Search PubMed⌕ Search

Biomedical subjects

K Murakami

Publications and source records attributed to K Murakami.

At least 379 records · Page 21Linked to original sources
PubMed1997

rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation.

We have previously demonstrated that recombinant human soluble (rhs) thrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pulmonary vascular permeability by inhibiting leukocyte activation. In the present study, we examined whether rhs-TM could inhibit the ET-induced increase in pulmonary vascular permeability in rats by activating protein C. rhs-TM did not inhibit ET-induced increases in pulmonary vascular permeability when its protein C activation ability was selectively inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12). Histological examination revealed that neutrophil infiltration in lung tissues after ET administration was significantly reduced by rhs-TM, but infiltration was not reduced by MAb R5G12-pretreated rhs-TM. ET-induced intravascular coagulation was prevented by rhs-TM and by MAb R5G12-pretreated rhs-TM. However, ET-induced coagulation was not prevented by rhs-TM that had been treated with MAb F2H5, which cannot bind thrombin or activate protein C. These observations strongly suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes through thrombin binding and the subsequent protein C activation and may prevent ET-induced intravascular coagulation through thrombin binding.

Animals↗
PubMed1997

Modulation of tissue angiotensinogen gene expression in genetically obese hypertensive rats.

Wistar fatty rats (WFR) show obesity and obesity-related features, including hypertension. In this study, we examined the expression of angiotensinogen mRNA in a variety of tissues at different times in WFR and control Wistar lean rats (WLR). WFR were obese and hypertensive at 16 and 24 wk. Plasma renin activity and plasma angiotensinogen concentration showed age-dependent increases in WFR but decreases in WLR. Northern blot analysis showed no significant differences in the levels of hepatic and renal angiotensinogen mRNA between WFR and WLR, and the levels of fat and adrenal angiotensinogen mRNA were lower in WFR than in WLR. On the other hand, the levels of cardiac angiotensinogen mRNA at 16 and 24 wk and those of aortic angiotensinogen mRNA at 16 wk were significantly higher in WFR than in WLR. These results show that the expression of tissue angiotensinogen mRNA is regulated differently in WFR and WLR and indicate that the development of hypertension in WFR is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as in cardiac and aortic angiotensinogen mRNA. Moreover, these results suggest the existence of obesity hypertension-linked and tissue-specific regulation of angiotensinogen gene expression.

Angiotensinogen↗
PubMed1997

Exercise-induced changes in beta-adrenergic-receptor mRNA level measured by competitive RT-PCR.

Competitive reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to clarify whether dynamic exercise-induced increases in beta-adrenergic-receptor (beta-AR) number in human lymphocytes are accompanied by increases in the beta-AR mRNA level. Sixteen healthy subjects performed cycle ergometry until exhaustion. Before and immediately after exercise, peripheral blood was drawn from a forearm vein for preparation of lymphocytes. Both the beta-AR mRNA level and the beta-AR number were significantly increased by exercise. The changes in beta-AR mRNA level and beta-AR number were significantly correlated (r = 0.63, P < 0.01). This finding suggests that a rapid increase in beta-AR mRNA level might be an early adaptive response of the sympathetic nervous system to dynamic exercise. In vitro incubation of lymphocytes with epinephrine had no effect on beta-AR mRNA levels, nor did adenosine 3',5'-cyclic monophosphate, protein kinase C, or intracellular Ca2+ increase the beta-AR mRNA level in vitro. Therefore, it appears that other mechanisms underlie the exercise-induced elevation of beta-AR mRNA levels in human lymphocytes.

Adult↗
PubMed1997

Primary purulent mediastinitis due to Streptococcus milleri.

Streptococcus milleri mediastinitis had resolved in a 44-year-old male after 3 weeks of combined parenteral antibiotic therapy including clindamycin, which showed the greatest in vitro activity against S. milleri isolated from this patient, and surgical drainage. This case demonstrates that primary purulent mediastinitis may be caused by a strain of S. milleri with or without other bacterial species, and suggests that S. milleri should be added to the list of causative organisms of purulent mediastinitis even when the patient has not undergone a surgical procedure.

Adult↗
PubMed1997

High human renin hypertension in transgenic rats.

We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither transgenic strain was hypertensive. These strains were then crossed, producing a double transgenic strain. The double transgenic rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269 +/- 381 (+/-SD) ng angiotensin I (Ang I)/mL per hour, plasma renin activity of 177 +/- 176 ng Ang I/mL per hour, rat angiotensinogen concentration of 1.49 +/- 1 microgram Ang I/mL, and human angiotensinogen concentration of 78 +/- 39 micrograms Ang I/mL (n = 49). Control rats had plasma renin activity of 3.7 +/- 3.9 ng Ang I/mL per hour and rat angiotensinogen of 1.32 +/- 0.16 micrograms Ang I/mL. Angiotensinogen transgene expression by RNase protection assay was ubiquitously present but most prominent in liver. Renin transgene expression was high in kidney but absent in liver. The rats featured severe cardiac hypertrophy, with increased cross section of cardiomyocytes but little myocardial fibrosis. The kidneys showed atrophic tubules, thickened vessel walls, and increased interstitium. Both the angiotensin-converting enzyme inhibitor lisinopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gene expressions are similar. The specificity of rodent and human renin is similarly documented. Although many elegant physiological studies can now be done in mice, rats nevertheless offer flexibility, particularly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simultaneous investigation of genetic and pathophysiological aspects of renin-induced hypertension. The fact that human renin can be studied in the rat is a unique feature of this model.

Angiotensinogen↗
PubMed1997

Overexpression of CuZn-superoxide dismutase reduces hippocampal injury after global ischemia in transgenic mice.

BACKGROUND AND PURPOSE: The role of copper, zinc-superoxide dismutase (CuZn-SOD) in hippocampal injury after transient global ischemia was studied using transgenic (Tg) mice and wild-type littermates. METHODS: Global ischemia was induced by bilateral common carotid artery occlusion. The hemisphere with the hypoplastic posterior communicating artery was determined and then the hippocampus in this hemisphere was evaluated qualitatively using a score of 0 to 4 and quantitatively using an image analyzer. RESULTS: Hippocampal injury was reduced in Tg mice after both 5 and 10 minutes of ischemia. In the 5-minute ischemia group, the mean score of the injury was significantly lower in Tg than nontransgenic (nTg) mice at 3 days. In the 10-minute group, the hippocampal injury was reduced more in Tg than nTg mice at 1 day. Quantitative evaluation by an image analyzer confirmed the qualitative data. Neurons with fragmented DNA were also studied in the hippocampal injury. In the 5-minute group, despite the reduction of the injury in Tg mice, their neurons with fragmented DNA were relatively increased at 1 day. In the 10-minute group, this ratio was almost the same in both nTg and Tg mice. CONCLUSIONS: CuZn-SOD plays a protective role in the pathogenesis of selective hippocampal injury after brief ischemia, whether the insult is relatively mild or intense. Furthermore, CuZn-SOD may reduce both necrotic and DNA fragmented neuronal death after global ischemia.

Animals↗
PubMed1997

Effect of nafamostat mesilate on pulmonary vascular injury induced by lipopolysaccharide in rats.

Nafamostat mesilate (NM) is a synthetic protease inhibitor that is capable of inhibiting the various coagulation factors such as factor VIIa and thrombin. To determine whether NM may also be useful in treating adult respiratory distress syndrome (ARDS) related in sepsis, we investigated the effect of NM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intraperitoneal administration of NM prevented the pulmonary vascular injury and coagulation abnormalities induced by LPS. DEGR-factor VIIa, a selective inhibitor of factor VIIa, prevented the coagulation abnormalities, but not the pulmonary vascular injury, induced by LPS. NM did not reduce LPS-induced increase in pulmonary accumulation of leukocytes. NM did not inhibit the increase in the plasma concentration of tumor necrosis factor-alpha (TNF-alpha) observed after administration of LPS. NM did not inhibit the function of activated neutrophils in vitro. Plasma values of total serum hemolytic complement (CH50) were markedly decreased after the administration of LPS. NM inhibited the LPS-induced decrease in plasma CH50 values. Findings suggest that NM may reduce the pulmonary vascular injury as well as the coagulation abnormalities induced by LPS. The former effect may be independent of the anticoagulant effect but dependent on the inhibitory effect of the activation of the complement system in rats administered LPS.

Animals↗
PubMed1997

Novel histamine H3 receptor antagonists: synthesis and evaluation of formamidine and S-methylisothiourea derivatives.

In order to obtain a new, potent and selective histamine H3 receptor antagonists, chemical modifications of thioperamide, a well-known H3 receptor antagonist, were conducted. A new series of compounds has been synthesized by modifying the thiourea and cyclohexyl groups of thioperamide, and tested for H3 affinity by receptor binding assay using plasma membrane from rat cerebral cortex. The thiourea group of thioperamide was found to be replaceable with a basic moiety such as formamidine or S-methylisothiourea. Replacement of the cyclohexyl group in thioperamide by a 1-adamantyl or an exo-2-norbornyl group increased the affinity for H3 receptor. Among the compounds synthesized, N-(1-adamantyl)-N',N'-[3-(4(5)-1H-imidazolyl)pentamethylene] formamidine 3f (AQ0145) showed the highest H3 receptor affinity, having a potent antagonistic activity. This compound was at least 1,000-fold more active towards H3 than towards H1 and H2 receptors.

Amidines↗
PubMed1997

Effects of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) in surface lymph nodes of rhesus monkeys (Macaca mulatta) chronically infected with simian immunodeficiency virus (SIVmac239).

We studied the effects of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG), an antiretroviral drug, in surface lymph nodes of rhesus monkeys (Macaca mulatta) chronically infected with simian immunodeficiency virus (SIV). The rhesus monkeys were treated with 25 mg/kg of 6-Cl-ddG every 8 hr for 2 weeks. We performed sequential biopsies of the surface lymph nodes three times: before, during, and after the drug treatment. The 6-Cl-ddG dramatically decreased the number of infectious virus (measured by limiting dilution assay) in lymph node mononuclear cells. This decrease was consistent with the decrease in the number of viral RNA-positive cells in lymph nodes (analyzed by in situ hybridization). Histopathological analysis revealed that hyperplastic lymphoid follicles were reduced in size, especially, enlarged areas of centroblasts in lymphoid follicles (the so-called dark areas of germinal centers) were declined. Our results demonstrated that 6-Cl-ddG decreased the viral burden concomitantly with reduced hyper-activation of germinal centers in lymphoid follicles of SIV-infected rhesus monkeys.

Animals↗
PubMed1997

Efficacy of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) on an ARC/AIDS rhesus macaque (Macaca mulatta) infected with simian immunodeficiency virus.

The efficacy of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) was investigated in vivo by using a male ARC/AIDS rhesus macaque infected with simian immunodeficiency virus (SIVmac251/32H). He was administered subcutaneously 6-Cl-ddG (50 mg/kg B.W.) every 8 hr for 14 days when he showed clinical features of recurrent weight loss, severe diarrhea and neuropathy. The number of CD4+, CD8+ cells and total T cells increased rapidly after administration of 6-Cl-ddG and a high level was maintained for 2 months, but the B cell count decreased during the treatment. The antibody titer to SIV did not change significantly during or after the treatment, but the virus load in the plasma measured by RT-PCR dropped to one-third at the start of the 6-Cl-ddG treatment. Within 3 days after the start of 6-Cl-ddG administration, he began to show recovery in clinical signs including weight increase, and disappearance of diarrhea and neuropathy. These findings suggested that 6-Cl-ddG was effective at the stage of ARC/AIDS in a rhesus monkey infected with SIV.

Animals↗
PubMed1997

Reduction of spinal cord injury by administration of iloprost, a stable prostacyclin analog.

To investigate whether iloprost, a stable analog of prostacyclin, is useful for the prevention of posttraumatic spinal cord injury, we examined its effects on compression trauma-induced spinal cord injury in rats. Spinal cord injury was induced by applying a 20-g weight for 20 minutes to the spinal cord at the level of T-12, resulting in motor disturbances in the hindlimbs. These motor disturbances, evaluated using Tarlov's index, were markedly attenuated in rats with nitrogen mustard-induced leukocytopenia. Administration of iloprost also attenuated the motor deficits. Histological examination revealed that intramedullary hemorrhages observed 24 hours after trauma were significantly attenuated in leukocytopenic animals and in animals that received iloprost. The accumulation of leukocytes at the site of trauma, evaluated by measuring tissue myeloperoxidase activity, significantly increased with time following the trauma, peaking at 3 hours postinjury. Spinal cord myeloperoxidase activity in sham-operated animals did not increase postoperatively. Leukocyte depletion and administration of iloprost reduced the accumulation of leukocytes in the damaged spinal cord segment 3 hours posttrauma. These findings indicate that iloprost attenuates motor disturbances induced by spinal cord trauma and that its therapeutic efficacy can be partly explained by its inhibition of leukocyte accumulation at the traumatized site.

Animals↗
PubMed1997

The neuronal isoform of constitutive nitric oxide synthase is up-regulated in the macula densa of angiotensinogen gene-knockout mice.

Angiotensinogen gene-knockout (Atg -/-) mice lacking angiotensin II exhibit chronic hypotension and an increase in renal renin gene expression. The present study was designed to provide evidence for the possible involvement of neuronal type nitric oxide synthase (N-NOS) at the macula densa in the increased renin production in Atg -/- mice. The enzyme activity of N-NOS was histochemically detected by NADPH diaphorase (NADPHd) reaction combined with N-NOS immunohistochemistry. N-NOS mRNA expression in the renal cortical tissue was determined using reverse transcription-PCR in a semiquantitative manner. The levels of renal renin mRNA were evaluated by Northern blot analysis. In the kidneys of wild-type (Atg +/+) mice, N-NOS activity was localized to the macula densa as reported previously. On the other hand, N-NOS-positive macula densa cells of Atg -/- mice were distributed beyond the original location of the macula densa. They often occupy the entire cross-sectional profiles of the tubules. In addition, Atg -/- mice showed a stronger signal intensity for the enzyme reaction than Atg +/+ mice. The mean total number of N-NOS-positive cells per 100 glomeruli was 6 times higher in Atg -/- mice than in Atg +/+ mice. Semiquantitative reverse transcription-PCR revealed an increase in the N-NOS mRNA level in renal cortical tissue of Atg -/- mice compared with Atg +/+ mice. Furthermore, the selective inhibition of N-NOS activity by 7-nitrondazole significantly decreased the level of renal renin mRNA in Atg -/- mice. These results suggest that increased N-NOS activity at the macula densa is involved a renal renin overproduction in Atg -/- mice.

Angiotensinogen↗
PubMed1997

Activated and inactivated renin-angiotensin system in transgenic animals: from genes to blood pressure.

Much of our knowledge about blood pressure regulation has come from a huge number of biochemical, endocrinologic, pharmacologic, clinical, and physiologic studies. The renin-angiotensin system, composed of enzymatic and signal-transduction cascades, has a key role in regulating arterial blood pressure and in developing certain forms of experimentally induced hypertension and hypertension in human beings. Angiotensin peptides, the products of this system, exert a wide range of physiologically important effects on many tissues, including those of the cardiovascular system, through their actions on angiotensin receptors. Recently, several groups have succeeded in generating animals transgenic for the renin or angiotensinogen genes, or with a targeted disruption of the component genes of the renin-angiotensin system. This brief review describes advances of the in vivo analysis of blood pressure regulation by focusing on the renin-angiotensin system.

Amino Acid Sequence↗
PubMed1997

Acceleration of atherosclerotic lesions in transgenic mice with hypertension by the activated renin-angiotensin system.

The present study was designed to investigate the development of atherosclerotic lesions in hypertensive transgenic mice carrying both the human renin and angiotensinogen genes (Tsukuba hypertensive mice; THM). THM and C57BL/6J control mice 2 to 3 months of age were fed with either an atherogenic or a normal diet for 14 weeks. Although the systolic blood pressure of either strain remained the same regardless of diet, it was significantly higher in THM than in C57BL/6J on both diets. Total plasma cholesterol concentrations in mice on the atherogenic diet were significantly higher than those in mice fed the normal diet. Lipoprotein profiles of cholesterol in THM were fundamentally similar to those in C57BL/6J on either the atherogenic or normal diet. Compared with controls, however, microscopic analyses revealed accelerated damage of cellular structure in the aortic root in THM fed with the atherogenic diet. Remarkably, the surface area of atherosclerotic lesion in THM was shown by quantitative image analysis to be 4 times larger than that in C57BL/6J on the same atherogenic diet. These findings suggested that hypertension induced by the activated renin-angiotensin system is involved in the development of atherosclerotic lesions. Therefore, THM should be a useful animal model for the study on the pathogenesis of atherosclerosis.

Angiotensinogen↗
PubMed1997

The role of tumor-associated antigen in bovine leukemia virus-induced lymphosarcoma.

Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis (EBL), which is the most common neoplastic disease of cattle. To clarify the way in which BLV-infected cattle progress from the asymptomatic stage to the lymphoma stage, we produced a monoclonal antibody (MAb) c143 which recognized a tumor-associated antigen (TAA) that is phosphorylated in the transformed state of BLV-infected B-lymphoid cells. Since the nature of c143 TAA was likely to be that of the major histocompatibility complex (MHC) class II antigens, we isolated cDNAs for bovine MHC (BoLA) class II a-chains and b-chains, produced transfectants that expressed a single type of BoLA class II molecules and analyzed them by flow cytometry with c143 MAb. The c143 MAb recognized the transfectant expressing BoLA-DR but not BoLA-DQ. However, the treatment of lymphocytes with c143 or anti-BoLA-DR MAb induced different effects. Although mixed lymphocyte reaction (MLR) was inhibited by the addition of anti-BoLA-DR MAb, the c143 MAb did not inhibit a proliferative response of T cells in MLR. Increased spontaneous proliferation of lymphocytes in healthy donors was obtained in the presence of c143 MAb but not anti-BoLA-DR MAb, and was much in lymphocytes from the carrier. Moreover, the patterns of immunohistological staining for c143 MAb in BLV-infected sheep showed distinguishing differences from those of anti-BoLA-DR MAbs.

Animals↗
PubMed1997

[Staging of pancreatic ductal adenocarcinoma using dynamic MR imaging].

Single breath-hold gradient echo images were obtained before and immediately after bolus intravenous administration of Gd-DTPA (dynamic MR imaging) in the study of the pancreas. Of 37 patients with pathologically proved pancreatic ductal adenocarcinoma, seventeen patients who underwent both dynamic MR imaging studies and curative surgery were included in this study. Correlations between histologic findings in the resected specimens and MR images were analyzed as to tumor extension and staging according to the General Rules for the Study of Pancreatic Cancer (4th Edition) published by the Japan Pancreas Society. In comparison with conventional MR images, dynamic MR imaging improved the detectability of pancreatic carcinoma and delineation of the vasculature by clarifying the margin of the tumor and the vessels. Nonenhanced T1-weighted imaging is the best sequence to estimate peripancreatic tumor extension, because the contrast between the tumor and peripancreatic fat deteriorates with the use of contrast material. There is a tendency to overestimate vascular invasion on MR images, the reason for which is considered to be the contractive nature of fibrotic change induced by pancreatic carcinoma. The diagnostic efficacy of lymph node metastasis remains insufficient on MR images because some cases show no enlargement of lymph nodes in spite of the existence of pathological metastasis. Our results suggest that dynamic MR imaging has the advantage of improving the conspicuity of the tumor and the vasculature.

Adult↗