Y Uehara

The University of Tokyo, Tokyo, Tokyo-to, Japan

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Publications (90)283.76 Total impact

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    ABSTRACT: Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level in plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients.
    Nephron 05/2001; 87(4):321-7. · 13.26 Impact Factor
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    ABSTRACT: Lipocalin-type prostaglandin D synthase (L-PGDS), which is responsible for the biosynthesis of PGD2, has recently been found to be present in the atherosclerotic plaque of the human coronary artery and also to be secreted in human serum. We measured the serum L-PGDS level and compared it with the expressions of the platelet membrane surface glycoprotein and neutrophil adhesion molecule in patients undergoing PTCA. The L-PGDS level significantly decreased (P < 0.01) and the platelet surface expression of CD62P (P-selectin) significantly increased (P < 0.01) immediately after PTCA in the coronary sinus blood. Both changes were inversely correlated (R = -0.72, P < 0.001). Although the L-PGDS level in the coronary sinus blood remained equivalent to the baseline level in patients who experienced restenosis, the level increased over the baseline level (P < 0.01) at 48 h after PTCA in patients without restenosis. Neutrophil surface expression of CD11b (alpha subunit of Mac-1) significantly increased at 24 h (P < 0.01) to 48 h (P < 0.001) after PTCA in the coronary sinus blood in patients with restenosis but the change showed less significant in patients without restenosis. The changes in the L-PGDS level and the CD11b expression at 48 h after PTCA were inversely correlated (R = -0.55, P < 0.05). An increased serum L-PGDS level at 48 h after PTCA possibly predicts the avoidance of late restenosis. It is suggested that reduction in PGD2 synthesis triggers platelet activation and that a subsequent increase in the PGD2 synthesis suppresses inflammatory reaction at the intervention site indicated by neutrophil activation and inhibits development of restenosis. Pharmacological or biological intervention that increases endogenous PGD2 synthesis should be tested as a new strategy to prevent restenosis.
    Thrombosis and Haemostasis 01/2001; 85(1):165-70. · 5.76 Impact Factor
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    ABSTRACT: PGD2 and its metabolites PGJ2 and 15-deoxy-delta12,14-PGJ2 have been reported to inhibit iNOS induction in cultured vascular smooth muscle cells. The present study was undertaken to determine whether these prostanoids inhibit iNOS induction in the isolated rat mesenteric artery. The artery without endothelium was incubated with and without lipopolysaccharide (LPS) at 37 degrees C for 6 hrs, then washed and mounted in an organ bath to measure isometric changes in tension. L-arginine but not D-arginine (10(-6) - 10(-3) M) induced concentration-dependent relaxations only in the artery preincubated with LPS, the relaxations of which were attenuated by L-N(G)-nitroarginine methyl ester (LNAME, 10(-4) M), a non-selective iNOS inhibitor, and 1400W (10(-5) and 10(-4) M), a selective iNOS inhibitor. Co-treatment of cycloheximide (10(-5) M), a protein synthesis inhibitor, or actinomycin D (10(-7) M), an RNA synthesis inhibitor with LPS inhibited the development of relaxing ability in response to L-arginine, indicating iNOS induction by LPS. PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 but not PGE2, PGI2 or PGF2alpha also inhibited the development of relaxing ability in response to L-arginine when added during incubation with LPS. Incubation of the artery with LPS at 37 degrees C for 6 hrs markedly increased production of nitric oxide (NO), which was abolished by 15-deoxy-delta12,14-PGJ2 (10(-5) M). An imunohistochemical study using antibody against murine iNOS showed that 15-deoxy-delta12,14-PGJ2 (10(-5) M) inhibited the expression of iNOS protein in isolated rat mesenteric arteries. These results demonstrated that PGD2 and its metabolites inhibit iNOS induction by LPS in isolated rat mesenteric arteries, resulting in reduced relaxing ability in response to L-arginine.
    Life Sciences 05/2000; 66(22):2173-82. · 2.30 Impact Factor
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    ABSTRACT: Sarcolemma integrity is stabilized by the dystrophin-associated glycoprotein complex that connects actin and laminin-2 in contractile machinery and the extracellular matrix, respectively. Interruption of the connection by the primary gene defect or acquired pathological burden can cause cardiac failure. The purposes of the present study were to verify whether dystrophin is disrupted in acute myocardial injury after the isoproterenol overload (10 mg/kg) and to examine its relation to myocardial cell apoptosis in rats. This injury from 4-16 h at the subendocardium was accompanied by dystrophin disruption and dislocation from subsarcolemma to cytoplasm, which were confirmed by immunohistology and Western blotting. However, delta-sarcoglycan was thoroughly preserved in sarcolemma. The dystrophin degradation preceded the appearance of apoptotic cells and exactly coincided with the transferase-mediated dUTP-biotin nick end labeling-positive cardiomyocytes (TUNEL), as was verified by double-staining. These data suggest that beta-adrenergic stimulation induces dystrophin breakdown followed by apoptosis.
    Journal of Cardiovascular Pharmacology 02/2000; 36 Suppl 2:S25-9. · 2.11 Impact Factor
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    ABSTRACT: The delta-sarcoglycan (SG) gene is deleted in hamsters with hereditary cardiomyopathies. Immunological analyses of heart before, but not after, the progression of cardiomyopathy (CM) revealed that the BIO 14.6 strain, a model of hypertrophic CM, heterogeneously preserved alpha- and gamma-SG with loss of beta- and delta-SG. In contrast, the TO-2 strain, a model of dilated CM, did not show either SG. Furthermore, in vivo transfer of the full length delta-SG gene to TO-2 hearts expressed all four SGs. Thus, this age- and strain-dependent features suggest a more feasible setting for TO-2 than BIO 14.6 to verify both CM progression and the efficacy of gene therapy.
    FEBS Letters 10/1999; 458(3):405-8. · 3.34 Impact Factor
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    ABSTRACT: The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 microg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 microg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.
    Hypertension 10/1999; 34(3):496-502. · 7.63 Impact Factor
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    ABSTRACT: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B2) receptor specific antagonist. Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B2-receptor antagonist, HOE-140. Long-term infusion of subdepressor dose of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B2 receptor.
    Nephron 03/1999; 81(2):183-93. · 13.26 Impact Factor
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    ABSTRACT: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-1 receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-1 antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se.
    American Journal of Hypertension 02/1999; 12(1 Pt 1):21-7. · 3.40 Impact Factor
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    ABSTRACT: BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.
    Journal of Cardiovascular Pharmacology and Therapeutics 11/1998; 3(4):327-336. · 3.07 Impact Factor
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    ABSTRACT: This investigation was to assess the role of genetic loading of hypertensive parents in the determination of blood pressure (BP) in their normotensive offspring. The medical check-up data from 7279 Japanese university students aged 19.22 +/- 0.01 years were analysed of which 641 students had only one hypertensive parent with or without hypertensive grandparents, and from this number 609 cases were available for the present analysis. The BP in the students having only one hypertensive parent were in the normotensive range, but was significantly higher than in those students without hypertensive relatives. Analyses of the data from the students having only one hypertensive parent revealed that systolic BP (SBP) and body mass index (BMI) were higher in the male than in the female students. In addition, there were no differences in BP and BMI between the male students with a hypertensive father and the male students having a normotensive father. However, multivariate analyses revealed that BMI was an independent predictor of SBP solely in the male students having a hypertensive father, but not in the male students having a normotensive father. Such a relationship between BMI and BP determination was not observed in the female students with one hypertensive parent. It is suggested that there are different mechanisms for the determination of BP in normotensive offspring of hypertensive parents, and genetic loading of a hypertensive father plays a critical role in the determination of BP through BMI.
    Journal of Human Hypertension 08/1998; 12(7):441-5. · 2.69 Impact Factor
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    ABSTRACT: Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D2 (PGD2) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD2 modulates NO metabolism in rat VSMCs. PGD2 at a concentration of 10(-7) mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1beta (IL-1beta). In a dose-response analysis of IL-1beta and nitrite accumulation, PGD2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD2 at cytokine receptors. Northern analysis showed that PGD2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1beta-stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A2 (TXA2) analogue, U46619 (10(-5) mol/L), produced less inhibition of NO generation than did PGD2. Neither the PGI2 analog carbaprostacyclin nor PGE1 showed any inhibition. PGD2 dose-dependently inhibited NO generation despite the addition of the TXA2 antagonist SQ29548. PGJ2, delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2, all metabolites of PGD2, were as potent as or slightly stronger than PGD2 in the inhibition of NO generation. These data suggest that PGD2 suppresses NO generation in VSMCs by inhibiting iNOS mRNA expression, most likely through the cascade of the PGJ2 series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD2 regulates NO metabolism in vascular lesions.
    Circulation Research 03/1998; 82(2):204-9. · 11.09 Impact Factor
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    ABSTRACT: Monocrotaline (MCT)-induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY-046) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist (ONO-8809) on the development of MCT-induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY-046 or ONO-8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV + S) increased significantly in MCT-treated rats compared with the control rats. The %MT was attenuated by the administration of ONO-8809. Either OKY-046 or ONO-8809 attenuated the increase in RV/LV + S. In addition, both TXA2 inhibitors reduced urinary excretion of 11-dehydro-TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT-induced PH in rats, probably by inhibiting platelet aggregation.
    Respirology 01/1998; 2(4):283-9. · 3.50 Impact Factor
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    ABSTRACT: Serum N-acetyl-beta-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16 wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22 wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats; this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus.
    Hypertension Research 10/1997; 20(3):193-9. · 2.94 Impact Factor
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    ABSTRACT: We report here a case of membranous glomerulonephritis associated with chronic hepatitis B (HB) virus infection and describe differential localization of HB antigens in glomeruli. The patient showed mild proteinuria and was positive for hepatitis B surface (HBs) antigen, hepatitis B envelope (HBe) antigen, and antibody to hepatitis B core (HBc) antigen in the serum. The antibody against hepatitis C was negative. A renal biopsy revealed membranous glomerulonephritis with mesangial proliferation. The immunohistochemical studies using monoclonal antibodies localized the HBe antigen along the capillary wall and the HBs antigen in the mesangial area. The immunoelectron microscopic study confirmed the localization of HB antigens: HBe antigen was located in the subepithelial and intramembranous electron dense deposits and HBs antigen in the mesangial deposits. Our present results provide the first report of the differential localization of HB antigens in glomeruli at both the light and electron microscopic levels. The differential localization of HB antigens will provide insight into the pathogenesis of membranous glomerulonephritis.
    Clinical nephrology 08/1997; 48(1):44-7. · 1.23 Impact Factor
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    ABSTRACT: We investigated the effects of the immunosuppressant HR-325 on arterial lesions in Dahl rats with salt-induced hypertension. Forty-eight 6-wk-old Dahl salt-sensitive (DS) rats were divided into 1) a low-salt (0.3% NaCl) group, 2) a high-salt (4% NaCl) group, 3) a high-salt and low-dose (1 mg/kg) HR-325 group, and 4) a high-salt and high-dose (30 mg/kg) HR-325 group. The rats were treated for 8 wk. Various variables of renal function and morphological alterations in the kidney were assessed. Blood pressure was measured by the tail-cuff method. HR-325 significantly decreased systolic blood pressure in a dose-dependent manner throughout the study. HR-325 tended to decrease plasma creatinine level and increase creatinine clearance rate. Morphological studies revealed that HR-325 treatment strikingly resolved infiltration of immune-related cells in perivascular and intraluminal lesions, thereby decreasing the total arterial injury score by 32%. High-dose HR-325 also attenuated glomerulosclerosis and tubular injury by 35% and 34%, respectively, as compared with untreated high-salt Dahl S rats. Reduced levels of immune-related cells resulted in a decrease in urinary nitrite excretion. These data indicate that long-term treatment with the immunosuppressant HR-325 decreases systolic blood pressure in Dahl salt-sensitive rats, and that this decrease is associated particularly with resolution of infiltration of immune-related cells in arterial lesions. Hyperimmune state is responsible in part for the susceptibility of Dahl S rats to hypertensive organ damage.
    Hypertension Research 07/1997; 20(2):91-7. · 2.94 Impact Factor
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    ABSTRACT: Nitric oxide (NO) has various actions on the cardiovascular system, although its pathophysiological significance in myocardial cells remains obscure. The aim of the present study was to identify direct NO actions on cardiomyocytes by gene transfection in vivo using a newly developed vector under physiological conditions. Liposomes containing the beta-galactosidase (beta-gal) gene alone or with the human endothelial cell nitric oxide synthase (ecNOS) gene were coated with UV-inactivated Sendai virus and injected into the left ventricular wall of rat heart in vivo. Histological examination confirmed that the transfection efficiency was comparable to adenovirus-mediated transfection and that the new vector per se caused no inflammation. beta-Gal expression was confined to cardiomyocytes between two intercalated discs, suggesting that the transfected gene did not permeate the discs. An immunohistochemical study showed that cotransfection of the ecNOS gene induced massive myocardial cell shrinkage in both transfected cells and the adjacent myocytes in a time- and dose-dependent manner. Histochemical findings in shrunk cells coincided with apoptosis as identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling. Electron microscopy of the lesion revealed myofibrillar degradation and accumulation of mitochondria but no apoptotic bodies. Pre-treatment with the NOS inhibitor N omega-nitro-L-arginine methyl ester abolished these morphological alterations. The efficient expression of the human ecNOS gene in vivo suggests that NO or its toxic metabolite caused myocardial degradation, a part of which was compatible with apoptosis of the transfected cardiomyocytes themselves and the adjacent cells as a paracrine effect. These morphological features mimicked acute myocarditis or ischemic injury.
    Circulation 06/1997; 95(10):2441-7. · 14.95 Impact Factor
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    ABSTRACT: Angiotensin II (Ang II) progresses to remodeling of the cardiovascular system through nonhemodynamic as well as hemodynamic effects. There have been few data in vivo on whether subpressor concentration of Ang II is exerted to injure directly the cardiovascular system in hypertension. To test this hypothesis, we investigated, using Dahl salt-sensitive (Dahl S) rats, whether subpressor dose of Ang II progresses to cardiovascular injury observed in salt-induced hypertension. Recent studies have provided evidence that renin-angiotensin inhibition protects against renovascular injury in human hypertension as well as in experimental animals. Particularly in the case of Dahl salt-sensitive rats, a genetic model of volume-dependent hypertension in humans, they are likely to develop more severe arterial and renal injuries than those seen in spontaneously hypertensive rats with similar blood pressure levels. The mechanism of the susceptibility to hypertensive injuries is uncertain; however, renin-angiotensin inhibition significantly improved morphologic and functional injuries in the kidney of Dahl S rats. Conversely, subpressor dose of Ang II infusion exacerbated renal function and progressed to glomerulosclerotic lesions. Alterations of Ang II concentration in physiologic range influenced morphologic and functional injuries in Dahl S rats. Multivariate analysis revealed that activity of the renin-angiotensin system is an independent risk factor to glomerular injury in salt-induced hypertension. These data are in favor of the therapeutic strategy in human hypertension that inhibition of renin-angiotensin system is of value to produce beneficial effects of blood pressure reduction on organ injuries.
    American Journal of Hypertension 06/1997; 10(5 Pt 2):102S-106S. · 3.40 Impact Factor
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    ABSTRACT: We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. A subdepressor dose of purified rat urinary kallikrein (RUK) (700 ng/day) was infused intravenously by an osmotic minipump for 4 weeks in male Dahl S rats fed a high-salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure. However, urinary protein excretion was significantly decreased, and the glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl S rats. The kallikrein infusion increased the urinary excretion of bradykinin and stimulated the excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by the RUK infusion. The alterations induced by such infusion were potentiated by the concomitant administration of the angiotensin converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl S rats, and this is probably mediated by an enhanced function of the kallikrein-kinin-prostaglandin and nitric oxide systems.
    American Journal of Hypertension 06/1997; 10(5 Pt 2):83S-88S. · 3.40 Impact Factor
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    ABSTRACT: We investigated the role of lipid metabolism in renal protection by chronic cicletanine treatment in Dahl salt-sensitive (Dahl S) rats with salt-induced hypertension. Forty-four 6-week old Dahl S rats were divided into four groups: (1) low-salt (0.3% NaCl) control group: (2) high-salt (4% NaCl) control group; (3) low-dose (10 mg/kg/day) cicletanine (CICL)-treated group given a high-salt diet; and (4) high-dose (30 mg/kg/day) cicletanine-treated group given a high-salt diet. The rats were treated for 6 weeks; blood pressure was measured by the tail-cuff method. Cicletanine significantly reduced the systolic blood pressure in a dose-dependent manner (223 mmHg in the high-salt controls vs 195 mmHg in the high-dose, high-salt group, p < 0.01). Cicletanine treatment did not affect plasma concentration of total cholesterol or triglyceride or free fatty acid; in contrast, it significantly decreased low-density lipoprotein (LDL) cholesterol and increased high-density lipoprotein (HDL) cholesterol. Morphological examination demonstrated that glomerulosclerosis in the kidney was significantly improved by 15% with high-dose cicletanine (p < 0.01). Multivariate analysis revealed that glomerular sclerosis was determined independently by LDL cholesterol levels and arterial injury score, but not by total cholesterol or HDL cholesterol levels or blood pressures. LDL cholesterol was also an independent predictor of urinary excretion of protein. Thus, it is suggested that cicletanine treatment lowers the levels of LDL cholesterol in Dahl salt-sensitive rats, and that besides blood pressure reduction, this decrease in LDL cholesterol level contributes, in part, to regression of glomerular injury in salt-induced hypertension.
    Blood Pressure 05/1997; 6(3):180-7. · 1.61 Impact Factor
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    ABSTRACT: The established associations between blood pressure (BP) and electrolytes are mostly based on either dietary intake or urinary excretion data. We measured office BP, ambulatory BP (ABP) using the automated oscillometric ABPM-630 device, and plasma electrolytes in 82 essential hypertensive patients to examine the relation between BP and plasma electrolytes. Significant negative correlations were observed between plasma potassium concentration and 24-h systolic BP (r = -0.336) and diastolic BP (r = -0.298) in our patients. Plasma potassium concentration inversely correlated also with both daytime and nighttime systolic and diastolic BPs. There was no relation between office BP and plasma potassium concentration. These findings indicate that in essential hypertensives plasma potassium concentration is inversely related to ABP including daytime and nighttime BPs and suggest that potassium may be a factor determining the whole day BP in essential hypertension.
    American Journal of Hypertension 04/1997; 10(3):337-40. · 3.40 Impact Factor

Publication Stats

923 Citations
283.76 Total Impact Points


  • 1983–2000
    • The University of Tokyo
      • • Department of Internal Medicine
      • • Division of Internal Medicine
      • • Center for Health Service
      • • School of Medicine
      • • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan
  • 1987–1997
    • Dokkyo Medical University
      • • School of Medicine
      • • Division of Cardiology and Pneumology
      Tochigi, Tochigi-ken, Japan
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 1989–1996
    • Niigata Teishin Hospital
      Niahi-niigata, Niigata, Japan
  • 1991
    • Yokohama City University
      • Department of Medicine
      Yokohama, Kanagawa, Japan