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Biomedical subjects

M Yano

Publications and source records attributed to M Yano.

At least 19 recordsLinked to original sources
PubMed1995

Effects of perchlorate on depolarization-induced conformational changes in the junctional foot protein and Ca2+ release from sarcoplasmic reticulum.

Perchlorate is one of the most potent activators of skeletal muscle excitation-contraction (E-C) coupling reported in the literature, but the detailed mechanism of its action remains to be elucidated. In an attempt to further resolve the mode of perchlorate action, the effects of increasing concentrations of perchlorate on the voltage-dependent (T-tubule-mediated) and voltage-independent portions of Ca2+ release were investigated using the isolated triad model. Low concentrations of perchlorate (< or = 10 mM) activated SR Ca2+ release only when the T-tubule moiety was chemically depolarized. Higher concentrations of perchlorate (30-100 mM), on the other hand, produced significant activation of SR Ca2+ release, regardless of whether or not the T-tubule was depolarized. In order to gain further insights, we monitored the conformational change in the junctional foot protein (JFP), which presumably is an important intermediate step in E-C coupling [Yano, M., El-Hayek, R., & Ikemoto, N. (1995) J. Biol. Chem. 270, 3017-3021], using the fluorescently labeled triad preparation. Again, low concentrations of perchlorate (< or = 10 mM) produced a preferential activation of voltage-dependent protein conformational change, while higher concentrations of perchlorate produced significant activation of voltage-independent protein conformational change. An increase in the ryanodine binding by perchlorate occurred only in the higher concentration range where the voltage-independent protein conformational change was activated. These results suggest that perchlorate activates E-C coupling by acting on at least two different steps: at lower concentrations, on the T-tubule-to-JFP signal transmission step; at higher concentrations, on the JFP directly.

Animals↗
PubMed1995

Autocatalytic inactivation of lysosomal cathepsins is associated with inhibition of protein breakdown by insulin-like growth factor-1 (IGF-1) in myotubes.

Protein breakdown was monitored in C2C12 myotubes as the rate of release of radioactivity after prelabeling cell protein with [3H] tyrosine. IGF-1 (13 nM) and insulin (100 nM) prolonged the half-life of long-lived proteins. Enzymatic activities of cathepsins B and B+L were inhibited by the addition of IGF-1 or insulin. Immunoblotting of cathepsins B and L revealed extensive degradation of heavy chain forms by IGF-1. However, neither expression of cathepsins B and L genes nor expression of cystatin beta, an intrinsic inhibitor for cathepsins, was influenced. The addition of E-64, L-3-carboxy-trans-2,3-epoxypropionyl-leucylamide-(4-guanidin o) butane, a inhibitor of cathepsins B and L, increased protein contents of heavy chains of cathepsins B and L in the IGF-1 treated cells. Inhibition of protein breakdown by IGF-1 is mediated by autocatalytic inactivation of lysosomal cathepsins B and L.

Analysis of Variance↗
PubMed1995

Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 myotubes.

1. A cell culture system of C2C12 myotubes was established as a model of the muscle. With the aid of this model, the half-lives of intracellular proteins as well as the activities and mRNA levels of proteasomes (26S and 20S) and cathepsins (B, L, and H) were examined in the presence of various amounts of cytokines. 2. It was found that 100 units/ml recombinant human interleukin-6 somewhat shortened the half-life of long-lived proteins to 23.79 +/- 1.55 h (control: 25.60 +/- 1.87 h). When 1% fetal bovine serum contained in the culture medium was replaced by 0.5 mg/ml bovine serum albumin, interleukin-6 was more effective since 10 units/ml of interleukin-6 shortened the half-life to 19.09 +/- 2.87 h (control: 22.26 +/- 321 h). Interleukin-6 (100 units/ml) increased the activity of 26S proteasome by 31.5%, of cathepsin B by 53.5% and of cathepsin B+L by 21.3%. These increases occurred in association with an increase in their transcription. 3. On the other hand, 1000 units/ml of recombinant human tumour necrosis factor alpha prolonged the half-life of long-lived proteins while reducing the protease activities of 20S proteasome (-27.1%), cathepsins B (-64.6%) and B+L (-54.9%). 4. These results suggest that interleukin-6 induces degradation of long-lived intracellular proteins by activating both the non-lysosomal (proteasomes) and lysosomal (cathepsins) proteolytic pathways. It is therefore concluded that interleukin-6 is a candidate for a proteolysis-inducing factor in myotubes and may play an important role in the progression of muscle degradation in systemic inflammatory responses induced by sepsis or severe injury.

Animals↗
PubMed1995

Catalytic role of an arginine residue in the highly conserved and unique sequence of phosphoenolpyruvate carboxylase.

Phosphoenolpyruvate carboxylase (PEPC) [EC 4.1.1.31] has a highly conserved and unique sequence, 578-FHGRGGSIGRGGAP-591 (on Escherichia coli, PEPC), in which a GRGG motif is repeated twice with two intervening residues. Since previous chemical modification studies suggested the functional importance of arginine residues, the invariant Arg587 in this region was replaced with Ser, and the enzymatic properties of the resulting mutant enzyme (R587S) were investigated. Replacement led to virtual loss of the catalytic activity to form oxaloacetate. The specific activity was 37 nmol.min-1.mg-1, which corresponds to 2 x 10(-4)-fold the activity of the wild-type enzyme. However, the activity of bicarbonate- and Mg(2+)-dependent hydrolysis of phosphoenolpyruvate (PEP) to pyruvate appeared for the mutant enzyme with a specific activity of 2.1 mumol.min-1.mg-1. In view of the stepwise reaction mechanism proposed for PEPC, this activity can be attributed to impairment of the subsequent partial reaction(s) following the formation of the intermediate carboxyphosphate. The half-saturation concentration (S0.5) of HCO3- in R587S was about 100-fold that in the wild-type enzyme, whereas the respective values for PEP and Mg2+ were 20- and 15-fold, indicative of this residue participating in the binding of HCO3-.

Amino Acid Sequence↗
PubMed1995

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat.

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

Animals↗
PubMed1994

Cholangiocytes express the aquaporin CHIP and transport water via a channel-mediated mechanism.

Cholangiocytes line the intrahepatic bile ducts and regulate salt and water secretion during bile formation, but the mechanism(s) regulating ductal water movement remains obscure. A water-selective channel, the aquaporin CHIP, was recently described in several epithelia, so we tested the hypothesis that osmotic water movement by cholangiocytes is mediated by CHIP. Isolated rodent cholangiocytes showed a rapid increase in volume in the presence of hypotonic extracellular buffers; the ratio of osmotic to diffusional permeability coefficients was > 10. The osmotically induced increase in cholangiocyte volume was inversely proportional to buffer osmolality, independent of temperature, and reversibly blocked by HgCl2. Also, the luminal area of isolated, enclosed bile duct units increased after exposure to hypotonic buffer and was reversibly inhibited by HgCl2. RNase protection assays, anti-CHIP immunoblots, and immunocytochemistry confirmed that CHIP transcript and protein were present in isolated cholangiocytes but not in hepatocytes. These results demonstrate that (i) isolated cholangiocytes and intact, polarized bile duct units manifest rapid, mercury-sensitive increases in cell size and luminal area, respectively, in response to osmotic gradients and (ii) isolated cholangiocytes express aquaporin CHIP at both the mRNA and the protein level. The data implicate aquaporin water channels in the transcellular movement of water across cholangiocytes lining intrahepatic bile ducts and provide a plausible molecular explanation for ductal water secretion.

Animals↗
PubMed1994

Cardiovascular effects of intrathecally administered endothelins and big endothelin-1 in conscious rats: receptor characterization and mechanism of action.

In conscious rats, the intrathecal (i.t.) injection of endothelin-1 (ET-1; 65-650 pmol) and endothelin-3 (ET-3; 162-650 pmol) produced dose-dependent increases of mean arterial blood pressure (MAP) accompanied by either a tachycardia or a bradycardia. A number of animals died by a sudden respiratory arrest. ET-3 was less toxic and less potent than ET-1 on MAP and heart rate (HR) while BQ-3020, a selective ETB agonist, had no toxic effect and exhibited only a weak pressor effect on blood pressure. The prior i.t. injection of 65 nmol BQ-123, a selective ETA receptor antagonist, blocked both the cardiovascular and toxic effects of ET-1 but failed to modify the cardiovascular effect evoked by i.t. substance P (6.5 nmol) or to cause intrinsic cardiovascular and toxic effects. While the pressor response to ET-1 was significantly inhibited after i.v. injection of phentolamine, the bradycardia was blocked by pentolinium. The cardiovascular response to ET-1 was, however, unaffected in rats either sympathectomized with 6-hydroxydopamine or pretreated with capsaicin. Furthermore, big ET-1 (100 pmol) caused toxic effects and delayed cardiovascular changes which were prevented by the prior i.t. administration of either BQ-123 (65 nmol) or 100 nmol phosphoramidon, an endothelin-converting enzyme (ECE) inhibitor. These results suggest: (1) that the cardiovascular and toxic effects of i.t. endothelins are mediated by ETA receptors in the rat spinal cord; (2) that the pressor response and bradycardia are likely due to the activation of the sympatho-adrenal nervous system and to a vagal reflex mechanism, respectively; and (3) that a phosphoramidon-sensitive ECE converts big ET-1 to ET-1 in the rat spinal cord.

Amino Acid Sequence↗
PubMed1994

Dual cardiovascular effects of endothelin-1 dissociated by BQ-153, a novel ETA receptor antagonist.

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide that elicited both vasodilator and vasoconstrictor responses in anesthetized pigs. Within 1.0 min after the first injection of ET-1 (0.4 nmol/kg, intravenously, i.v.) there was a transient decrease in mean arterial pressure (MAP 82 +/- 4 to 64 +/- 5 mm Hg; p < or = 0.01). The vasodepressor response was accompanied by reductions in left ventricular (LV) + dp/dtmax (1,834 +/- 104 to 1,493 +/- 87 mm Hg/s, p < or = 0.001), LV - dp/dt (2,600 +/- 149 to 1,865 +/- 136 mm Hg/s; p < or = 0.001) and cardiac output (CO 2.6 +/- 0.1 to 2.0 +/- 0.1 L/min, p < or = 0.001). The short (< 3.0 min) vasodilatory phase was followed by a prolonged (> 15 min) vasopressor response in which MAP (82 +/- 4 to 103 +/- 5 mm Hg; p < or = 0.001) and pulmonary arterial pressure (PAP 11 +/- 1 to 15 +/- 1 mm Hg; p < or = 0.01) increased. With each subsequent dose (0.4 nmol/kg i.v.) of ET-1, the initial vasodilatory component diminished progressively, only a monophasic vasoconstrictor response was observed after the fourth dose. The reductions in CO progressively decreased from 2.6 to 0.1 to 1.7 +/- 0.1 L/min (p < or = 0.001) by the end of the experiment. In contrast to the systemic circulation effects, ET-1 produced consistent and reproducible reductions in renal blood flow (RBF 105 +/- 16 to 21 +/- 6 mm Hg; p < or = 0.004) that lasted approximately 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Suppression of proliferative responses of lymphocytes to food antigens by an anti-allergic drug, ketotifen fumarate, in patients with food-sensitive atopic dermatitis.

Experimental studies have shown that ketotifen fumarate inhibits reaginic antibody-mediated hypersensitivity reactions. In this study, the proliferative responses of peripheral blood mononuclear cells (PBMCs) to ovalbumin (OA) in children with atopic dermatitis (AD), who are sensitive to hen's egg, were significantly higher than those of healthy children. The proliferative responses of PBMCs to OA were dose-dependently inhibited by ketotifen in patients with hen's egg-sensitive AD. Moreover, the inhibition resulted from the effects of ketotifen on T cells. In contrast, the proliferative responses of PBMCs to phytohemagglutinin and tetanus toxoid were not inhibited by ketotifen. These results suggest that ketotifen inhibits food antigen-specific proliferative responses of PBMCs in patients with food-sensitive AD.

Child, Preschool↗
PubMed1994

[A case of nonseminomatous germ cell tumor: usefulness of alphafetoprotein subfraction].

Alfa-fetoprotein (AFP) is an indispensable examination in the management of non-seminomatous germ cell tumor. However, many liver diseases also frequently show the elevation of AFP. Therefore, it is essential to discriminate between yolk sac-derived component and liver-derived one. A 32-year-old male who had suffered from chronic hepatitis, visited our clinic in December, 1991. He complained of left scrotal atrophy and dull pain. Surgical specimen was histologically diagnosed as embryonal carcinoma with syncytiotrophoblastic giant cell. The levels of tumor markers, such as AFP, beta-human chorionic gonadotropin (beta-HCG), were estimated. Both of them were elevated, and radiographical studies demonstrated metastatic lesions of bilateral lung field and retroperitoneal lymph nodes (RPLN). After three courses of cisplatin based chemotherapy, lung and RPLN metastases diminished and serum beta-HCG had normalized. However, the serum AFP persisted to show an abnormally high concentration. The subfraction profile with lens culinaris hemagglutinin (LCA) was estimated. The one after the first course was compared with the one after third course. The latter one showed complete diminution of peak 2. This implied the diminishment of yolk sac element.

Adult↗
PubMed1994

[The indication and the evaluation of IFN treatment of chronic hepatitis C].

The indication and the evaluation of IFN treatment for chronic hepatitis type C has been discussed. Good response to IFN depend on the level of HCV RNA just before the treatment. The patients who has low level of HCV RNA (less than 1 Meq/ml by DNA probe assay) could be able to estimate the response more than 80%. On the contrary, it is less than 10% for the patients with high level of HCV RNA. The evaluation of IFN treatment for chronic hepatitis were divided into 3 groups. Cure was defined as the continuous normalization of serum ALT and disappearance of HCV RNA during 12 month or more after the treatment. Partial response was defined as continuous normalization of ALT level but positive for HCV RNA. The others were defined as non responder. First and second group should be evaluated for the IFN treatment. Final purpose for IFN treatment should be prevent to develop liver cirrhosis or hepatocellular carcinoma.

Alanine Transaminase↗
PubMed1994

[Long-term prognosis after interferon therapy in chronic hepatitis type C].

263 patients with chronic hepatitis C who received interferon therapy were followed up for an average 2.7 years after therapy. 36% of patients showed complete response, 16% of patients showed partial response, 48% of patients showed no response. 96 patients underwent liver biopsy after therapy and were observed long-term prognosis. 13 cases developed to liver cirrhosis. Histopathology before and after interferon, HCV-DNA probe before therapy were examined.

Adult↗
PubMed1993

The ligand-receptor interactions of the endothelin systems are mediated by distinct "message" and "address" domains.

Pharmacologic responses to endothelins (ETs) are mediated by two subtypes of G-protein-coupled receptors, termed ETA and ETB. A chimeric receptor that has the transmembrane domains (TMDs) IV-VI with the adjacent loop regions from ETB embedded in the remaining regions from ETA exhibits specific binding to the N-terminally truncated ETB agonists 125I-BQ3020 and 125I-IRL1620, to the same level as that of wild-type ETB receptor. Furthermore, the ETA-selective antagonist BQ123 competed for the binding of these ETB-selective radioligands to this chimeric receptor, with Ki values similar to those determined by using wild-type ETA receptor and 125I-ET-1. These findings indicated that the endothelin systems consist of two distinct parts, both on the ligand and receptor sides. The N-terminal loop structure of the agonists and the TMDs IV-VI with adjoining loops of the receptors determine the isopeptide/subtype selectivity. On the other hand, the C-terminal linear portion of the isopeptides and the TMDs I-III and VII plus adjacent loops of the receptors are probably involved in ligand-receptor binding itself. This scheme can be explained by the classic "message-address" concept proposed for a number of peptidergic ligand families.

Binding, Competitive↗
PubMed1993

Two receptor subtypes are involved in the contractile component of the guinea pig ileum responses to endothelins.

Endothelin-1 (ET-1) and endothelin-3 (ET-3) induced a biphasic response (relaxation and contraction) in the guinea pig ileum. Short-term activation of protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu) inhibited the contractile but not the relaxing component of the responses, as did H-7. Long-term pretreatment with PDBu reversed the short-term inhibition but did not affect the tachyphylaxis induced by ET-1. These results suggest that PKC contributes to ET-1 contraction but not to tachyphylaxis. The ETA antagonist BQ-123, at 34 nM, competitively inhibited ET-1 contraction, but at 340 nM the inhibition was noncompetitive. Dose-response curves for ET-1 relaxation were shifted to the left. For ET-3, BQ-123 (340 nM) only decreased the maximal contractile response of the dose-response curve without affecting the relaxation. We suggest that in this tissue there is one receptor for ET-1-induced contraction, which is competitively antagonized by BQ-123, and another one for ET-3-induced contraction, which is noncompetitively antagonized by BQ-123.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

ETA-dependent pressor effects and release of prostacyclin induced by endothelins in pulmonary and renal vasculature.

BQ-123, a selective endothelin A (ETA) receptor antagonist, was used to study the receptors involved in the ET-1-induced release of prostacyclin (PGI2) in perfused rat lung and rabbit kidney and the pressor effects of ET-1 in rabbit renal vasculature. In perfused rat lung, infusion of ET-1 (5 nM) significantly increased the release of PGI2, which was markedly reduced after a 15-min infusion of BQ-123 (1 microM). In rabbit kidney, the PGI2 release induced by ET-1 (10 nM) was abolished by a 15-min pretreatment with BQ-123 (1 microM). In both preparations the ET-1-induced release of PGI2 was fully restored 60 min after the interruption of BQ-123 infusion. In rabbit kidney a dose-dependent increase of perfusion pressure was also observed after bolus injections of ET-1 (5 and 10 pmol). The pressor responses to ET-1 were abolished by BQ-123 (0.1 microM), and 60 min after interruption of the infusion of the antagonist, the responses to ET-1 were restored to 68% and 99% of control values, respectively. Two selective ETB receptor agonists, IRL 1620 and BQ-3020, were inactive as pressor and prostanoid-releasing agents at doses and concentration 25-50 times higher than for ET-1 in perfused rabbit kidney. A higher concentration of BQ-123 (1 microM) did not modify the pressor responses to angiotensin II (5 nmol). Our results support the hypothesis that ET-1-induced release of vasodilatory prostanoids from perfused rat lung and rabbit kidney and constriction of rabbit renal vasculature are triggered by activation of ETA receptors.

Animals↗
PubMed1992

Suppressive effects of the endothelin receptor (ETA) antagonist BQ-123 on ET-1-induced reduction of lipoprotein lipase activity in 3T3-L1 adipocytes.

Endothelin (ET)-1 reduced heparin-releasable lipoprotein lipase (LPL) activity in 3T3-L1 adipocytes in a concentration-dependent manner. However, a selective ETB receptor agonist, [Ala1,3,11,15]ET-1, did not act like ET-1. The ET-1-induced decrease in LPL activity was suppressed by a selective ETA receptor antagonist, BQ-123: the concentration-response curve for the ET-1 reduction of LPL activity was shifted to the right in the presence of BQ-123 in a concentration-dependent manner. This antagonistic effect of BQ-123 clarifies that the ETA receptor is responsible for the ET-1-induced reduction of LPL activity in 3T3-L1 adipocytes, which suggests that there is therapeutic potential for ETA antagonists in LPL-related lipoprotein disorders.

3T3 Cells↗
PubMed1992

Protective effect of a selective endothelin receptor antagonist, BQ-123, in ischemic acute renal failure in rats.

To elucidate the pathophysiological role of endogenous endothelin (ET), we examined the effects of the newly synthesized ETA receptor-selective antagonist, BQ-123, on ischemic acute renal failure induced by bilateral clamping of renal artery and vein followed by reperfusion in rats. BQ-123, when given by i.v. infusion of 0.5 mg/kg per min for 2.5 h during the pre- and post-ischemic period, was found to prevent the decrease in creatinine clearance and increases in blood urea nitrogen, plasma creatinine and the fractional excretion of sodium. Morphological observation also showed an effect of BQ-123, i.e. prevention of proximal tubular (S3 segment) necrosis. At 2 h after the start of reperfusion, the ET-1 content in the kidney increased to its maximal level. At this time, the Ca2+ content in the mitochondrial fraction of the renal cortex increased, with a concomitant increase in blood urea nitrogen. However, these increases were limited by treatment with BQ-123. Thus, BQ-123 was effective to both prevent mitochondrial Ca2+ accumulation in the early phase of ischemic acute renal failure and protect proximal tubular cells from post-ischemic degeneration. We conclude that ET may be at least partially involved in the pathogenesis of tubular cell injury in this acute renal failure model.

Acute Kidney Injury↗