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Objectives: Congenital midureteral stricture (CMS), which develops from obstructive lesion between pyeloureteral junction and ureterovesical junction, is relatively rare and its clinical condition and therapeutic strategy have not yet been established. We analyzed the clinical characteristics and surgical outcomes of CMS., Patients and Methods: From November 2006 to December 2012, out of 137 patients presented with congenital hydrohephrosis, we identified 4 pediatric patients diagnosed with CMS at our institutions. We retrospectively investigated clinical characteristics and surgical outcomes in these 4 patients., Results: Three boys and one girl were identified in this study. All patients were detected hydronephrosis by fetal ultrasonography. The median age at the diagnosis of CMS was 1 year and 11 months. Three patients had obstructive lesion in left side and 1 patient in right. CMSs were located at the level of L4 in 2 patients, and at the level of L5 and S1 in each 1. Split renal function was decreased less than 45% in 3 of 4 patients. Ipsilateral pyeloureteral junction obstruction and ipsilateral hypoplastic kidney were identified in 2 and 1 patient, respectively. One patient developed urosepsis and underwent nephrostomy. Partial ureterectomy and ureteroureterostomy, pyeloplasty were performed in 3 and 1 patient, respectively. Extrinsic obstruction was detected in just 1 patient intraoperatively. In all patients, there were no protruded lesion and atrophied, fibrotic and ischemic muscles were not detected in pathological finding. Neither urinary tract infection nor recurrence of obstructive lesion was detected in all patients at the mean follow-up period of 3 years and 1 month., Conclusion: We analyzed the clinical characteristics of 4 pediatric patients with CMS. In order to prevent critical infection and maintain renal function, it could be considered that surgical intervention is undertaken just after making the diagnosis of CMS.

Increasing evidences suggest an association between estrogens and colorectal cancer (CRC), especially in postmenopausal women. Inhibitory role has been suggested by CRC risk reduction among women treated with exogeneous hormones or by decrease of estrogen receptor (ER)-beta expression in CRC compared with normal epithelium. Controversial results have been reported in epidemiological studies on endogeneous hormones or CRC cell line assays. Progressive role has been suggested by studies directly examining estrogenic conditions in CRC surgical materials. To further understand the role of estrogens in the pathobiology of colorectal cancer, where wide variety exists, a large, systematic, and comprehensive study considering sex, age, locus, stage, grade, clinical outcome, microsatellite instability, ER-beta status, and estrogen related gene polymorphism is needed.

We analyzed the target enzymes of drugs containing new active ingredients (NAIs) focusing on the characteristics of the reaction of the enzymes, and attempted to prepare a comprehensive overview of the changes in the approval of the drugs over a 3 decade period from 1980 to 2009 in Japan. Fifty-eight enzyme therapeutic targets of 235 NAIs were found to be primarily distributed to EC1, EC2 and EC3 classes, and the enzymes were unevenly distributed to 21 of 64 sub-classes and 34 of 264 sub-subclasses, respectively, classified by the enzyme nomenclature of the International Union of Biochemistry and Molecular Biology (IUBMB). Though the number of NAIs approved that targeted EC1 class enzymes decreased over the time frame studied, the number of NAIs which targeted EC2 class enzymes increased over the same time. There was no clear change in the number of NAIs which targeted other classes of enzymes. More than 80% of NAIs targeted one enzyme as a primary target, and less than 20% of NAIs targeted more than two enzymes as secondary targets. NAIs which primarily targeted EC2 and EC3 class enzymes had more secondary target enzymes than other classes. The results of this study revealed the characteristics of the reactions of the target enzymes of NAIs and the changes in NAI approvals in Japan during the three decades studied, and provided information regarding possible future trends of NAIs.

We analyzed the therapeutic target molecules and biochemical properties of 893 new drugs with new molecular entities approved over three decades from 1980 to 2009 in Japan. According to our analysis of the therapeutic targets, 26.2% of new drugs were enzymes. Membrane receptors were found to be the second-most frequent molecular targets of the new drugs, representing 25.3% of the new drugs approved. The biochemical properties of the drugs were found to have changed over time. Though the total number of new drugs approved from the year 2000 was smaller than that in the 1980s and 1990s, the number of new protein drugs approved in the 2000s, largely recombinant bioactive substances and monoclonal antibodies, increased significantly compared with those approved in the 1980s and 1990s. The results obtained in this study indicated changes in the therapeutic targets, biochemical properties and therapeutic areas of new drugs approved over the last 30 years and suggest the aspects of the future development of new drugs.

This article reports a case of a 59-year-old male who suffered from left brachial plexopathy occurring at night in bed. He had experienced multiple surgical courses of thyroid tumor resection including neck dissection and had presented left secondary jugular phlebectasia Jugular phlebectasia is mainly congenital and sometimes secondarily induced by compression, mechanical ventilation, trauma, thrombosis, etc. Brachial plexopathy is usually caused by neck and arm trauma, additionally caused by iatrogenic nerve and vessel injury. To our knowledge, this is the first report of brachial plexopathy accompanied by ipsilateral jugular phlebectasia. We hypothesized the etiology of this case through multimodal examinations and reviewed the literature about jugular phlebectasia and brachial plexopathy.

Purpose: The postoperative outcome was evaluated in each group of surgical indications of vitreous surgery for proliferative diabetic retinopathy (PDR), to investigate the factors responsible for postoperative visual prognosis., Methods: Primary vitrectomy was performed in 119 eyes of 92 patients with PDR. Average postoperative follow-up period was 19 months. The indications for vitrectomy included vitrous hemorrhage in 58 eyes, macular tractional retinal detachment in 17 eyes, extramacular tractional retinal detachment in 10 eyes, macular heterotopia in 11 eyes, and progressive fibrovascular proliferation in the posterior fundus in 23 eyes., Results: The visual acuity finally improved by 2 lines or more in 91 eyes (77%), remained unchanged in 10 eyes (8 %), and decreased by 2 lines or more in 18 eyes (15%). Final postoperative visual acuity was significantly better in cases of vitreous hemorrhage or progressive fibrovascular proliferation in the posterior fundus than in others. Preoperative rubeosis iridis and macular tractional retinal detachment were probably responsible for the final visual impairment, and intraocular tamponade affected the difference in visual prognosis between the groups of surgical indication. Multivariate analysis in all cases revealed that factors influencing visual outcome were preoperative rubeosis iridis and anemia., Conclusion: Rubeosis iridis and macular tractional retinal detachment were prognostic factors of the surgery. Vitrectomy for PDR may be effective in improving postoperative visual acuity if performed in the early stage of progressive fibrovascular proliferation in the posterior fundus after sufficient retinal photocoagulation.

Chronic subdural hematoma (CSDH) is mainly a disease of the elderly. Widespread use of CT and MRI has resulted in the discovery of CSDH cases with no or minimum symptoms in the elderly. Treatment is by surgical evacuation, although small hematoma may resolve spontaneously. Treatment of CSDH in elderly patients of more than 80 years of age with minimum symptoms is still undetermined. Many conservative treatments such as those with steroids and diuretics have been reported with some good results. Conservative treatment cannot become the procedure of choice for fear of side effects. We report successful treatment for CSDH cases among the very elderly with a Kampo medicine (Japanese traditional herbal medicine). Among a total eleven cases, four were recurrent after surgical evacuation and seven showed significant hematoma with minimal symptoms. Gorei-san-ryo, a Kampo medicine, was administered for 3 to 12 months. Some cases showed rapid hematoma resolution after administration. Only one of them required subsequent surgical intervention. This conservative treatment with Kampo medicine for CSDH may be a potential alternative to surgery especially for the elderly.

We report an elderly case of sarcoidosis with multiple pulmonary cysts. An 80-year-old woman was admitted to our hospital for detailed examinations of multiple cysts in both lungs. Chest radiography and chest CT revealed multiple cystic lesions with thin walls which were clearly separated from normal lung. A transbronchial lung biopsy revealed epitheloid cell granuloma, indicating sarcoidosis. Although elderly cases of sarcoidosis with multiple pulmonary cysts are very rare, sarcoidosis should be considered in the differential diagnosis.

Mast cell-derived chymase seems to be important in the regulation of local angiotensin (A) II formation in cardiovascular tissues. In human heart, chymase accounts for 80% of A II formation. Therefore, the chymase-dependent A II pathway may play an important role in the pathogenesis of A II-related cardiovascular diseases. For example, cardiac chymase was activated earlier than ACE and this activation lasted longer than that of ACE after myocardial infarction (MI) in hamsters. Treatment with a specific chymase inhibitor treatment, but not an ACE inhibitor, improved post-MI survival as well as cardiac function and the extent of the beneficial effects was similar to that observed for an AT1-receptor antagonist treatment in this model. The survival benefit after MI seems to be related to an antiarrhythmic effect of the chymase inhibitor because chymase inhibition reduces the incidence of ventricular arrhythmias during periods of heart ischemia in a dog MI model. Thus, an antiarrhythmic effect of the chymase inhibitor may contribute to a reduction in mortality rate during the acute phase after MI.

Extracellular proteolysis is an essential process for cell migration in several diseases such as tumor invasion, metastasis, and angiogenesis. In an invasive process, matrix metalloproteinases (MMPs) play a central role as degradation enzymes of extracellular matrix. Immunohistochemical staining (IHC) or ELISA methods have been carried out for the detection of tissue MMP proteins, and MMP activities have been mainly measured by gelatin zymography. Recently, film in situ zymography (FIZ) was developed for the regional detection of tissue MMP activities. FIZ uses a polyester film coated with gelatin uniformly and thinly. Frozen sections are incubated on the film at 37 degrees for optimal time. After gelatin staining with Biebrich Scarlet, the unstained area corresponds to MMP activities. The regional detection of tissue MMP activities by FIZ is simple and quantitative, and it is a useful tool for the studies of many diseases involving MMP. The detection of precise localization of MMP activity in tissues by FIZ may contribute the new classification of diseases involving MMP.

Single nucleotide polymorphism (SNP) is high-density genetic marker that could be utilized to dissect genetic traits that influence susceptibility to common diseases and responsiveness to drugs. Requirement for massive SNP analysis has enhanced development of various SNP genotyping technologies. DNA chip is one of such methods, which detects SNPs in parallel on an array of surface bound oligonucleotides. Recent application of DNA chip for high-throughput SNP analysis as well as clinical diagnosis will be presented.

A 71-year-old man was referred to our hospital complaining of cough. Chest radiography revealed a mass opacity in the right upper lung field. A transbronchial biopsy specimen revealed non-specific inflammatory changes. Percutaneous lung aspiration biopsy under ultrasound guidance demonstrated gram-positive rods, suggesting actinomyces. On the diagnosis of pulmonary actinomycosis, the patient was treated with penicillin-G and his symptoms were relieved. In a three-month follow-up, the mass shadow in the right upper lung field was found to have increased in size. Squamous cell lung cancer was diagnosed on the basis of repeated transbronchial tumor biopsies, and right upper lobectomy was performed. Most cases of pulmonary actinomycosis have been diagnosed from post-surgical tumor specimens taken on suspicion of the presence of lung cancer. However, the lung cancer in this case was difficult to diagnose because the lung cancer was co-existent with pulmonary actinomycosis.

The Fawn-Hooded Rat (FHR) spontaneously develops pulmonary hypertension (PH) at sea level, and an increased severity of this disease is observed upon exposure to mild hypoxia. A recent report suggested that lung hypoplasia with decreased alveolarization and altered vascular growth led by the decreased activity of endothelial nitric oxide synthase may contribute to the development of PH in the FHR. Exposure to mild hypoxia (P1O2 = 120 mmHg) leads to severe PH in FHR but not in Tester Moriyama rat, a strain that has a serotonin platelet storage-pool deficiency (PSPD) similar to that of the FHR. A serotonin PSPD does not appear to predispose FHR to PH. Endothelin-1 (ET-1) mRNA and peptide levels are increased in the hypertensive lungs of mildly hypoxic FHR. ET-1 may at least partly contribute to the development of PH in this strain.

A 64-year-old man with uveitis was admitted to our hospital for detailed investigation of an abnormal shadow on his chest X-ray. Chest radiography and computed tomography of the chest showed mediastinal lymphadenopathy and a tumor shadow in the left hilum. Transbronchial tumor biopsy revealed squamous cell carcinoma. Left upper lobectomy and drainage of bilateral hilar and mediastinal lymph nodes were performed. Histopathological examination revealed the coexistence of squamous cell carcinoma with many non-caseating epithelioid cell granulomas in all hilar and mediastinal drainage lymph nodes, but no metastasis. Non-caseating epithelioid cell granulomas were also seen in the interstitium and alveolar spaces. Coexistence of sarcoidosis and lung cancer in the same patient is not common, and only 29 cases, including ours, have been reported. This case also provides the concept that surgical tumor resection should be considered even if bilateral mediastinal lymphadenopathy is found in a case of lung cancer complicated with sarcoidosis.

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.

A 20-year-old man presented with microcytic hypochromic anemia (hemoglobin: 9.3 g/dl, MCV: 82.0 fl, MCHC: 29.5 g/dl) and dimorphism RBCs in circulating blood (RDW: 26.8%). Ringed sideroblasts accounted for 29.5% of bone marrow erythroblasts. Iron overload was also observed. Because the patient had a clear family history of anemia, he was given a diagnosis of X-linked sideroblastic anemia. The activity of delta-aminolevulinic acid synthase (ALAS) in bone marrow erythroblasts was low. However, we did not detect mutation of the gene for ALAS. The patient has responded well to a treatment regimen consisting of oral vitamin B6, Fe-chelation therapy, and phlebotomy.

Estrogen is involved in the growth and development of female organs such as uterus and mammary gland. On the other hand, from clinical point of view, it is recently suggested that estrogen is effective to protect postmenopausal women from osteoporosis, coronary heart disease and Alzheimer disease. In order to study the molecular mechanism of estrogen action, we have identified an estrogen responsive gene, efp (estrogen-responsive finger protein), which might mediate estrogen action in various target organs at diverse stages and targeted mutagenesis of efp gene could help clarify physiologic actions of estrogen.

A 68-year-old man experienced systemic pruritus since he was 63 years old, and systemic sclerosis and skin pigmentation were observed when he was 64. When he developed dyspnea the same year, he was admitted and SSc was diagnosed on the basis of the clinical and skin biopsy findings, lung fibrosis on X-P and TBLB findings. At 65, his dyspnea reappeared along with elevated blood pressure, acute renal failure and lung congestion, and he was diagnosed as having a scleroderma renal crisis (SRC) from the clinical and renal biopsy findings. Hemodialysis was started because he showed mental disturbance, and this and other acute symptoms were subsequently reduced. As he showed no recovery from his renal failure, the patient has been maintained on hemodialysis for over four years now. In the meantime, his sclerosis has improved and antinuclear antibody almost disappeared. Hemodialysis appears to be the most likely reason for his improvement, although spontaneous remission, D-penicillamine and angiotensin converting enzyme (ACE) inhibitor therapy may also have contributed, considering the short period and the small amount of drugs given until improvement.

Compounds that show their pharmacological actions via specific receptors are considered potential candidates for new drugs. Recently, several compounds that have specific binding sites and show certain pharmacological actions have been identified, but neither their binding sites, their endogenous substances, nor the functional role of the binding sites have been clarified. Regardless of the exact role of the binding sites of the compounds, research into the sites has opened up new areas of receptor investigation, and also new strategies for developing drugs. The sigma-ligand is one such kind of compound, and the existence of a binding site for the ligand was first postulated to account for the psychotomimetic effects of N-allylnormetazocine and related racemic benzomorphans. The binding site of the sigma-ligand is widely distributed in the central nervous system and peripheral systems. However, it still remain to be established whether sigma-ligand binding sites are to be referred to as "receptors". The classification of the ligands as agonists or antagonists at the sites and the heterogeneity and the functional role of the binding sites have not yet been clarified. Furthermore, the therapeutic targets have not been clearly determined. However, the sigma-ligands have high potential for developing new drugs. One of the possible targets of the sigma-ligands as new forms of drugs is schizophrenia. Recently, we identified two potent and highly selective sigma-ligands, FH-510 and NE-100. Together with the data on the binding properties and pharmacological actions of these compounds, the possibilities of the sigma-ligand as a new therapeutic drug were discussed.

Pituitary MR imaging was performed in 32 patients with clinically diagnosed pituitary dwarfism and 12 normal controls. The patients were divided into two groups according to the severity of pituitary dwarfism based on endocrinological data. The two patients with severe dwarfism showed transection of the pituitary stalk, ectopic posterior lobe and atrophy of the anterior lobe on MR imaging, while the 27 patients with mild dwarfism showed no abnormal MR findings of the pituitary gland. The former group corresponds to typical pituitary dwarfism and the latter to partial GH deficiency, which was recently proposed as another type of pituitary dwarfism. In conclusion, pituitary MR imaging may differentiate partial GH deficiency from typical (stalk-transected) pituitary dwarfism.

Two-dimensional time-of-flight magnetic resonance angiography (2D TOF MRA) of mediastinal and pulmonary hilar vessels was performed in 10 patients, seven men and three women with a mean age (range) of 65.7 (48-88) years. The rate of visualization of the vessels and the diagnostic ability of 2D TOF MRA were assessed in comparison with contrast-enhanced CT. A radiofrequency-spoiled gradient echo sequence (SPGR) was used during repeated breath-holding (8-27 seconds) in coronal (8 patients) and axial (2 patients) imaging planes on a 1.5 Tesla superconducting scanner under the following conditions: repetition time/echo time/flip angle/excitation: 25-33/7-8 ms/45 degrees/1, field-of-view: 30 x 30 cm, slice thickness: 2.5 mm, 32 slices, 256 (frequency) x 192 (phase) matrix, with gradient moment nulling technique. Visualization sufficient to enable diagnosis of the vascular lesion was obtained in 95 (52%) vessels, mere visualization in 63 (35%), and non-visualization in 24 (13%) of the 182 evaluable vessels. The rates of good visualization of pulmonary hilar vessels (26/86, 30%) and veins (26/48, 54%) were significantly lower than that of arteries (43/48, 90%, p < 0.05). The sensitivity and specificity of 2D TOF MRA were 77% (10/13) and 100% (83/83), respectively, in 96 evaluable vessels of nine patients. 2D TOF MRA of mediastium and pulmonary hili is clinically feasible, and may be useful because of its high specificity.

99mTc-ECD SPECT and 99mTc-HMPAO SPECT with or without Matas test were performed in a 62-year-old woman with meningioma in the left anterior cranial fossa. After injection of 740 MBq 99mTc-ECD or HMPAO, 64 projection images were collected with a rotating Gamma camera. Matas test was carried out by compressing the left common carotid artery for about one minute immediately after RI injection. Although 99mTc-ECD SPECT showed non-accumulation in the tumor, 99mTc-HMPAO SPECT demonstrated increased accumulation in it. This area of increased accumulation disappeared on 99mTc-HMPAO SPECT with Matas test which causes decrease in blood flow of the tumor. These findings suggest 99mTc-ECD and 99mTc-HMPAO have a different mechanisms of accumulation in the meningioma.

A 33-year-old male was admitted to our hospital because of an abnormal shadow in the right superior mediastinum on chest X-ray, which was first noted about half a year before his admission. Several diagnostic procedures, including fiber bronchoscopy, CT scan and MRI; however, no final diagnosis could be made. Thoracotomy was performed with the presumed diagnosis of benign mediastinal cystic tumor. Entry of the right thoracic duct into the cyst was observed at operation. Histological examination revealed that the cyst was lined by mono-layered cuboidal epithelial cells with lymphocytic infiltration in the wall of the cyst. The mono-layered cuboidal epithelium of the thoracic duct gradually changed to the epithelium of the cyst. Twenty ml of colorless transparent fluid was aspirated from the cyst. Analysis of aspirated fluid revealed low concentration of several substances except LDH compared to the values of the previously reported normal standards and other reported cases. From these findings, the cyst was diagnosed as mediastinal lymphatic cyst. Entry of the thoracic lymphatic duct into the mediastinal lymphatic cyst is a rare occurrence, and it is of interest to speculate on its relationship to the origin of the lymphatic cyst.

One of 99mTc-hexakis, 99mTc-methoxyisobutyl isonitrile (MIBI), has been demonstrated to have a myocardial uptake proportional to regional coronary blood flow. In this study, 99mTc-MIBI myocardial scintigraphy were performed for 16 patients with ischemic heart disease. After injection of 740 MBq of 99mTc-MIBI, 64 projection images were collected during a 360-degree rotation. Three-dimensional (3D) display of the left ventricle was reconstructed with depth-shading method from 99mTc-MIBI SPECT images, which were reconstructed by filtered back projection method. In 9 of the patients, left ventricular cineangiography were performed as diagnostic gold standard. Four physicians blinded to patients' clinical informations interpreted 3D images and SPECT images on separate occasions. Diagnosis of hypoperfusion by 3D displays agreed with those of SPECT in 92.9% (104/112 segments), and disagreed in 7.1% (8 segments). Sensitivity and specificity of 3D images were 87.0 and 93.9%, which were not statistically different (p less than 0.05) from that of SPECT images (91.3, 97.0%). Receiver operating characteristic (ROC) analysis revealed nearly identical curves for the two. Although 3D display had nearly identical diagnostic ability with SPECT, observers reported that 3D images were easier to diagnose than SPECT images. An advantage of the 3D display is that the display gives a more realistic impression of the left ventricle to an observer than tomography or planar imaging. Another advantage is that 3D display can reduce the amount of data storage compared with that of SPECT. In conclusion, 3D images may be useful for diagnosis of hypoperfusion of left ventricle.

Radiology reporting system using a speech recognition apparatus was applied to generation of reports on brain scintigram and SPECT. The number of words or phrases that were selected for the reporting system by the authors was 259. Rates of correct recognition at the first, second, and third or more utterance of the voices were 91.1, 5.0, and 3.9%, respectively. The recognition rates decreased from 96.6 to 88.0% when the mean lengths of the words or phrases varied from 6.4 to 3.3. Net time for the generation of 8 reports by the system was 21 minutes 26 seconds, while that by the traditional dictation-transcription method was 15 minutes and 53 seconds. This system seems to be useful because of much longer input time expected for an average doctor, who usually is not well trained in using a Japanese-word processor, and convenience for database management offered by the system.

The present experiment was performed to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The rings of the thoracic aorta were obtained from age-matched SHR and WKY, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the rings from SHR were significantly weaker than those obtained in WKY. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase-inhibitor (indomethacin) or thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) both in the SHR and WKY rings. A thromboxane A2 synthetase inhibitor (OKY-046) did not affect the acetylcholine-induced relaxation in the rings from SHR or WKY. In the organ bath solution, following acetylcholine stimulation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations increased, but prostaglandin F2 alpha and thromboxane B2 concentrations did not increase. Exogenous prostaglandin H2, a stable analogue of thromboxane A2 (STA2) and prostaglandin F2 alpha induced contractions of the SHR rings at a lower concentration than prostaglandin E2, prostaglandin D2 and prostaglandin I2. These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin synthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endothelium-derived contracting factor is produced and released by acetylcholine stimulation not only in the aorta of SHR but also in that of WKY. The results also suggest that prostaglandin H2, a precursor of the released prostaglandins, is a strong candidate for endothelium-derived contracting factor produced by acetylcholine stimulation.

The inhibitory effects of oxaprozin, a new non-steroidal anti-inflammatory drug, on platelet aggregation and prostaglandin (PG) synthetase activity were studied. In arachidonic acid (AA)-induced rabbit platelet aggregation in vitro, oxaprozin exhibited a dose-dependent inhibitory effect, and its median inhibitory concentration was 124.2 microM. The effect of oxaprozin was less potent than that of indomethacin and piroxicam, equipotent as that of aspirin and phenylbutazone, and 2 times as potent as that of ibuprofen. In collagen-induced rat platelet aggregation ex vivo, oxaprozin showed a weak but significant inhibitory effect with oral dose of 300 mg/kg. Indomethacin, aspirin and ibuprofen exhibited an inhibitory effect with 100 mg/kg. Although phenylbutazone also exhibited an inhibitory effect with 300 mg/kg, the effect was more potent than that of oxaprozin. ADP-induced platelet aggregation both in rabbit in vitro and rat ex vivo was not affected by oxaprozin. Moreover, oxaprozin administered orally inhibited dose-dependently AA-induced pulmonary thrombotic mortality in mice, and its median effective dose was 56.4 mg/kg. The effect of oxaprozin was less potent than of sulindac, piroxicam and ibuprofen, equipotent as that of aspirin, and 5 times as potent as that of phenylbutazone. On the other hand, oxaprozin inhibited dose-dependently PG synthetase activity. The inhibitory effect of oxaprozin was less potent than that of indomethacin and piroxicam, almost equipotent as that of ibuprofen, and more potent than that of phenylbutazone and aspirin. These results suggest that oxaprozin, like many other acidic non-steroidal anti-inflammatory drugs, suppresses platelet aggregation by mainly inhibiting PG synthetase activity.