Three dinucleotide repeat polymorphisms at the D8S1217, D8S1220, and D8S1221 loci.
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Animals↗
Biomedical subjects
T Ogihara
Publications and source records attributed to T Ogihara.
A highly polymorphic dinucleotide repeat at the D8S1222 locus.
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Base Sequence↗
Dinucleotide repeat polymorphism at the D8S1054.
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Adenine Nucleotides↗
Colonic mucosal hemodynamics and tissue oxygenation in patients with ulcerative colitis: investigation by organ reflectance spectrophotometry.
Colonic mucosal hemodynamics were investigated at the rectosigmoidal region of the colon in 46 patients with ulcerative colitis and in 18 normal subjects by organ reflectance spectrophotometry under colonoscopy. The value for the index of mucosal hemoglobin concentration (IHb) was significantly higher, and value for the index of mucosal hemoglobin oxygen saturation (ISO2) was significantly lower in patients with active ulcerative colitis than values in the normal controls or in patients with inactive ulcerative colitis. The results indicate mucosal congestion and hypoxemia in patients with active ulcerative colitis. The changes in IHb and ISO2 correlated well with the severity of ulcerative colitis scored by endoscopic findings and with the number of infiltrating inflammatory cells in the mucosa analyzed histologically in biopsy samples. In conclusion, the colonic mucosal microcirculation in patients with active ulcerative colitis was disturbed and showed congestion and hypoxemia. The analysis of hemodynamic changes may be helpful for assessing the activity of ulcerative colitis.
Adult↗
Amino acids in the medulla oblongata contribute to baroreflex modulation by angiotensin II.
We investigated the underlying mechanisms of baroreflex alteration produced by intravenous angiotensin II (ANG II) by monitoring the release of amino acids from the rostral ventrolateral medulla (VLM) using a brain microdialysis technique. Reflex changes in heart rate were elicited by bolus intravenous injection of phenylephrine (2-40 micrograms/kg) before and 120 min after the initiation of administration of a subpressor dose of ANG II (5.4 pmol/kg/min) or vehicle. The slope of the regression line obtained from changes in mean arterial pressure and heart rate elicited by phenylephrine was used as an index of baroreceptor reflex sensitivity. ANG II administration for 120 min significantly attenuated the baroreflex sensitivity (from -0.59 +/- 0.10 to -0.30 +/- 0.08 bpm/mmHg). This attenuation was accompanied with an increase in the release of glutamate and glycine from the VLM (+40% and +20%, respectively) at 120 min. Glycine perfusion into this area resulted in an attenuation of baroreflex sensitivity with a magnitude similar to that obtained with infusion of a subpressor dose of ANG II, whereas glutamate perfusion caused a resetting of baroreflex. These results suggest that glycine and glutamate are involved in cardiovascular regulation in the VLM. Furthermore, the augmented releases of these amino acids may account for the underlying mechanism of ANG II-induced attenuation of baroreflex function.
Amino Acids↗
Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives.
The association of hypertension with insulin resistance has been reported. Troglitazone (CS-045) is a newly developed antidiabetic agent that enhances insulin sensitivity. Its antidiabetic effects have been confirmed in diabetic animals and patients. The present study was performed to evaluate whether the amelioration of hyperinsulinemia by troglitazone lowers blood pressure in essential hypertensives. Troglitazone was administered orally to 18 outpatients with essential hypertension complicated by mild diabetes at a dose of 200 mg twice a day for 8 weeks. Blood pressure was decreased from 164 +/- 3/94 +/- 2 mm Hg to 146 +/- 3 (P < .001)/82 +/- 3 (P < .05) mm Hg at 8 weeks of the treatment period. Pulse rate did not change. Fasting plasma glucose changed from 159 +/- 10 mg/dL to 144 +/- 14 mg/dL at 8 weeks (P < .05). Plasma insulin (IRI) levels changes from 9.1 +/- 1.2 microU/mL to 6.3 +/- 0.8 microU/mL at the endpoint of treatment (P < .1). Decrease in mean blood pressure from the control period to the endpoint of the treatment correlated significantly with decrease in IRI (r = 0.59, P < .05). In summary, troglitazone treatment induces improvement in both glucose metabolism and blood pressure control in essential hypertensive patients with diabetes mellitus. These results suggest that insulin resistance or plasma insulin level plays a role in the pathogenesis of essential hypertension.
Aged↗
Proton-cotransport of pravastatin across intestinal brush-border membrane.
PURPOSE: The purpose of the present study is to clarify the intestinal brush-border transport mechanism of a weak organic acid, pravastatin, an HMG-CoA reductase inhibitor. METHODS: The transport of pravastatin was studied by using intestinal brush-border membrane vesicles prepared from rabbit jejunum, and uptake by the membrane vesicles was measured using rapid filtration technique. RESULTS: The initial uptake of [14C]pravastatin was markedly increased with decreases in extravesicular pH and showed a clear overshoot phenomenon in the presence of a proton gradient (pHin/out = 7.5/5.5). A protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, significantly reduced the uptake of [14C]pravastatin. In addition, an ionophore for sodium, potassium and proton, nigericin, stimulated the uptake of [14C]pravastatin in the presence of a potassium gradient ([K+]in/[K+]out = 0/145 mM). On the other hand, neither the imposition of an inwardly directed sodium gradient nor an outwardly directed bicarbonate gradient stimulated the uptake of [14C]pravastatin. In the presence of a proton gradient (pHin/out = 7.5/5.5), the initial uptake of pravastatin was saturable with the apparent Kt of 15.2 +/- 3.2 mM and Jmax of 10.6 +/- 1.21 nmol/mg protein/10 sec. The uptake of pravastatin was significantly inhibited by monocarboxylic acid compounds such as acetic acid and nicotinic acid in a competitive manner but not by di- or tricarboxylic acids, or acidic amino acid. CONCLUSION: It was concluded that a pH-dependent transport of pravastatin across the brush-border membrane occurs by a proton-gradient dependent carrier-mediated mechanism rather than by simple diffusion of its unionized form.
Animals↗
Persistent inhibition of the pressor and aldosterone responses to angiotensin-II by TCV-116 in normotensive subjects.
TCV-116 is an orally active, nonpeptide antagonist of angiotensin-II type-1 receptor. The angiotensin-II antagonistic potency of TCV-116 was evaluated in normal volunteers. TCV-116 was administered at single doses of 1, 2.5, and 5 mg orally on separated days. Before, and 4, 8, and 24 h after the drug administration, angiotensin-II was infused intravenously at the rate of 2.5 to 40 ng/kg/min for 5 min each. At 2.5 mg of TCV-116, the pressor response to angiotensin-II was significantly suppressed at 4 and 8 hours after drug administration. TCV-116 at 5 mg produced a reduction of basal blood pressure and a suppression of pressor response to angiotensin-II, which persisted for 24 h. Aldosterone response to exogenous angiotensin-II was suppressed to 10% at 8 h after 5 mg of TCV-116 administration and remained suppressed to 48% until 24 h. These results suggest that TCV-116 is a highly potent and long-lasting antagonist of angiotensin-II receptor in man. The renin-angiotensin system may play a role in the regulation of blood pressure even in normotensive subjects.
Administration, Oral↗
cGMP upregulates nitric oxide synthase expression in vascular smooth muscle cells.
8-Bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), an analogue of cyclic guanosine monophosphate (cGMP), induced a time- and dose-dependent enhancement of interleukin-1-induced nitric oxide production in vascular smooth muscle cells. Human atrial natriuretic polypeptide, which stimulates cGMP accumulation in vascular smooth muscle cells, also enhanced interleukin-1-induced nitric oxide release at a concentration of 100 nmol/L. In contrast, coincubation with 10 mumol/L methylene blue, an inhibitor of soluble guanylate cyclase, inhibited interleukin-1-induced nitric oxide release from vascular smooth muscle cells. Furthermore, coincubation with 8-Br-cGMP also enhanced the interleukin-1-induced increase in inducible nitric oxide synthase messenger RNA in vascular smooth muscle cells. However, the enhancement of nitric oxide production induced by 8-Br-cGMP was significantly prevented by coincubation with neutralizing antibody against tumor necrosis factor-alpha. Furthermore, 8-Br-cGMP enhanced the interleukin-1-induced increase in tumor necrosis factor-alpha messenger RNA level in vascular smooth muscle cells. These findings indicate that cGMP may upregulate inducible nitric oxide synthase gene expression through the stimulation of tumor necrosis factor-alpha production in vascular smooth muscle cells. Thus, there may be a positive feedback mechanism between nitric oxide and the cGMP system in vascular smooth muscle cells.
8-Bromo Cyclic Adenosine Monophosphate↗
Endothelin-1 enhances nitric oxide-induced cytotoxicity in vascular smooth muscle.
Prolonged incubation with 1 nmol/L interleukin-1 induced high levels of nitric oxide release and cytotoxicity in vascular smooth muscle cells. NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, inhibited interleukin-1-induced cytotoxicity at a concentration of 3 mmol/L. Furthermore, prolonged incubation with 0.1 mmol/L sodium nitroprusside, a nitric oxide donor, also induced cytotoxicity. On the other hand, endothelin-1 at concentrations from 10(-10) to 10(-7) mol/L induced a concentration-dependent enhancement of cytotoxicity induced by interleukin-1. However, endothelin-1 did not affect interleukin-1-induced nitric oxide production. Coculture study of vascular smooth muscle cells and endothelial cells without direct cell contact revealed that incubation for 72 hours with interleukin-1 induced high levels of nitric oxide release from cocultured vascular smooth muscle cells to the same degree as release from vascular smooth muscle cells alone. However, interleukin-1-induced cytotoxicity was more enhanced in cocultured vascular smooth muscle cells than in vascular smooth muscle cells alone. Furthermore, coincubation with 20 nmol/L BQ-485, an antagonist of one type of endothelin receptor (ETA), prevented the enhancement of interleukin-1-induced cytotoxicity in cocultured vascular smooth muscle cells. These findings suggest that endothelin-1 secreted from endothelial cells may enhance nitric oxide-induced cytotoxicity by means of the ETA receptor in vascular smooth muscle cells.
Animals↗
Transient decrease in high blood pressure by in vivo transfer of antisense oligodeoxynucleotides against rat angiotensinogen.
The renin-angiotensin system plays an important role in blood pressure regulation. Angiotensinogen, which is mainly produced in the liver, is a unique component of the renin-angiotensin system, because angiotensinogen is only known as a substrate for angiotensin I generation. It is unclear whether circulating angiotensinogen is a rate-limiting step in blood pressure regulation. Recent findings of genetic studies and analyses suggest that the angiotensinogen gene may be a candidate as a determinant of hypertension. To test the hypothesis that angiotensinogen may modulate blood pressure, we transfected antisense oligonucleotides against rat angiotensinogen into the rat liver via the portal vein using liposomes that contain viral agglutinins to promote fusion with target cells, a technique that has been reported to be highly efficient. Transfection of antisense oligonucleotides resulted in a transient decrease in plasma angiotensinogen levels in spontaneously hypertensive rats from day 1 to day 7 after the injection, consistent with the reduction of hepatic angiotensinogen mRNA. Plasma angiotensin II concentration was also decreased in rats transfected with antisense oligonucleotides. Moreover, a transient decrease in blood pressure from day 1 to day 4 was observed, whereas transfection of sense and scrambled oligonucleotides did not result in any changes in plasma angiotensinogen level, blood pressure, or angiotensinogen mRNA level. Overall, our results demonstrate that transfection of antisense oligonucleotides against rat angiotensinogen resulted in a transient decrease in the high blood pressure of spontaneously hypertensive rats, accompanied by a decrease in angiotensinogen and angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Nitric oxide mediates cytotoxicity and basic fibroblast growth factor release in cultured vascular smooth muscle cells. A possible mechanism of neovascularization in atherosclerotic plaques.
To define the pathophysiological role of nitric oxide (NO) released from vascular smooth muscle cells (VSMC), we examined whether NO released from VSMC induces cytotoxicity in VSMC themselves and adjacent endothelial cells (EC) using a coculture system. Prolonged incubation with interleukin-1 (IL-1) induced large amounts of NO release and cytotoxicity in VSMC. NG-Monomethyl-L-arginine, an inhibitor of NO synthesis, inhibited both NO release and cytotoxicity induced by IL-1. In contrast, DNA synthesis in cocultured EC was not inhibited but rather stimulated by prolonged incubation with IL-1 or sodium nitroprusside (SNP), a NO donor. However, IL-1 and SNP did not stimulate but inhibited DNA synthesis in EC alone. On the other hand, conditioned medium from VSMC incubated for a long period with IL-1 or SNP stimulated DNA synthesis in EC alone. Furthermore, the concentration of basic fibroblast growth factor in the conditioned medium was increased and correlated with the degree of cytotoxicity in VSMC. These results indicate that NO released from VSMC induces VSMC death, which results in release of basic fibroblast growth factor, which then stimulates adjacent EC proliferation. Thus, NO released from VSMC may participate in the mechanism of neovascularization in atherosclerotic plaques.
Animals↗
Identification of a new susceptibility locus for insulin-dependent diabetes mellitus by ancestral haplotype congenic mapping.
The number and exact locations of the major histocompatibility complex (MHC)-linked diabetogenic genes (Idd-1) are unknown because of strong linkage disequilibrium within the MHC. By using a congenic NOD mouse strain that possesses a recombinant MHC from a diabetes-resistant sister strain, we have now shown that Idd-1 consists of at least two components, one in and one outside the class II A and E regions. A new susceptibility gene (Idd-16) was mapped to the < 11-centiMorgan segment of chromosome 17 adjacent to, but distinct from, previously known Idd-1 candidates, class II A, E, and Tap genes. The coding sequences and splicing donor and acceptor sequences of the Tnfa gene, a candidate gene for Idd-16, were identical in the NOD, CTS, and BALB/c alleles, ruling out amino acid changes in the TNF molecule as a determinant of insulin-dependent diabetes mellitus susceptibility. Our results not only map a new MHC-linked diabetogenic gene(s) but also suggest a new way to fine map disease susceptibility genes within a region where strong linkage disequilibrium exists.
Animals↗
Plasma copper and antioxidant status in Wilson's disease.
It has been demonstrated that the level of serum copper unbound to ceruloplasmin (loosely bound copper) is increased in Wilson's disease, although the total serum copper concentration is usually low, reflecting a low ceruloplasmin level. To assess the contribution of free radical reactions catalyzed by nonceruloplasmin copper to the development of complications in this disease, we investigated copper and antioxidant status in four untreated patients who had hepatic dysfunction with or without hemolytic anemia and made a comparison with five patients controlled on penicillamine therapy and 19 age-matched healthy children. We found that loosely bound copper in plasma measured by the phenanthroline assay was detectable in three of four untreated patients with Wilson's disease, but was not detectable in the patients during therapy or in the healthy controls. Among the various antioxidants, the ascorbate and urate levels were markedly reduced before treatment (mean +/- SD, 23 +/- 16 microM for ascorbate and 90 +/- 59 microM for urate) compared with the values in the patients during treatment with penicillamine (67 +/- 19 and 302 +/- 78 microM, p < 0.05) and in control children (60 +/- 8 and 254 +/- 48 microM, p < 0.05). We also demonstrated that the plasma concentration of allantoin, an oxidation product of uric acid and a possible marker of radical generation in vivo, was markedly elevated in the untreated patients (11.0 +/- 1.8 versus 4.3 +/- 0.5 microM in patients on therapy and 6.5 +/- 0.8 microM in controls, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Allantoin↗
Insulin receptor gene polymorphism and hyperinsulinemia in hypertensive patients.
Although insulin resistance often occurs in association with hypertension, considerable variation is observed in the degree of insulin resistance among hypertensive patients. Since there is evidence of a genetic basis in the development of insulin resistance in hypertension, we analyzed the contribution of genetic factors to insulin resistance in hypertensive patients. Sixty-six Japanese hypertensive patients were studied. These patients were divided into two groups (hyperinsulinemia group and normoinsulinemia group) according to plasma insulin response during a 75-g oral glucose tolerance test (75g-OGTT). Insulin receptor gene (INSR) was studied for association with insulin resistance in hypertensive patients. A microsatellite polymorphism in intron-2 of the insulin receptor gene was analyzed by the polymerase chain reaction method. Five alleles were detected in the INSR microsatellite. The frequency of C/C genotype in the hyperinsulinemia group was significantly higher than that in the normoinsulinemia group (73% vs. 43%, p = 0.02). There was no difference in genotype frequency of INSR between hypertensive patients and control subjects. When the hypertensive patients were divided into two groups, the frequency of C/C genotype in the hyperinsulinemia group was significantly higher than that in the control group (73% vs. 45%, p = 0.014). There was no significant difference between the normoinsulinemia group and control group. These data suggest that the insulin receptor gene may contribute to insulin resistance in hypertensive patients with hyperinsulinemia.
Alleles↗
Gap junction protein locus on chromosome 18 cosegregates with body weight in the spontaneously hypertensive rat.
To detect genetic predisposing factors for hypertension, we screened the genome of the spontaneously hypertensive rat (SHR). We determined the genotypes of all F2 rats at polymorphic sites between the two strains, using the DNA of F2 rats derived from mating of SHR and Wistar-Kyoto rats (WKY). Cosegregation analysis was conducted to assess whether the genotypes of polymorphic markers associate with any phenotypic parameters such as directly measured blood pressure, heart rate or body weight. All measurements in F2 rats were performed at 15 weeks of age. Two polymorphic markers on chromosome 18 cosegregated with body weight. Gap junction protein (heart connexin 43) gene showed the most significant association with body weight as a recessive trait, but no association was noted with other parameters. We conclude that the gap junction protein locus is a new candidate for the determinant gene of body weight in SHR.
Analysis of Variance↗
Hormonal mechanisms in blood pressure reduction during hemodialysis in patients with chronic renal failure.
To elucidate the hormonal mechanisms of blood pressure (BP) reduction during hemodialysis in patients with chronic renal failure (CRF), we performed this study using 7 normotensive (NT) and 17 hypertensive (HT) patients who were strictly matched in age, body weight, body weight gain from the last HD, and duration of HD. Blood pressure, pulse rate, plasma norepinephrine (NE), and plasma dopamine levels were used as indices of sympathetic nerve activity, before, at 50% of hemodialysis (HD) and at 100% of HD (at the end of HD) on the third day after the last HD. As hemodialytic BP reduction was defined as BP decline of more than 10% in pre-HD mean BP, in normotensive patients with CRF, hemodialytic BP reduction was recognized in 0/7 (0%) at 50% of HD and 4/7 (57%) at 100% of HD, and in hypertensive patients it was recognized in 3/17 (18%) at 50% of HD and 4/17 (24%) at 100% of HD. Percentile changes in plasma NE levels increased slightly following hemodialysis in normotensive patients with hemodialytic BP reduction and in hypertensives without BP reduction, while those in normotensives without BP reduction and in hypertensives with BP reduction did not change. However, percentage changes in plasma dopamine (DA) levels decreased significantly at the end of HD (NT; p < 0.05, HT; p < 0.01) following hemodialysis in both normotensive and hypertensive patients with hemodialytic BP reduction, while changes in patients without BP reduction, percentage changes in DA did not change (patients with BP reduction vs. patients without BP reduction). In conclusion, hemodialytic BP reduction may be predisposed by abnormal sympathetic nerve responsiveness.
Adult↗
Free and total dopamine in human plasma: effects of posture, age and some pathophysiological conditions.
Although dopamine (DA) has an important role also outside the central nervous system, the physiological significance of DA in the peripheral plasma is not clearly known. In the present study, we assayed the levels of free and total (free plus conjugated) DA in the human plasma to examine the effect of posture, age and some pathophysiological conditions. Nine healthy volunteers were subjected for head up tilt study. For the examination of the effect of age and some pathophysiological conditions, venous blood samples were taken after overnight fast in 64 control subjects who have no obvious disease and patients who had essential hypertension or congestive heart failure (CHF). The plasma free adrenaline (AD), noradrenaline (NA) and DA were determined by a HPLC-diphenylethylenediamine method and total DA was determined by the same HPLC method after acid hydrolysis. After tilting neither free nor total DA changed significantly despite the increased plasma AD and NA levels. Plasma free NA, DA and total DA levels were correlated positively with age in control subjects but not in the hypertensive nor CHF patients. Patients with CHF showed higher levels of plasma free AD, NA and DA and freeDA/totalDA ratio than did in control subjects. We suspect that plasma DA increased with age partially due to change in renal catecholamine handling and cardiac function.
Adolescent↗