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Biomedical subjects

M Majima

Publications and source records attributed to M Majima.

At least 55 records · Page 3Linked to original sources
PubMed1999

Effect of prolonged administration of a urinary kinase inhibitor, ebelactone B on the development of deoxycorticosterone acetate-salt hypertension in rats.

The effect of prolonged administration of a carboxypeptidase Y-like kininase inhibitor, ebelactone B (EB) (2-ethyl-3, 11-dihydroxy-4, 6, 8, 10, 12-pentamethyl-9-oxo-6-tetradecenoic 1, 3-lactone), on the development of deoxycorticosterone acetate (DOCA)-salt hypertension was tested. The systolic blood pressure (SBP) of non-treated 6-week-old Sprague-Dawley strain rats was gradually increased by DOCA-salt treatment from 137+/-2 mmHg (n=11) to 195+/-7 mmHg at 10 weeks of age. With daily oral administration of lisinopril (5 mg kg(-1), twice a day), which is an inhibitor of angiotensin converting enzyme, a major kininase in plasma, the development of hypertension was not suppressed. By contrast, administration of EB (5 mg kg(-1), twice a day), completely inhibited the development of hypertension (SBP: 146+/-1 mmHg, n=5, 10 weeks old). The reduced SBP at 10 weeks of age was equal to the SBP before any treatment (142+/-1 mmHg, n=5). Direct determination of mean blood pressure (MBP) in conscious, unrestrained rats confirmed that MBP elevation was completely inhibited by EB. Continuous subcutaneous infusion (5 mg kg(-1) day(-1)) of HOE140, a bradykinin B2 receptor antagonist, restored the elevation of SBP, which was suppressed by EB. The weights of left ventricle of DOCA-salt treated rats 10-weeks-old (0.36+/-0.02 g 100 g body weight(-1), n=11) was significantly reduced by EB (0.27+/-0.01, n=5), as were the sodium levels in serum, cerebrospinal fluid and erythrocyte. These findings suggested that EB is effective in preventing salt-related hypertension presumably by eliminating sodium retention.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats.

1 This study aimed to examine whether administration of potassium or ATP-sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium-induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups. 3 Administration of the KATP channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on the potassium-induced increase in renal KK secretion. 6 Renal KK secretion increased in slices of kidney cortex incubated with PNU-37883A within 10 min of superfusion. 7 In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker.

Adamantane↗
PubMed1999

Dilatation and constriction of rat gastric mucosal microvessels through prostaglandin EP2 and EP3 receptors.

BACKGROUND: Prostaglandin (PG)E2 has both a vasodilating action and a protective function in the gastric mucosa. There are four subtypes of PGE2-sensitive, or EP, receptors. AIM: To identify the subtype of EP receptors in the microvessels of the rat gastric mucosa using EP2 and EP3 receptor agonists. METHODS: The posterior wall of the anaesthetized rat stomach was secured in a chamber and superfused with Tyrode's solution, and the gastric microcirculation of the mucosal base was observed through a window with transillumination. PGE2 and its derivatives (20 microL) were applied topically in the window. RESULTS: PGE2 (0.001-10 micromol/L), misoprostol (EP2/EP3 receptor agonist; 0.01-100 micromol/L) and butaprost (EP2 receptor agonist; 1-1000 micromol/L) dilated the arterioles dose-dependently, but M&B 28 767 (EP3 receptor agonist; 0.001-10 micromol/L) did not alter their diameters. M&B 28 767 constricted the venules and collecting venules dose-dependently whereas butaprost dilated them. PGE2 and misoprostol had bell-shaped dose-response curves: constriction by low doses of PGE2 and misoprostol (0.001-0.1 micromol/L and 0.01-1 micromol/L) and dilation by high doses of PGE2 and misoprostol (0.1-100 micromol/L and 1-100 micromol/L). CONCLUSIONS: These results suggest that PGE2 dilated both arterioles and venules in the rat gastric mucosa through the EP2 receptors and constricted the venules through the EP3 receptors.

Alprostadil↗
PubMed1999

Interaction between collagens and glycosaminoglycans investigated using a surface plasmon resonance biosensor.

The interactions of glycosaminoglycans with collagens and other glycoproteins in extracellular matrix play important roles in cell adhesion and extracellular matrix assembly. In order to clarify the chemical bases for these interactions, glycosaminoglycan solutions were injected onto sensor surfaces on which collagens, fibronectin, laminin, and vitronectin were immobilized. Heparin bound to type V collagen, type IX collagen, fibronectin, laminin, and vitronectin; and chondroitin sulfate E bound to type II, type V, and type VII collagen. Heparin showed a higher affinity for type IX collagen than for type V collagen. On the other hand, chondroitin sulfate E showed the highest affinity for type V collagen. The binding of chondroitin sulfate E to type V collagen showed higher affinity than that of heparin to type V collagen. These data suggest that a novel characteristic sequence included in chondroitin sulfate E is involved in binding to type V collagen.

Animals↗
PubMed1999

[Involvement of chymase in angiogenesis in hamster sponge granulomas].

We investigated the angiogenic effect of chymase, an alternative angiotensin II-generating enzyme, on angiogenesis using hamster sponge implant model. Exogenous administration of angiotensin II (Ang II) or angiotensin I (Ang I) directly into the sponges enhanced angiogenesis, as determined from the hemoglobin contents in the sponge granuloma tissues. Chymostatin, an inhibitor of chymase, inhibited angiogenesis induced by Ang I but not by Ang II, suggesting the presence of a chymase-like Ang II-generating activity in the sponge granuloma. TCV-116 (5 mg/kg p.o.), an antagonist of Ang II type 1 receptor, and chymostatin suppressed bFGF-induced angiogenesis, suggesting the significance of the endogenous angiotensin system. Chymase activity in the sponge granuloma increased in parallel with the rise in hemoglobin contents induced by bFGF. We also examined the effects of direct administration of human pro-chymase gene or purified hamster chymase, and demonstrated that in vivo human pro-chymase gene transfection and direct injection of purified chymase enhanced angiogenesis, which was 50% inhibited by TCV-116. Sponge granulomas treated with Ang II was supressed by vascular endothelial growth factor (VEGF) antisense. Our results suggest that chymase enhanced angiogenesis partly through the local production of Ang II, followed by up-regulation of VEGF.

Angiotensin I↗
PubMed1998

Novel mitochondrial DNA mutation in tRNA(Lys) (8296A-->G) associated with diabetes.

Mutation in the mitochondrial gene at position 3243 was recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated insulin secretion in pancreatic beta-cells, we therefore searched for such mutations to detect a candidate gene for diabetes. We screened 10 diabetic subjects with clinical features suggesting mitochondrial DNA mutations. An adenine to guanine point mutation in tRNA(Lys) in at position 8296 (the 8296 mutation) was newly identified. Subsequently, we screened 1216 diabetic subjects, 44 patients with sensorineural deafness subjects and 300 non-diabetic control subjects for this mutation. We identified the mutation in 11 (0.90%) unrelated diabetic subjects, one (2.3%) patient with deafness and no non-diabetic control subject. Seven of these 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands. Four family pedigrees showed maternal inheritance of diabetes over two or three generations. Subjects carrying the 8296 mutation may develop diabetes and the mutation can explain as high as ca. 1% of the causes of diabetes.

Base Sequence↗
PubMed1998

Effect of the Kobe earthquake on stress and glycemic control in patients with diabetes mellitus.

OBJECTIVE: To examine the effects of the Kobe, Japan, earthquake, a life-threatening event, on stress and glycemic control in diabetic patients. PATIENTS AND METHODS: Hemoglobin A1c levels before and after the earthquake were evaluated in diabetic patients in Kobe (N = 157; magnitude, 7.2) and in Osaka, Japan, as a control (N = 277; magnitude, 4.2), where little damage to houses and traffic facilities occurred. Glycosylated hemoglobin levels were also compared with those of 2 years before and 1 year after the earthquake. The General Health Questionnaire (GHQ) and a self-administered questionnaire regarding damage to houses and relatives killed or injured were used to assess psychological and mental stresses on earthquake survivors. RESULTS: Glycemic control was aggravated in diabetic patients after the earthquake in Kobe but not in Osaka. THe GHQ scores were significantly higher in the patients in Kobe than those in Osaka. Increased hemoglobin A1c concentrations and high scores on the GHQ were especially evident in diabetic patients with severe damage to houses and/or with relatives killed or injured. CONCLUSION: These results suggest an association between chronic, life-threatening stress and the worsening of metabolic control in patients with diabetes mellitus.

Adult↗
PubMed1998

Possible background mechanisms of the effectiveness of cyclooxygenase-2 inhibitors in the treatment of rheumatoid arthritis.

Cyclooxygenase (COX)-2 was induced in an acute exudative inflammatory model (rat carrageenin-induced pleurisy) in which prostaglandin E2, 6-keto-prostaglandin F1alpha, and thromboxane B2 were generated in the pleural fluid. Selective COX-2 inhibitors, such as NS-398, inhibited the plasma exudation and generation of prostaglandin E2, but not that of thromboxane B2 and 6-keto-prostaglandin F1alpha, in the pleural fluid. In proliferative inflammatory models, COX-2 was induced, and selective COX-2 inhibitors suppressed granuloma formation, particularly, microvessel formation. COX-2 was induced during angiogenesis in a sponge model implanted into skin of rat, and the COX-2 inhibitor suppressed the angiogenesis. As induction of COX-2 was reported in osteoblasts, COX-2 was involved in most characteristic responses of acute exudative inflammation, granuloma formation, bone resorption, and pain in rheumatoid arthritis. The prevention of these COX-2 responses provides a rationale for the effectiveness of COX-2 inhibitors in the treatment of rheumatoid arthritis.

Animals↗
PubMed1998

Ion-spray mass spectrometry for identification of the nonreducing terminal sugar of glycosaminoglycan.

Various oligosaccharides from hyaluronic acid, which have glucuronic acid or N- acetylglucosamine at the nonreducing terminal, were prepared by digestion with a combination of testicular hyaluronidase and beta-glucuronidase. These oligo saccharides were analyzed by negative-mode ion-spray mass spectrometry (MS) with an atmospheric pressure ion source. Introduction of collisionally activated dissociation tandem mass spectrometry (CAD-MS/MS) produced ions derived from cleavage of the glycosidic bonds, allowing the structure to be analyzed. The CAD-MS/MS spectrum showed an intense and characteristic fragment ion at m/z 193 for oligosaccharides having glucuronic acid at the nonreducing terminal. On the other hand, this ion was not observed in the spectra of oligosaccharides having N- acetylglucosamine at the nonreducing terminal. Therefore, the fragmentation pattern revealed by CAD-MS/MS provides useful information for distinguishing glucuronic acid and N- acetylglucosamine at the nonreducing terminal of oligosaccharides derived from hyaluronic acid and other glycosaminoglycans. This ion-spray CAD-MS/MS technique was also applied successfully to the characterization of glycosaminoglycans reconstructed by glycotechnology.

Animals↗
PubMed1998

Evidence for a role of kallikrein-P6nin system in patients with shock after blunt trauma.

Bradykinin (BK) is activated via plasma and/or tissue kallikrein-kinin (K-K) system pathways during hypotension after blunt trauma. The precise role of the K-K system in human subjects has not been defined. We developed a new method for measuring levels of BK in the blood and examined the role of the K-K system in patients with shock after trauma. Eight patients were entered into this study. We measured the levels of a high-molecular-weight kininogen (HMWK), a low-molecular-weight kininogen (LMWK), BK, and (1-5)-BK in the blood of patients in an unstable state (Pre) and a stable state (Post). At Pre, the blood BK level was significantly elevated, the HMWK and LMWK levels were significantly lower, and the (1-5)-BK level was significantly higher than the respective levels at Post. Our data suggest a significant role for the K-K system in the pathogenesis of shock after blunt trauma. This newly developed method for determination of the activation of the plasma K-K system appears to be useful for determining the severity of a trauma.

APACHE↗
PubMed1998

[The reaction of the nasal mucosa in allergic rhinitis to cold saline stimulus].

To clarify the nature of the reaction pattern of the nasal mucosa in allergic rhinitis, nasal lavage using a cold saline solution of 4 degrees C and a warm saline solution was attempted in 8 patients with nasal allergy to the pollen of the Japanese cedar and cypress in a non-scatter season, and the concentration of protein contents in the nasal washings was determined. The concentrations of total protein, albumin and 26 kD protein were higher in cold saline than in the warm saline lavage. In particular, the concentration of 26 kD protein was 5.3 times higher. However, the concentration was not very high compared with the value obtained by warm saline lavage in the scatter season. These findings indicate that the nasal mucosa of patients with allergic rhinitis is reactive to cold saline stimuli even in the non-scatter season.

Adult↗
PubMed1998

Effects of a neutral endopeptidase inhibitor, BP102, on the development of deoxycorticosterone acetate-salt hypertension in kininogen-deficient Brown Norway Katholiek rats.

The nature of all of the peptides critical to the mechanism(s) of the antihypertensive action of neutral endopeptidase (NEP) inhibitors is still unclear, but bradykinin is thought to be one such peptide. This study was designed to assess the effectiveness of an NEP inhibitor in deoxycorticosterone acetate (DOCA)-salt treated kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. Oral administration of BP102 (10-100 mg/kg), an NEP inhibitor, increased urine volume and urinary sodium excretion in a dose-dependent manner in anesthetized Sprague-Dawley rats. DOCA-salt hypertension was induced in both BN-Ka and Brown Norway Kitasato (BN-Ki) rats after left nephrectomy. The development of DOCA-salt hypertension in normal BN-Ki rats was prevented, and that in BN-Ka rats was also significantly reduced, by an 8-day administration of BP102. When BP102 was administered for 5 weeks, the high blood pressure of DOCA-salt treated BN-Ka rats was markedly lowered, and their heart weights were reduced. These results suggest that kinins play no role in the antihypertensive effect of this inhibitor and that other factors may be involved in this effect.

Administration, Oral↗
PubMed1998

Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension.

Tissue kallikrein and low molecular weight kininogen are localized in the particular cells of the connecting tubules, indicating that kinin is immediately generated in the lumina of the lower nephrons. The role of the renal kallikreinkinin system was studied using mutant kininogen-deficient Brown NorwayKatholiek (BN-Ka) rats, and compared with that in normal BN-Kitasato rats of the same strain. Mutant BN-Ka rats showed no visible changes, but they were very sensitive to excess sodium ingestion and to the tendency of sodium to accumulate in the body by aldosterone released by angiotensin II, so that sodium was accumulated in erythrocytes and cerebrospinal fluid in BN-Ka rats and hypertension was induced. After four days infusion of 0.3 M NaCl solution to conscious and unrestrained mutant BN-Ka rats, the sensitivity of the vascular smooth muscle to norepinephrine and angiotensin II increased 30-fold and 10-fold, respectively. Bradykinin was degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like exopeptidase (CPY) in rat and human urine. Daily oral administration of a selective inhibitor of CPY, ebelactone B, or that of NEP, BP1O2, prevented development of deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats. These results indicate that: 1) the renal kallikrein-kinin system allows excretion of excess sodium in the body, 2) decreased sodium excretion due to reduced excretion of urinary kallikrein in patients with essential hypertension or in genetically hypertensive rats may cause hypertension, and 3) urine kininase inhibitors such as ebelactone B may emerge as a new antihypertensive drug.

Animals↗
PubMed1997

Role of the renal kallikrein-kinin system in the development of hypertension.

Role of renal kallikrein-kinin system has been studied using mutant Brown-Norway Katholiek (BN-Ka) rats, in which both high- and low-molecular weight kininogens were almost absent in plasma and kinin in urine was mainly not detectable. Mutant BN-Ka rats were very sensitive to increased salt intake, resulting in raised systemic blood pressure that is linked to reduced urinary excretion of sodium, when compared with normal BN-Kitasato (BN-Ki) rats. Consequently, sodium accumulated in erythrocytes and cerebrospinal fluid in mutant BN-Ka rats. Subcutaneous infusion of angiotensin II (20 mg/day/rat) also enhanced the concentration of sodium in erythrocytes and in cerebrospinal fluid and increased the systemic pressure by releasing aldosterone. A 4-day infusion of 0.3 M sodium solution (6 ml/kg/h) to the abdominal aorta of conscious and un-restrained mutant BN-Ka rats increased the pressor responses of the arterioles to norepinephrine and angiotensin II (i.a.) by 30- and 10-fold, respectively. Infusion of ebelactone B, (a selective inhibitor of carboxypeptidase Y-like exopeptidase, a kininase in rat urine), to normal BN-Ki rats during induction of hypertension with DOCA and salt, resulted in the reduction of the raised blood pressure, indicating that a site of action of kinins was at the luminal membrane of the renal tubule cells. Our results support the view that the role of renal kallikrein-kinin system is to excrete 'excess sodium' and a reduction in the generation of renal kinins may be a factor in the development of hypertension as a result of the sodium accumulation in the body.

Aldosterone↗
PubMed1997

Effects of an orally active non-peptide bradykinin B2 receptor antagonist, FR173657, on plasma exudation in rat carrageenin-induced pleurisy.

1. Effects of an orally active non-peptide (BK) B2 receptor antagonist, FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinoli nyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl] acrylamide) on the plasma exudation in rat carrageenin-induced pleurisy were investigated. 2. Plasma exudation induced by intrapleural injection of bradykinin (BK, 3 nmol per rat) into male SD strain rats (SPF, 8 weeks old) were significantly inhibited by oral administration of novel B2 receptor antagonist FR173657 (3-30 mg kg-1, 1 h before BK injection) in a dose-dependent manner, whereas that induced by histamine was not. 3. The inhibitory effect of 30 mg kg-1 FR173657 persisted for more than 4 h. 4. Intrapleural injection of lambda-carrageenin (2% (w/v), 0.1 ml per rat) caused marked plasma exudation and accumulation of exudates from 1 h after carrageenin injection. The maximum plasma exudation response was observed 5 h after carrageenin. The oral administration of FR173657 to rats (30 mg kg-1, 1 h before carrageenin) significantly (by 50-77%) blunted the plasma exudation 1, 3, 5, and 7 h after carrageenin, causing a significant parallel reduction (by 42-57%) in the volume of exudates. 5. The anti-inflammatory effect of FR173657 on rat carrageenin-induced pleurisy was almost equipotent with that of the peptide B2 antagonist Hoe140 (1 mg kg-1, i.v.), a plasma kallikrein inhibitor, soy bean trypsin inhibitor (0.3 mg per rat, intrapleural injection) and bromelain (10 mg kg-1, i.v.). 6. In pleurisy induced by intrapleural injection of a histamine releaser, compound 48/80, the plasma exudation was observed only within 20 min after the injection. This plasma exudation was not affected by FR173657, although it was completely inhibited by a mixture of pyrilamine (5 mg kg-1, i.v.) and methysergide (3 mg kg-1, i.v.). 7. These results indicate that FR173657 is an orally active, promising anti-inflammatory agent for kinin-dependent inflammation.

Animals↗
PubMed1997

[Multiple roles of inducible cyclooxygenase-2 and its selective inhibitors].

Cyclooxygenase (COX) is the enzyme that catalyzes the conversion of arachidonic acid to prostaglandin endoperoxides. In addition to constitutive COX-1, inducible COX-2 has been discovered. COX-2 is induced not only in acute exudative rat carrageenin-induced pleurisy, but in granuloma formation/proliferative inflammation for the acceleration of angiogenesis. This means that COX-2 is induced in the healing process of wounds such as in granuloma of gastric ulcer and the proliferative stage of endometrium. COX-2 is also introduced in ovulation and parturition. Osteoblasts induce COX-2 to accelerate bone absorption. Induction of COX-2 in colon carcinoma is a recent, very exciting topic of investigation. We can learn about many unknown roles of COX-2 from its knockout mouse, but the results must be interpreted cautiously. Development of selective COX-2 inhibitors, such as NS-398, opened a new era in which the side effects of gastric and renal lesions by NSAIDs could be ignored. However, prolongation of would healing by the inhibitors and transient expression of COX-2 must be considered in medical intervention with selective COX-2 inhibitors. Nevertheless, acute exudative inflammation, granuloma formation and bone absorption in rheumatoid arthritis are good targets for these inhibitors and application of these inhibitors will be extended to dysmenorrhea, interruption of abortion and increasing survival rate of patients with colon carcinoma.

Animals↗
PubMed1997

Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants.

Angiogenesis in rat sponge implants, as determined from the concentration of hemoglobin in the sponge granuloma tissues, was gradually increased over a 14-day experimental period. The inducible cyclooxygenase COX-2 was detected in the sponge granuloma tissues at day 4 by Western blot analysis using specific mouse COX-2 antibody. Angiogenesis in the sponge implants was enhanced by daily topical injections of human recombinant basic fibroblast growth factor (bFGF) or human recombinant epidermal growth factor (EGF) (100 or 1000 ng/sponge/day) for 4 days. These treatments clearly enhanced the expression of COX-2 in the sponge granuloma tissues. In immunohistochemical studies, COX-2-positive staining was mainly observed in the endothelial cells of the neovasculature and in the fibroblasts of the granuloma capsule. Administration of the selective COX-2 inhibitor NS-398 (p.o., 3 mg/kg, 3 times a day) for 14 days significantly inhibited the angiogenesis. The angiogenesis enhanced with bFGF or EGF (day 4) was inhibited by administration of indomethacin or NS-398, both in the above regimen, and fell to the level obtained without growth factor treatment. These results suggest that COX-2 induced in the sponge granuloma tissues may participate in neovascularization through prostaglandin formation.

Animals↗