[Rickettsial myocarditis].
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Diagnosis, Differential↗
Biomedical subjects
S Morimoto
Publications and source records attributed to S Morimoto.
Molecular cloning of mouse epiregulin, a novel epidermal growth factor-related protein, expressed in the early stage of development.
A cDNA clone encoding a novel epidermal growth factor (EGF)-related growth regulator, epiregulin, was isolated from a cDNA library prepared from a mouse fibroblast-derived tumor cell line, NIH3T3/clone T7. The predicted amino acid sequence revealed that the purified epiregulin peptide of 46-amino acids was synthesized as an internal segment of a 162-amino acid putative transmembrane precursor. The structural organization was similar to that of TGF-alpha precursor among the members of the EGF family. Although epiregulin transcript was not detected in several adult normal tissues by Northern blot analysis, approximately 4.8-kb transcript was present in 7-day-old mouse embryo and then diminished to very low or undetectable levels. Our results suggest that epiregulin may play an important role in the regulation of epithelial cell growth during early development.
3T3 Cells↗
Role of endothelin-1 in hypertension induced by long-term inhibition of nitric oxide synthase.
We examined the effect of long-term nitric oxide (NO) synthase inhibition on vascular and renal endothelin-1 levels and evaluated the antihypertensive effect of endothelin ETA receptor antagonist FR139317 ((R)2(-)[(R)-2(-)[(S)-2(-)[[1-(hexahydro-1H-azepinyl)]- carbonyl]amino-4-methyl-pentanoyl]amino-3(-)[3-(1-methyl-1H- indolyl)]propionyl]amino-3-(2-pyridyl) proprionic acid] on rats in which NO synthase was blocked. Chronic NO blockade was produced by oral administration of the NO synthase inhibitor NG-nitro-L-arginine for 4 weeks, which produced sustained hypertension. At the end of this time, there were no significant changes in aortic and renal immunoreactive-endothelin levels between NG-nitro-L-arginine-treated hypertensive rats and normotensive control rats. Intravenous injection of FR139317 (10 mg/kg), which had a sufficient hypotensive effect on deoxycorticosterone acetate-salt hypertensive rats, to NG-nitro-L-arginine-treated hypertensive rats produced only a moderate hypotensive effect, to the same degree as seen in normotensive rats. The results indicate that long-term NO synthase inhibition did not affect vascular and renal endothelin-1 levels in these rats. It seems likely that endothelin-1 and ETA receptors do not contribute to the sustained hypertension induced by NO synthesis blockade.
Administration, Oral↗
Troponin isoform dependent pH dependence of the Ca(2+)-activated myofibrillar ATPase activity of avian slow and fast skeletal muscles.
The effects of acidic pH were examined on the Ca(2+)-sensitive ATPase activity of chicken fast and slow skeletal muscle myofibrils. In both types of myofibrils the Ca(2+)-sensitivity declined on decreasing pH from 7.4 to 6.2, but the slow skeletal muscle myofibrils were found to exhibit a Ca(2+)-sensitive ATPase activity which was more resistant to acidic pH compared to the fast skeletal muscle myofibrils. The results obtained by using a novel method for replacing whole troponin complex in myofibrils provide the first evidence that troponin is responsible for this higher resistibility of slow skeletal muscle myofibrils to acidosis.
Animals↗
Lysophosphatidylcholine causes Ca2+ influx, enhanced DNA synthesis and cytotoxicity in cultured vascular smooth muscle cells.
The effects of lysophosphatidylcholine (LPC), a vasoactive phospholipid, on intracellular free calcium concentration ([Ca2+]i), DNA synthesis and cytotoxicity of vascular smooth muscle cells (VSMC) were studied. LPC from 10(-7) to 10(-5) mol/l dose-dependently induced a sustained increase in [Ca2+]i. In contrast to the response of [Ca2+]i induced by angiotensin II, that induced by LPC was totally abolished when extracellular Ca2+ was removed, was not affected by pretreatment of the cells with islet-activating protein, and was not desensitized by repeated addition. 8-(N,N-Diethylamino)octyl 3,4,5-trimethoxybenzoic acid (TMB-8), an inhibitor of Ca2+ release from intracellular Ca2+ stores, 1-(5-isoquinolinesulfonyl)-2-methylpiperadine dihydrochloride (H-7), an inhibitor of protein kinase C, KT5823, an inhibitor of protein kinase G, and Ca2+ channel blockers failed to suppress the LPC-induced increase in [Ca2+]i. LPC at 10(-5) mol/l caused significant stimulation of [3H]thymidine incorporation into VSMC, and at concentrations of 10(-5) mol/l and higher dose-dependently stimulated release of lactate dehydrogenase in cell culture supernatants. Moreover, digitonin mimicked the effects of LPC on [Ca2+]i, and also caused similar effects to those of LPC on DNA synthesis and cytotoxicity in VSMC. These observations suggest that LPC causes both cell growth and cell injury of VSMC, at least partly, through its detergent action, causing membrane leakiness and resultant [Ca2+]i overload in vitro, thus indicating the possible participation of LPC in atherosclerosis and/or injury of the vascular wall.
Animals↗
Alterations of bone mineral density of the femurs in hemiplegia.
We evaluated the bone mineral density (BMD) of the bilateral femurs in 112 patients with hemiplegia using dual-energy X-ray absorptiometry in order to elucidate the effect of disuse and immobilization. BMD of the paretic side was significantly reduced compared with that of the non-paretic side in hemiplegic patients (femoral neck 0.582 +/- 0.014 g/cm2 versus 0.623 +/- 0.014 g/cm2 and total femur 0.645 +/- 0.02 g/cm2 versus 0.702 +/- 0.017 g/cm2; mean +/- SEM, P < 0.01, respectively). Femoral BMD in both the paretic and nonparetic limb had significantly (P < 0.01) lower values than in age- and sex-matched controls, but the paretic side had a more significant reduction of BMD; femoral neck -20% versus -14% and total femur -24% versus -18%. In addition, patients with impaired activities of daily living (ADL), evaluated by a mobility score, had significantly decreased BMD ratios of paretic/nonparetic side than patients with improved ADL (femoral neck 91% versus 97%, P < 0.01 and total femur 89% versus 94%, P < 0.05). Our results indicated that BMD of both femurs of patients with hemiplegia was reduced, although the paretic side showed a greater BMD decrease. This decrease might be prevented or reduced by improvement of ADL.
Activities of Daily Living↗
Urinary angiotensin-converting enzyme activity in type 2 diabetes mellitus: its relationship to diabetic nephropathy.
Urinary angiotensin-converting enzyme (ACE) and urinary N-acetyl-beta-D-glucosaminidase (NAG) were measured after a 5-year interval in 38 non-azotemic type 2 diabetic patients. Of these patients at baseline, 16 had nil nephropathy, 15 had incipient nephropathy, and 7 had overt nephropathy. During the follow-up, 6 and 1 of the 16 patients with nil nephropathy developed incipient and overt nephropathy, respectively. Four of the 15 patients with incipient nephropathy progressed to overt nephropathy. The 7 patients with overt nephropathy continued to have overt nephropathy, with slight azotemia in one. Urinary ACE and NAG levels were normal at baseline and showed no significant elevations at follow-up in the patients with nil nephropathy, no significant changes in baseline and modest elevations at follow-up in the patients with incipient nephropathy, and high at baseline and marked elevations at follow-up in the patients with overt nephropathy. In all patients, urinary ACE during the follow-up was positively correlated with urinary albumin or NAG, but not with glomerular filtration rate. Urinary ACE may be of poor prognostic value for the follow-up of diabetic patients, which is at variance with urinary albumin.
Acetylglucosaminidase↗
HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression.
HLA-DRB1 allele typing was performed by the PCR-RFLP method on 59 ulcerative colitis (UC) patients and 136 healthy controls. Phenotypic frequencies of HLA-B52 and DR2 were significantly increased among the UC patients, serologically. DNA typing of HLA-DRB1 revealed that the genotypic frequency of DRB1*1502 was higher in UC than in the controls (49.2% vs 17.6%; P < 0.0001). In the analysis of clinical parameters, 82.8% of patients bearing DRB1*1502 were treated with corticosteroids. DRB1*1501 and DRB1*1502 differ in only one amino acid at residue 86 (valine vs glycine), and 66% of the UC patients carried two glycines at position 86 in the HLA-DR beta-chain (vs 51% of control; P < 0.05). These observations suggest that the presence of Gly-86 in the HLA beta-chain and surrounding amino acid sequence of HLA-DRB1*1502 is strongly associated with susceptibility to UC.
Adolescent↗
Interaction between nitric oxide and angiotensin II on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.
We examined the effects of NG-nitro-L-arginine (NOARG) on antidiuresis and norepinephrine (NE) overflow in anesthetized dogs, induced by renal nerve stimulation (RNS), with or without blockade of an action of endogenous angiotensin II (AII) on the AT1 receptors by losartan. RNS (2.5-5.0 Hz) caused significant reductions in renal blood flow (RBF), glomerular filtration rate (GFR), filtration fraction (FF), urine flow (UF), and urinary excretion of sodium (UNaV) and increases in the differences in renal arteriovenous NE concentrations (NEC). Intrarenal arterial (i.r.a.) infusion of NOARG (40 micrograms/kg/min) significantly decreased RBF and UF, and increased FF, but did not alter GFR. When losartan 100 micrograms/kg/min was infused simultaneously, NOARG reduced RBF, UF, and GFR but had no effect on FF. With high-frequency RNS, NOARG enhanced the RNS-induced decreases in RBF, GFR, UF, and UNaV and the increases in NEC. During losartan infusion, NOARG-induced enhancements on renal actions in response to RNS were observed in a manner qualitatively similar to that without losartan. Most likely endogenous nitric oxide (NO) plays the role of inhibitory modulator of renal noradrenergic neurotransmission. Enhancement of renal noradrenergic neurotransmission induced by NO blockade is likely to be independent of an action of endogenous AII on the AT1 receptors.
Angiotensin II↗
Androgen receptor in the rat pancreas: genetic expression and steroid regulation.
Androgens influence the incidence and prevalence of pancreatic cancer in humans and animal models. To our knowledge there has been molecular demonstration of the presence of neither the androgen receptor (AR) nor transcripts of the AR gene. Reverse-transcription polymerase chain reaction (RT-PCR)-Southern blotting was employed for molecular detection and measurement of the androgen receptor messenger ribonucleic acid (AR mRNA) in pancreas. Total RNA obtained from pancreas, prostate, seminal vesicles, and testes of neonatal and adult male and female rats, as well as castrated males substituted with testosterone cyclopentylate, was analyzed by Northern blot technique. Positive hybridization to AR cDNA was obtained in all tissues assayed but not in the pancreas. However, a clear AR 32P cDNA hybridization signal was obtained in pancreatic tissues after cDNA synthesis using RT-PCR-Southern blotting. The levels of the AR transcripts obtained by RT-PCR in the various pancreatic samples were as follows: adult females and neonatal animals > castrated adult males > adult males > castrated adult males substituted with testosterone. These results indicated that the pancreatic tissue possessed transcriptional activity of the AR gene, although to a lesser extent than the typical androgen responsive tissues (prostate and seminal vesicles). In conclusion, transcriptional activity of the AR gene in the pancreas seemed to be modulated by the androgenic milieu in the tissue similar to that reported for the classical androgen-responsive organs.
Androgens↗
Role of endothelin-1 and the ETA receptor in the maintenance of deoxycorticosterone acetate-salt-induced hypertension.
1. To search for a possible role for endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt-induced hypertension, we examined changes in concentration of ET-1 in vascular and renal tissue in DOCA-salt hypertensive rats and evaluated the antihypertensive effect of the ETA receptor antagonist, FR139317. 2. There was an increase in aortic immunoreactive-ET (IR-ET) concentrations in association with hypertension-induced treatment. There were no significant changes in ET-1 levels in the kidney with DOCA-salt treatment. 3. In DOCA-salt hypertensive rats, a significant correlation (r = 0.83, P < 0.01) was found between aortic IR-ET concentrations and systolic blood pressure. 4. High-performance liquid chromatography analysis of the aortic extract from DOCA-salt rats revealed one major component corresponding to the elution position of synthetic ET-1. 5. The intravenous bolus injection of FR139317 (10 mg kg-1) produced a slight decrease in blood pressure in the control rats and in the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect. 6. We propose that ET-1 production in vascular tissues is increased in DOCA-salt hypertensive rats. In addition, our study indicates the pathophysiological importance of increased endogenous ET-1 in the maintenance of DOCA-salt-induced hypertension, through interaction of the peptide with ETA receptors.
Animals↗
Ca(2+)-insensitive sustained contraction of skinned smooth muscle after acidic ADP treatment.
After an acidic treatment in the presence of ADP, Triton X-100-skinned rabbit aortic smooth muscle strips were found to develop a large sustained, Ca(2+)-insensitive tension when returned to a relaxing solution with neutral pH. The presence of ADP during treatment was essential for the manifestation of the Ca(2+)-insensitive contraction. This contraction was reversibly eliminated by withdrawal of MgATP or addition of vanadate and was found to be accompanied by an extraordinarily high level of 20-kDa myosin light-chain (MLC20) phosphorylation. The rate constant for dephosphorylation of MLC20 in treated strips was about one-twenty-fifth that in untreated control, when determined after removal of Ca2+, Mg2+, and ATP. Two-dimensional phosphopeptide mapping of tryptic digests of MLC20 showed that most incorporated phosphate was in the peptides which would be phosphorylated by myosin light-chain kinase. These results provide strong evidence that ADP inactivates myosin light-chain phosphatase under acidic conditions.
Acids↗
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↗
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↗
Antihypertensive effect of sesamin. I. Protection against deoxycorticosterone acetate-salt-induced hypertension and cardiovascular hypertrophy.
We investigated the antihypertensive effect of sesamin, a lignan from sesame oil, using deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The animals were unilaterally nephrectomized, and then separated into a sham-operated group (sham group) and a DOCA-salt-treated group. The latter was further separated into a normal diet group (control group) and a sesamin-containing diet group (sesamin group). The systolic blood pressure of control group progressively increased in comparison with that of sham group. This DOCA-salt-induced hypertension was markedly suppressed by feeding a sesamin-containing diet. Systolic blood pressure after 5 weeks was 130.6 +/- 1.9 mmHg in the sham group, 198.1 +/- 7.3 mmHg in the control group and 152.5 +/- 8.4 mmHg in the sesamin group, respectively. The treatment with DOCA and salt for 5 weeks significantly increased the weight of the left ventricle plus the septum. However, this increase was significantly suppressed in the sesamin group. When the degree of vascular hypertrophy of the aorta and superior mesenteric artery was histochemically evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in the control group, compared with the sham. Sesamin feeding ameliorated the development of DOCA-salt-induced vascular hypertrophy in both the aorta and mesenteric artery. These findings strongly suggest that sesamin is useful as a prophylactic treatment in the development of hypertension and cardiovascular hypertrophy.
Animals↗
Antihypertensive effect of sesamin. II. Protection against two-kidney, one-clip renal hypertension and cardiovascular hypertrophy.
We investigated the antihypertensive effect of sesamin, a lignan from sesame oil, using two-kidney, one-clip (2K,1C) renal hypertensive rats. After clipping the left renal artery, animals were assigned to either a normal diet group (control group) or a sesamin-containing (1% (w/w)) diet group (sesamin group). The sham-operated rats (sham group) were fed a normal diet and tap water. The systolic blood pressure of the control group increased progressively in comparison with the sham group. This 2K,1C-induced hypertension was markedly reduced by feeding the sesamin-containing diet. The systolic blood pressure after 4 weeks was 123.60 +/- 4.01 mmHg in the sham group, 187.43 +/- 5.69 mmHg in the control group and 145.57 +/- 6.78 mmHg in the sesamin group, respectively. There were significant increases in left ventricle plus septum weight-body weight ratio in the control group compared with the sham group. This rise was also significantly reduced in the sesamin group. When the thoracic aorta was histochemically evaluated, the wall thickness and wall-to-lumen ratio in the control group were significantly increased, compared with the sham group, indicating that vascular hypertrophy had occurred in the control group. The sesamin diet tended to ameliorate this vascular hypertrophy, although its effect was not statistically significant. These findings suggest that sesamin is useful as prophylactic treatment to combat the development of renal hypertension and cardiac hypertrophy.
Animals↗
Effects of phosphoramidon on endothelin-1 and big endothelin-1 production in human aortic endothelial cells.
Using cultured human aortic endothelial cells, we examined the effects of phosphoramidon, an endothelin converting enzyme (ECE) inhibitor, on the release of endogenous endothelin-1 (ET-1) and big endothelin-1 (big ET-1), and on the generation of ET-1 from exogenously applied big ET-1. Phosphoramidon, at concentrations of 10(-6) to 2 x 10(-4) M, caused a biphasic alteration of the ET-1 release, i.e., at lower concentrations of the drug, there were slight but unexpected increases of the release, whereas higher concentrations led to a decrease which is due to the drug-induced inhibition of ECE. The former effect appears to be based on the inhibition of ET-1 degradation by neutral endopeptidase 24.11 (NEP), since kelatorphan, a specific NEP inhibitor, produced a similar increasing effect on ET-1 release. Phosphoramidon enhanced the big ET-1 release from the cells in a concentration-dependent manner. When high concentrations of phosphoramidon were added, there was a dramatic increase in the release of big ET-1, which cannot be explained only by the drug-induced inhibition of ECE. This increase in big ET-1 release appeared to be partly due to a transient stimulation of the expression of prepro ET-1 mRNA. The amount of ET-1 generated from exogenously applied big ET-1 was markedly decreased by phosphoramidon in a concentration-dependent manner. In a similar fashion, phosphoramidon markedly inhibited ECE activity of the membrane fraction of cultured cells. Thus, ET-1 generation from exogenously applied big ET-1 reflects the functional phosphoramidon-sensitive ECE activities in human aortic endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesics↗