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Mizuo Miyazaki

Publications and source records attributed to Mizuo Miyazaki.

69 records · Page 4Linked to original sources
PubMed2002

Chymase inhibitor, BCEAB, suppressed peritoneal adhesion formation in hamster.

BACKGROUND: Mast cells are closely related to adhesion formation, while it has been unclear which factor in mast cells plays an important role in the development of adhesion formation. To clarify the role of chymase produced from mast cells in adhesion formation, we investigated the preventive effect of a specific chymase inhibitor, BCEAB, on adhesion formation in a hamster experimental model. MATERIALS AND METHODS: Hamsters were administered orally once daily with 100 mg/kg of BCEAB or placebo from the operated day to 1 week after the operation. The uterus was grasped and denuded by a swab. RESULTS: One week after the operation, the scores for adhesion formation in the chymase inhibitor-treated group were significantly decreased in comparison with those in the placebo-treated group (placebo-treated group, 2.80 +/- 0.20; chymase inhibitor-treated group 1.60 +/- 0.31: P < 0.01). The chymase activity in the injured uterus was also significantly suppressed in the chymase inhibitor-treated group (placebo-treated group, 17.3 +/- 2.69 mU/mg protein; chymase inhibitor-treated group 9.60 +/- 0.89: P < 0.05). After scraping the utelus, the level of transforming growth factor-beta in the peritoneal fluid was significantly increased in the placebo-treated group, while it was suppressed to 70% by the treatment with BCEAB. CONCLUSIONS: The specific chymase inhibitor BCEAB may be a useful drug for prevention of adhesion formation.

Animals↗
PubMed2002

Chymase inhibitors may prevent postoperative adhesion formation.

OBJECTIVE: To clarify the role of chymase produced from mast cells in adhesion formation, we measured chymase activity level and investigated the preventive effect of a chymase inhibitor, Suc-Val-Pro-Phe(p)(OPh)(2), on the postoperative adhesion formation. DESIGN: Prospective randomized study using a surgical model for adhesion formation. SETTING: Clean hamsters in an academic research environment. ANIMAL(S): Sixty-seven female Syrian hamsters. INTERVENTION(S): Hamsters were given a lesion, produced by uterus scraping, and the chymase inhibitor (10 microM) or placebo was injected into the abdomen. Chymase activities in uteri were measured 3 days after the operation, and the scores of adhesion formations were assessed at 2 weeks. MAIN OUTCOME MEASURE(S): Measurement of chymase activity and scoring of adhesion formation were performed. RESULT(S): A significant increase of chymase activity in the injured uterus reduced by treatment with the chymase inhibitor. The scores of adhesion formations in the chymase inhibitor-treated group were significantly decreased in comparison with those in the placebo-treated group. CONCLUSION(S): Chymase contained in mast cells plays an important role in adhesion formation, and a chymase inhibitor may be a useful drug for prevention of adhesion formation.

Animals↗
PubMed2002

Suppression of basic fibroblast growth factor-induced angiogenesis by a specific chymase inhibitor, BCEAB, through the chymase-angiotensin-dependent pathway in hamster sponge granulomas.

1. We investigated the profound involvement of mast cell chymase, an alternative angiotensin II-generating enzyme, in angiogenesis using a specific chymase inhibitor. We also studied the functional profiles of this novel inhibitor in basic fibroblast growth factor (bFGF)-induced angiogenesis. 2. In this study, angiogenesis was induced by daily injections of bFGF (0.3 micro g site(-1) day(-1)), angiotensin I (2 nmol site(-1) day(-1)) or angiotensin II (2 nmol site(-1) day(-1)) into sponges implanted to male hamsters subcutaneously for 7 days. Angiogenesis in the granulation tissue surrounding sponges was evaluated by measuring the haemoglobin (Hb) content and local blood flow as the parameters for angiogenesis. 3. A chymase inhibitor, BCEAB (4-[1-[[bis-(4-methyl-phenyl)-methyl]-carbamoyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid), was simultaneously administered into the implanted sponges (2 or 5 nmol site(-1) day(-1), for 7 days) treated with bFGF and strongly suppressed the haemoglobin contents in sponge granulomas. In the studies using a laser doppler perfusion imager, BCEAB (5 nmol site(-1) day(-1)) also attenuated the bFGF-induced increase of local blood flow around the implanted sponge granuloma. 4. In bFGF-induced angiogenesis, chymase activity in sponge granulomas was substantially increased. It was also confirmed that the chymase activity increased by bFGF was significantly and dose-dependently inhibited by BCEAB (2, 5 nmol site(-1) day(-1)). 5. BCEAB inhibited the Hb contents and the expression of vascular endothelial growth factor (VEGF) mRNA induced by angiotensin I but not by angiotensin II. 6. These results suggest that the significance of chymase in bFGF-induced angiogenesis was confirmed, and a novel inhibitor, BCEAB, strongly suppresses the bFGF-induced angiogenesis through the chymase-angiotensin II-VEGF dependent pathway.

Angiotensins↗
PubMed2002

Chymase and angiotensin converting enzyme activities in a hamster model of glaucoma filtering surgery.

PURPOSE: Two pathways for the formation of angiotensin II (Ang II) in local tissues are known to exist, one involving angiotensin-converting enzyme (ACE), and the other in which chymase plays a role. It has been shown that chymase activity is present in monkey, dog, and hamster eyes. Because chymase activates various cytokines by increasing Ang II formation, thereby promoting the production of extracellular matrix, the role of Ang II in wound healing has attracted much interest. In this work, we created sclerocorneal wounds in hamster eyes and measured the levels of ACE and chymase activities in the eye during the wound healing process. METHODS: Sclerocorneal wounds were made at 6 locations on the corneal limbus of one eye in each of 36 hamsters. Using the contralateral eyes as controls, we measured levels of chymase and ACE activities in the overall eye at 3, 7, and 21 days postoperatively. Histopathological evaluations of the sclerocorneal wounds in the treated eyes were also carried out for samples stained with toluidine blue. RESULTS: Chymase activity in the treated eyes tended to be higher than that in the control at 21 days. ACE activity in the treated eyes was significantly higher than that in the control at 3, 7, and 21 days postoperatively. Histopathological examination revealed increased mast cells in the subconjunctival tissue and around the tunnel opening in the sclerocornea. CONCLUSIONS: These findings show that not only ACE but also chymase contributes to the formation of Ang II in the healing of sclerocorneal wounds in hamster eyes. This leads to the suggestion that ACE inhibitors or chymase inhibitors could potentially inhibit scarring in glaucoma filtering surgery.

Animals↗
PubMed2002

Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters.

This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Recombinant human chymase produced by silkworm-baculovirus expression system: its application for a chymase detection kit.

Human chymase is a mast cell-derived serine proteinase, which is a non-angiotensin converting enzyme angiotensin II-generating enzyme. It appears to participate in various diseases, but it is unclear whether chymase plays major roles in physiological and pathophysiological functions in vivo. To obtain information on the physiological and pathophysiological functions of chymase and to search for diseases in which chymase participates, in the present study, we aimed at producing recombinant human chymase in large quantities and at developing an ELISA system using anti-human chymase antibodies. A recombinant human chymase was produced by a silkworm-baculovirus expression system. The recombinant chymase in active form was efficiently purified from larval hemolymph using cation-exchange and heparin column chromatography. This recombinant enzyme was enzymatically identical with native human chymase. On the other hand, the stability of the recombinant enzyme in cultured medium for mammalian cells at 37 degrees C was very high as compared with the stability of the native enzyme; 20% of the activity was maintained 120 h after addition of medium. These results indicated that the recombinant enzyme could also utilize in vitro and in vivo assay systems. We obtained several anti-chymase monoclonal antibodies by using the recombinant human chymase as antigen. These antibodies were used to construct an ELISA system for measuring the chymase concentration in blood. As a result of preliminary examination using this ELISA system, it was shown that the chymase concentration in each serum from hypertensive patients is significantly higher than in normal serum. The ELISA system will be applicable for clinical diagnosis and in vivo evaluation systems for chymase-targeting drugs.

Animals↗
PubMed2002

Therapeutic potential of a specific chymase inhibitor in atopic dermatitis.

A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613 (2-[5-amino-2-(4-fluorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-[1-[(5-methoxycarbonyl-2-benzoxazolyl)carbonyl]-2-phenylethyl]acetamide) dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation.

Acetamides↗
PubMed2002

Development of the chymase inhibitor as an anti-tissue-remodeling drug: myocardial infarction and some other possibilities.

Chymase leading to tissue remodeling is expected to be a potent pharmaceutical target. Its functions in vivo are still unclear, because of lack of orally available inhibitors. Recently, however, the chymase inhibitor NK3201 (2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2-heptyl] acetamide) was demonstrated to have oral activity against neointimal hyperplasia in dog models (Takai S. et al., Life Sci 69, 1725 - 1732 (2001)). In this review, by showing the efficacy of NK3201 in some hamster models, chymase functions in vivo are summarized, and the potency of this chymase inhibitor is introduced. In vitro study, NK3201 showed potent chymase specific inhibitory activity, and Dixon plot analysis indicated competitive inhibition. Oral administration of NK3201 into normal rats resulted in rapid spread over every tissue except the brain, and sufficient activity to inhibit tissue chymase was detected even after 24 h. In passive cutaneous anaphylaxis, myocardial infarction and bleomycin-induced pulmonary fibrosis models, orally administered NK3201 showed potent inhibition of inflammatory response, tissue angiotensin II formation, and fibrosis, respectively. These data suggest that chymase has a vital role in tissue remodeling through promotion of the inflammatory response, tissue angiotensin II and tissue fibrosis. Our recent data indicated chymase participation in bladder fibrosis, like interstitial cystitis. Therefore, the orally active chymase inhibitor NK3201 may have protective effects on tissue remodeling in several diseases.

Acetamides↗
PubMed2002

Effect of chymase inhibitor on vascular proliferation.

In vascular tissues, angiotensin II is potentially cleaved from angiotensin I by chymase and angiotensin-converting enzyme (ACE). In the normal state, vascular ACE regulates local angiotensin II formation and plays a crucial role in the regulation of blood pressure, whereas chymase is stored in mast cells and has no enzymatic activity. Chymase is activated immediately upon its release into the extracellular matrix in vascular tissues after mast cells have been activated by stimuli such as vessel injury by grafting or a balloon catheter. In dog grafted veins, chymase activity is increased, and the vascular proliferation is suppressed by either a chymase inhibitor or an angiotensin II receptor blocker. After balloon injury in dog vessels, chymase activity is significantly increased in the injured artery, and a chymase inhibitor is effective in preventing the vascular proliferation, but an ACE inhibitor is ineffective. Chymase plays an important role in the development of vascular proliferation via the induction of local angiotensin II formation in injured vessels.

Angioplasty, Balloon↗
PubMed2002

Oral administration of a novel chymase inhibitor, NK3201, prevents peritoneal adhesion formation in hamsters.

We investigated the preventive effect of an orally active chymase inhibitor, NK3201 (2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2heptyl]acetamide), on the adhesion formation in a hamster experimental model. Hamsters were administered orally once daily with 30 mg/kg of NK3201 or placebo from 3 days before uterus scraping to 7 days after it. A significant increase of chymase activity in the injured uterus was reduced by treatment with NK3201. The score of adhesion formations in the chymase inhibitor-treated group was significantly decreased in comparison with that in the placebo-treated group (P < 0.01). Oral administration of NK3201 may be a useful drug for prevention of peritoneal adhesion formation.

Acetamides↗
PubMed2002

Trandolapril reduces infarction area after middle cerebral artery occlusion in rats.

In this study, we investigated whether angiotensin-converting enzyme (ACE) is involved in the progression of cerebral infarct lesions after middle cerebral artery (MCA) occlusion in rats. After placebo or trandolapril was administered orally for 7 days, we infarcted in the territory of the right MCA by extracranial vascular occlusion and studied the effect of trandolapril on brain ACE activity and infarct size 7 days after MCA occlusion. In placebo-treated rats, brain ACE activity in the infarct side was increased by a significant 1.34-fold compared with that in the non-infarct side 7 days after MCA occlusion. Brain ACE activities in the infarct sides were suppressed to 39.8% by trandolapril treatment. The ratios of unilateral infarcts to the total coronal sectional areas in placebo- and trandolapril-treated rats were 48.1 +/- 3.3% and 37.4 +/- 2.3%, respectively, and the difference between these values was significant. These results demonstrate that inhibition of the increased brain ACE activity in infarct lesions can reduce the infarction area after MCA occlusion.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta.

Aortic aneurysm is a chronic degenerative condition associated with atherosclerosis. Recent studies have revealed that angiotensin (Ang) II plays important roles in atherosclerosis. In this study, to investigate the relationship between aortic aneurysm and Ang II, we measured the activities of the angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase-like enzyme, in human aneurysmal and control aortae. Aneurysmal aortic specimens were obtained from 16 aneurysm patients and control aortic specimens were obtained from 16 patients who underwent coronary artery bypass surgery (8 patients in each group were administered ACE inhibitors). The ACE and chymase-like enzyme activities were determined using extracts from vascular tissues. Both the ACE and chymase-like enzyme activities in the aneurysmal aortae were significantly higher than those in the control aortae (p < 0.01). In the patients treated with ACE inhibitors, the ACE activity in the aneurysmal aortae tended to be low, but the chymase-like enzyme activity tended to be high. In the aneurysmal aortae, the chymase-like enzyme activity in the adventitia was significantly higher than that in the intimal or medial layers (p < 0.01), while differences in ACE activity were not observed. Our results suggest that increases in local Ang II formation induced by chymase-like enzymes may play important roles in the pathogenesis of aneurysmal formation.

Aged↗
PubMed2002

The Role of Chymase in Vascular Proliferation.

In vascular tissues, angiotensin II is potentially cleaved from angiotensin I by chymase and angiotensin-converting enzyme (ACE). Chymase is stored in mast cells and has no enzymatic activity in the normal state. Chymase is activated immediately upon its release into the extracellular matrix in vascular tissues after mast cells have been activated by stimuli such as vessel injury by grafting or a balloon catheter. In dog grafted veins, chymase activity is increased, and the vascular proliferation is suppressed by either a chymase inhibitor or an angiotensin II receptor blocker. After balloon injury in dog vessels, chymase activity is locally increased in the injured artery, and a chymase inhibitor is effective in preventing the vascular proliferation, but an ACE inhibitor is ineffective. Chymase plays an important role in the development of vascular proliferation via the induction of local angiotensin II formation in injured vessels. (c) 2002 Prous Science. All rights reserved.

Journal Article↗
PubMed2002

[Involvement of angiotensin II in development of atherosclerosis].

Angiotensin II has been shown to be a potent vasoconstrictor, and it may promote in the development of atherosclerosis. Hyperlipidemia and hypertension is a risk factor for atherosclerosis, but reductions in lipid levels and blood pressure do not necessarily result in blocking lesion development in animal models of atherosclerosis. We previously reported that tissue angiotensin II levels in atherosclerotic lesion in monkeys fed a high cholesterol diet were increased significantly compared with that in normal lesion. In this atherosclerotic model, an angiotensin II type 1 receptor blocker(ARB) significantly reduced the progression of atherosclerosis, while it did not affect blood pressure and plasma cholesterol levels. Increase of angiotensin II action may play an important role in the development of atherosclerosis.

Angiotensin II↗