
PubMed1995

[Overexpressed p53 protein and cell-proliferative activity disappear or remarkably decrease in neoplastic CGA-positive endocrine and Paneth cells in cancer or dysplasia of ulcerative colitis].

We examined over-expression of p53 protein and proliferative activity of neoplastic endocrine and Paneth cells in cancer or dysplasia of ulcerative colitis (UC). The labeling index of p53 or Ki-67 of endocrine cells was counted with double immunostaining of p53 or Ki-67 and chromogranin A (CGA). 540 CGA-positive cells and 65 Paneth cells were all negative for p53. 5.1% of CGA-positive cells and none of 56 Paneth cells were positive for Ki-67 reaction. These observation suggest that even in cancer or dysplasia of UC cell-differentiation to neoplastic endocrine and Paneth cells decrease proliferative activity, and that these types of cell-differentiation suppress over-expression of p53 protein.

Cell Division↗
PubMed1995

Over-expression of p53 protein in neoplastic changes in ulcerative colitis: immunohistochemical study.

An immunohistochemical study using PAb1801, a monoclonal antibody specific to the human p53 protein (wild and mutant), was performed to detect over-expression of p53 protein in colorectal cancers and dysplasia complicating ulcerative colitis, compared with that in sporadic colorectal cancers and adenomas. The over-expression of p53 was demonstrated in 6/7 (85.7%) cancers and in 15/18 (75.0%) dysplasias complicating ulcerative colitis. The frequency of p53 over-expression was 126/200 (63.0%) in sporadic cancers and 4/120 (3.3%) in adenomas. This study suggests that alteration of the p53 gene is implicated in the development of cancers complicating ulcerative colitis, as it is in the development of sporadic colorectal cancers, and it appears to be involved at a relatively early stage.

Adenocarcinoma↗
PubMed1995

Coronary artery spasm induced under lumbar epidural anaesthesia.

A case of coronary artery spasm during lumbar epidural anaesthesia prior to surgery is presented. Three paroxysmal episodes of ST segment elevation in lead II without changes in V5 developed concomitantly when the patient complained of chest discomfort. A denervation of the cardiac sympathetic nerve seems to be the primary genesis of the attack in a patient prone to such events.

Adult↗
PubMed1995

[New sex pheromone isolated from the abdominal glands of male newt, Cynops pyrrhogaster].

Sodefrin, a novel decapeptide which attracts female newts, Cynops pyrrhogaster was isolated from the abdominal gland of the male of the same species. Synthetic sodefrin was tested for its activity with sexually active females and males and sexually inert females. It attracted only sexually active females. The effect of sodefrin was blocked by a bilateral nostril plugging with cotton balls soaked in melted vaseline. Immunoelectronmicroscopic study using antiserum against sodefrin revealed that sodefrin was located mainly in the secretory granules in the epithelial cells of the abdominal gland of the cloaca.

Abdomen↗
PubMed1994

Structure of a novel phosphocholine-containing glycoglycerolipid from Mycoplasma fermentans.

Mycoplasma fermentans is thought to be a pathogen of rheumatoid arthritis or cofactor of AIDS. A novel phosphocholine-containing glycoglycerophospholipid named GGPL-I was isolated from a M. fermentans-infected human helper T-cell culture. It was revealed that GGPL-I is a lipid component of the M. fermentans and a major immunological determinant. The GGPL-I was purified by DEAE-Sephadex column chromatography and repeated Iatrobeads column chromatography. The purified glycophospholipid was subjected to structural characterization by thin-layer chromatography, Fourier-transform infrared spectrometry, liquid secondary ion mass spectrometry, and nuclear magnetic resonance spectroscopy. Its structure was determined to be as follows: 6'-O-phosphocholine-alpha-glucopyranosyl-(1'-3)-1,2-diacyl-sn-glycerol. This glycoglycerophospholipid is unique in containing phosphocholine, which is attached to C-6 of glucose. The stereospecific numbering (sn) of naturally occurring GGPL-I was determined through comparison with chemically synthesized compounds.

Carbohydrate Conformation↗
PubMed1994

Expression of GATA-binding transcription factors in rat hepatocytes.

Recently, we demonstrated that a DNA-binding protein(s) is involved in transcriptional repression of the rat serine dehydratase gene in fetal liver. Here, we report that a GAT(A/T) motif is the target sequence for the DNA-binding protein. By screening a fetal liver cDNA library, we isolated a rat homolog of GATA-1. Rat GATA-1 expressed as a GST-fusion protein in E. coli bound to the GAT(A/T) motif in the serine dehydratase gene. Northern analysis show that GATA-1 and GATA-4 mRNAs are expressed in fetal hepatocytes.

Amino Acid Sequence↗