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Biomedical subjects

A Noma

Publications and source records attributed to A Noma.

At least 37 records · Page 2Linked to original sources
PubMed1998

Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes.

Anthranilic acid (AA) has attracted considerable attention as one of the L-tryptophan-kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 +/- 0.1 nmol/liter, which were 5. 7-33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations of L-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146-516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3-23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.

Animals↗
PubMed1998

Stimulatory effects of lipoprotein(a) and low-density lipoprotein on human umbilical vein endothelial cell migration and proliferation are partially mediated by fibroblast growth factor-2.

We previously reported a transient increase in plasma lipoprotein(a) (Lp(a)) concentrations following acute myocardial infarction and surgical operations, and demonstrated Lp(a) accumulation in healing tissues. In the present study, the stimulatory effect of Lp(a) on migration and proliferation of human umbilical vein endothelial cells (HUVEC) was assessed by quantitative assay methods and compared it with that of LDL. Lp(a) stimulated both migration and proliferation of HUVEC in a dose-dependent manner and the stimulatory activities for migration and proliferation were two times higher than those of LDL in terms of moles of apoB. In addition, this stimulatory activity of Lp(a) was not affected by the difference of Lp(a) phenotype. Although each neutralizing antibody to hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and interleukin-1beta (IL-1beta) had no further effect on migration and proliferation of HUVEC treated with Lp(a), only antibody to fibroblast growth factor-2 (FGF-2) partially suppressed them. Moreover, pertussis toxin, which inhibits FGF-2-stimulated endothelial cell movement, also partially suppressed Lp(a)-induced HUVEC migration. FGF-2 concentrations in the medium of HUVEC treated with Lp(a) were constant in spite of the increase in FGF-2 mRNA levels in HUVEC. Taken together, it is suggest that Lp(a) stimulates HUVEC migration and proliferation, which is mediated, at least in part, by FGF-2 and may promote the angiogenesis during wound healing.

Antibodies↗
PubMed1998

Interaction of the Na+-K+ pump and Na+-Ca2+ exchange via [Na+]i in a restricted space of guinea-pig ventricular cells.

1. The whole-cell Na+-K+ pump current (INa-K) and Na+-Ca2+ exchange current (INa-Ca) were recorded in guinea-pig ventricular myocytes to study the interaction between the two Na+ transport mechanisms. 2. INa-K was isolated as an external K+-induced current, and INa-Ca as an external Ca2+- induced or Ni2+-sensitive current. The experimental protocol used for one ion carrier did not affect the other. 3. The amplitude of INa-K decreased to 54 +/- 17 % of the initial peak during continuous application of K+ with 20 mM Na+ in the pipette. The outward INa-Ca, which was intermittently activated by brief applications of Ca2+, decreased during activation of INa-K, and recovered after cessation of INa-K activation. These findings revealed a dynamic interaction between INa-K and INa-Ca via a depletion of Na+ under the sarcolemma. 4. To estimate changes in Na+ concentration ([Na+]i) under the sarcolemma, the reversal potential (Vrev) of INa-Ca was measured. Unexpectedly, Vrev hardly changed during activation of INa-K. However, when INa-Ca was blocked by Ni2+ at the same time that INa-K was activated, Vrev changed markedly, maximally by +100 mV, immediately after the removal of Ni2+ and K+. 5. Subsarcolemmal [Na+]i was calculated from the Vrev of INa-Ca on the assumption that the subsarcolemmal Ca2+ concentration ([Ca2+]i) was fixed with EGTA, and mean [Na+]i was calculated from both the time integral of INa-K and the cell volume. The subsarcolemmal [Na+]i was about seven times greater than the mean [Na+]i. 6. The interaction between the Na+-K+ pump and Na+-Ca2+ exchange was well simulated by a diffusion model, in which Na+ diffusion was restricted to one-seventh (14 %) of the total cell volume.

Animals↗
PubMed1998

IL-1 beta and TNF-alpha suppress apolipoprotein (apo) E secretion and apo A-I expression in HepG2 cells.

The effect of cytokines on apolipoprotein E (apo E) production and secretion was investigated in a human hepatoma cell line HepG2. Incubation of HepG2 cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF-alpha) for 48 h resulted in a significant dose-related decrease of apo E concentration in the culture medium, while intracellular apo E content increased without change in mRNA level. In contrast, IL-1 beta and TNF-alpha decreased both intracellular and medium apo A-I. Elution profiles of cholesterol and apolipoproteins revealed that apo E was present in apo E-rich high density lipoprotein (HDL) fraction and apo A-I was in apo E-rich HDL and small HDL fractions. IL-1 beta and TNF-alpha decreased both apo E and apo A-I in these fractions. The present results suggest that IL-1 beta and TNF-alpha suppress hepatic apo A-I expression and secretion but not expression of apo E, which could contribute to the abnormal lipid metabolism in certain cytokine-mediated inflammatory diseases.

Apolipoprotein A-I↗
PubMed1998

The inhibitory effect of propranolol on ATP-sensitive potassium channels in neonatal rat heart.

1. Whole cell and single channel recordings of ATP-sensitive K+ current (I(K,ATP)) were carried out in ventricular myocytes isolated from neonatal rat hearts. 2. (+/-)-Propranolol, a commonly used beta-blocker, inhibited the whole cell I(K,ATP) in a concentration-dependent manner with a half-maximal concentration (IC50) of 6.7 +/- 1.4 microM, whereas it blocked the inward rectifier K+ current (I(K,I)) only at much higher concentrations (IC50 = 102.4 +/- 20.2 microM). The inhibition was time- and voltage-independent. 3. In the outside-out patch configuration, (+/-)-propranolol inhibited I(K,ATP) (IC50 = 9.8 +/- 2.9 microM) by decreasing the open probability of the channel without inducing additional noise in the open-channel current or a decrease of single channel conductance. The single channel current of I(K,I) was also blocked by (+/-)-propranolol in the same way as I(K,ATP). 4. (+)-Propranolol, an optic isomer having no beta-blocking effect, inhibited I(K,ATP) (IC50 = 5.8 +/- 1.0 microM), whilst atenolol, a selective beta1-blocker had no effect. Neither GDPbetaS (1 mM) nor GTPgammaS (200 microM) included in the pipette solution modulated the inhibitory effect of (+/-)-propranolol. 5. We concluded that the inhibitory effect of (+/-)-propranolol was not via the beta-adrenergic signal transduction pathway, but by direct inhibition of I(K,ATP) channels.

Adenosine Triphosphate↗
PubMed1998

Apo A-I and apo E concentrations in cerebrospinal fluids of patients with acute meningitis.

It has been demonstrated that apolipoproteins found in cerebrospinal fluid (CSF) play an important role in lipid metabolism in the central nervous system (CNS). Previously we reported that CSF apo A-I levels increased with the severity of neurological damage in poliovirus-infected macaques. In the present study, apo A-I was quantitatively analysed in CSF from patients with or without neurological diseases. In controls, CSF apo A-I level was significantly higher in males; 3.83 (0.40) mg/L, mean (SEM) (n = 19) compared with females, 2.42 (0.26) mg/L (n = 23, P < 0.05). CSF apo A-I concentrations in patients with acute meningitis increased at the active stage, 7.74 (1.78) mg/L (n = 10), but returned to basal concentrations at the convalescent stage 2.72 (0.38) mg/L (n = 10), while the CSF apo A-I level in patients with other neurological diseases remained in the same range as in controls. By contrast, CSF apo E was consistently elevated at either stage of acute meningitis. Furthermore, it was found that the levels of CSF apo A-I, but not of apo E, correlated positively with CSF albumin concentrations. These findings suggest that the CSF apo A-I and apo E have different origins and may play different roles in the lipoprotein metabolism in CNS.

Acute Disease↗
PubMed1997

Cerebrospinal fluid apo E and apo A-I concentrations in early- and late-onset Alzheimer's disease.

We compared cerebrospinal fluid (CSF) apolipoprotein (apo) A-I and apo E concentrations in early- and late-onset Alzheimer's disease (EOAD (n = 11), LOAD (n = 15), respectively) with those in control subjects (n = 23). CSF apo A-I levels in both EOAD and LOAD were consistent with control subjects. However, CSF apo E levels were significantly lower in EOAD group (mean +/- SD; 2.65 +/- 1.69 mg/l, P < 0.05) and higher in LOAD group (5.90 +/- 1.94 mg/l, P < 0.01) than those in control group (4.16 +/- 1.69 mg/l). In addition, the epsilon4 allele frequency was not different between EOAD and LOAD groups. Although the reason for the difference in CSF apo E concentrations between two groups is unknown, CSF apo E concentration seems to be associated with the pathogenesis of EOAD and LOAD. The rate of apo E production and/or catabolism in the brain may be different between them.

Aged↗
PubMed1997

Marked increases in concentrations of apolipoprotein in the cerebrospinal fluid of poliovirus-infected macaques: relations between apolipoprotein concentrations and severity of brain injury.

Apolipoproteins in cerebrospinal fluid (CSF) might have important functional roles in the pathophysiology of brain and lipid metabolism in the vascular component. The present study examined apolipoprotein A-I (apo-A-I) and apolipoprotein E (apo-E) levels in CSF and serum from poliovirus-infected macaques. Poliovirus-infected macaques developed motor deficits and were classified into three groups: (1) muscle weakness in one or both legs; (2) partial paralysis in one or both legs; (3) complete paralysis in one or both legs. No motor deficits were evident in the control or sham-treated macaques. Apo-A-I concentrations in CSF were markedly elevated in poliovirus-infected macaques with weakness, partial or complete paralysis, in comparison with either control or sham-treated animals, and were proportional to the severity of motor impairment. Apo-E concentrations in CSF were also significantly elevated in poliovirus-infected macaques with complete paralysis. The magnitude of increase in CSF apo-A-I or apo-E concentrations was also closely associated with the degree of histologic neurological damage and inflammation (lesion scores). However, no changes in serum apo-A-I and apo-E concentrations were observed in the poliovirus-infected macaques compared with control macaques. Furthermore there were no significant correlations apo-A-I or apo-E concentrations between serum and CSF. We hypothesize that the elevation of apo-A-I and apo-E concentrations after poliovirus infection is caused by immune stimulation within the central nervous system (CNS). Measures of CSF apo-A-I and apo-E levels might serve as a useful marker for the severity and/or the range of CNS injury.

Animals↗
PubMed1997

The sustained inward current in sino-atrial node cells of guinea-pig heart.

Single myocytes were dissociated from the sino-atrial (SA) node of guinea-pig hearts. Only a quite small fraction of the cell population showed spontaneous action potentials and these cells were characterized by the presence of the hyperpolarization-activated cation current If , the delayed rectifier K+ current IK and the L-type Ca2+ current ICa,L as well as by the absence of both the transient outward current Ito and the inward rectifier K+ current IK, 1. After blocking If and IK, depolarizing pulses from -80 mV revealed a large nicardipine-sensitive late current (NSLC). The NSLC was scarcely affected by decreasing extracellular [Ca2+] ([Ca2+]o) from 1.8 to 0.1 mM, while it was decreased significantly by depleting [Na+]o, differently from ICa,L. NSLC was blocked by nicardipine and was increased by Bay K 8644. NSLC was increased by isoprenaline and the additional application of acetylcholine reversed the increase of this current. We conclude that NSLC is largely composed of Ist described in the rabbit SA node pacemaker cells, and that Ist is unique for the pacemaker cells in mammalian SA node cells. Most of the quiescent cells showed neither If nor Ist.

Animals↗
PubMed1997

Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure.

OBJECTIVES: This study sought to examine plasma levels of soluble Fas/APO-1 receptor (sFas), an inhibitor of apoptosis, and soluble Fas ligand (sFas-L), an inducer of apoptosis, and their relation to each other and to other clinical variables, such as New York Heart Association functional class, tumor necrosis factor (TNF) and interleukin-6 (IL-6) in congestive heart failure (CHF). BACKGROUND: It has been recently reported that apoptotic cell death occurs in myocytes of dogs with CHF. Hypoxia is frequently seen in advanced CHF and can stimulate Fas/APO-1 receptors (Fas) to induce apoptosis in cultured myocytes. Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules. Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L. However, plasma sFas, a molecule lacking the transmembrane domain of Fas, blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L on the cell membrane. At present, it is unknown whether plasma sFas-L and plasma sFas increase in the presence of cardiac disease. METHODS: The study included 70 patients (mean [+/-SEM] age 65 +/- 2 years, range 21 to 93) with chronic CHF (coronary artery disease in 28, dilated cardiomyopathy in 27, valvular heart disease in 15) and 62 age- and gender-matched normal control subjects. Plasma levels of sFas, sFas-L, TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assays using monoclonal anti-human antibodies. RESULTS: There was no significant difference in sFas-L levels between normal subjects and patients in functional classes I to IV; however, sFas increased with severity of functional classification, independent of the underlying disease. sFas levels were significantly higher even in patients in functional class II than in normal subjects and those in functional class I, and were highest in patients in functional class IV (normal subjects; 2.2 +/- 0.1 ng/ml; functional class I: 2.2 +/- 0.2 ng/ml; functional class II: 3.1 +/- 0.2 ng/ml; functional class III: 3.9 +/- 0.3 ng/ml; functional class IV: 5.1 +/- 0.6 ng/ml). Plasma sFas levels were significantly higher in patients with elevated pulmonary artery wedge pressure and a decresed cardiac index than in those with values in the normal range. In patients in functional class IV, there was no significant difference in plasma sFas levels between the survivors and non-survivors during 6-month follow-up. However, plasma levels of sFas tended to decrease in nine patients with clinical improvement (baseline sFas: 5.2 +/- 0.8 ng/ml; 6-month sFas: 4.3 +/- 0.5 ng/ml, p = 0.07) but were similar in patients with no change in functional class. TNF-alpha and IL-6 were increased significantly only in patients in functional class IV, as previously reported, but were not related to sFas. CONCLUSIONS: We found elevated levels of plasma sFas and no increase in plasma sFas-L in human CHF. The increase in sFas may play an important role in the pathophysiologic mechanisms of CHF.

Aged↗
PubMed1997

Effects of dopamine on L-type Ca2+ current in single atrial and ventricular myocytes of the rat.

1. The effects of dopamine on the L-type Ca2+ current (ICa,L) of both atrial and ventricular single myocytes and on the force of contraction of atrial trabeculae in rat heart were investigated. 2. Dopamine increased atrial ICa,L at concentrations higher than 1 microM, but had little or no effect on ICa,L at lower concentrations. The increase in ICa,L at high concentrations was reversed by propranolol and acetylcholine, but not by phentolamine. Activation and inactivation kinetics of ICa,L were not altered by dopamine. 3. In rat ventricular myocytes in which the D4 receptor mRNA does not express, dopamine (20-100 microM) also increased the ICa,L amplitude and propranolol reversed this effect. 4. Clozapine, a potent D4 receptor antagonist, blocked the augmenting effect of dopamine on ICa,L. However, this effect could be explained by beta-antagonism, since clozapine also inhibited the isoprenaline effect. 5. In the atrial trabeculae, the increase in contraction by dopamine (1 to 30 microM) was reversed by 1 microM propranolol, but not by 2 microM phentolamine. Low doses of dopamine (0.01 to 0.3 microM) did not affect the contraction in the controls or during a modest stimulation of the beta-adrenoceptor with 0.01 microM isoprenaline. 6. These results indicate that the positive inotropic action of dopamine is mediated through direct stimulation of the beta-adrenoceptor in both atrial and ventricular myocytes. Involvement of D4 receptor appears unlikely in the regulation of the atrial contraction.

Animals↗
PubMed1997

Regulatory volume decrease of cardiac myocytes induced by beta-adrenergic activation of the Cl- channel in guinea pig.

A new method was developed to automatically measure the thickness of a single ventricular myocyte of guinea-pig heart. A fine marker was attached on the cell's upper surface and changes in its vertical position were measured by focusing it under the microscope. When the osmolarity of the bath solution was varied, the cell thickness reached a new steady level without any obvious regulatory volume change within the period of observation up to 15 min. The cell thickness was 7.8 +/- 0.2 microns (n = 94) in the control Tyrode solution and was varied to 130.4 +/- 3.1% (n = 10), 119.1 +/- 1.1% (n = 50), 87.2 +/- 1.9% (n = 9), and 75.6 +/- 3.2% (n = 5) of control at 50, 70, 130, and 200% osmolarity, respectively. The application of a Cl- channel blocker, 500 microM anthracene-9-carboxylic acid (9AC) did not modify these osmotic volume changes. We discovered that the application of isoprenaline induced a regulatory volume decrease (RVD) in cells inflated by hypotonic solutions. This isoprenaline-induced RVD was inhibited by antagonizing beta-adrenergic stimulation with acetylcholine. The isoprenaline-induced RVD was mimicked by the external application of 8-bromoadenosine 3':5'-cyclic monophosphate. The RVD was inhibited by blocking the cAMP-dependent Cl- channel (ICl, rAMP) with 9AC but was insensitive to 4,4'-diisothiocyanostilbene-2,2'-dissulphonate (DIDS). Taken together these data suggest an involvement of ICl, cAMP activation in the RVD. Whole cell voltage clamp experiments revealed activation of ICl, cAMP by isoprenaline under the comparable conditions. The cardiac cell volume may be regulated by the autonomic nervous activity.

Adrenergic beta-Agonists↗
PubMed1997

Development of muscarinic potassium current in fetal and neonatal rat heart.

Single atrial myocytes were isolated from fetal, neonatal, and adult rat hearts. The muscarinic K+ current activated by rapid application of acetylcholine (ACh) and adenosine (Ado) was recorded under the whole cell voltage clamp. The current density (pA/pF) of ACh-induced K+ current increased from gestation day 12 to the maximum on neonatal day 20 and decreased in the adult myocytes due to greater increase of the membrane capacitance. The development of Ado-induced K+ current followed a similar time course except for a remarkable decrease after neonatal day 10. No significant change was found in single-channel properties during the development. Receptor subtypes were M2 and A1 receptors for ACh and Ado, respectively. In the dose-response relationship, the half-maximal concentration for ACh-induced current markedly decreased with age, from 1.44 (fetus) to 0.17 microM (adult), whereas that for Ado increased from 0.45 (fetus) to 0.99 microM (adult). These changes of the muscarinic K+ current were discussed in relation to the functional development of cardiac myocytes and underlying mechanisms.

Acetylcholine↗
PubMed1997

Development of inwardly rectifying K+ channel family in rat ventricular myocytes.

The ATP-sensitive K+ current (I(K,ATP)), the inward rectifier K+ current (I(K1)), and the acetylcholine-activated K+ current (I(K,ACh)) were recorded in fetal, neonatal, and adult rat ventricular myocytes using the patch-clamp technique. The density (pA/pF) of I(K1) increased from gestation day 10 through neonatal day 1 and then decreased after neonatal day 30. The density of I(K,ATP) activated maximally by metabolic inhibition changed in parallel with the I(K1) density, and the density of I(K,ATP) channel distribution was 1.3 times higher than that of I(K1) throughout the development. We failed to observe developmental changes in the single-channel conductance and the mean open time of I(K1) and I(K,ATP) channels. However, the open probability of the I(K,ATP) channel was lower in fetuses, and the sensitivity to ATP was highest in 1-day neonates. I(K,ACh) were present in the ventricle at all stages of development but at a much lower density than in atrium. The relationship between the resting membrane potential and the development of the inwardly rectifying K-channel family is discussed.

Adenosine Triphosphate↗
PubMed1997

Immunolocalization of lipoprotein(a) in wounded tissues.

Fifty samples from inflamed tissues were examined by immunohistochemical techniques, using antibodies against apo(a), apo B, plasminogen, fibrinogen, proliferating cell nuclear antigen (PCNA), and various components of extracellular matrix. The immunohistochemical features of granulation tissues were characterized by different stages of wound healing. In the first stage, immunoreactivities for anti-apo(a) and anti-apo B were weak and focal, whereas those for anti-plasminogen and anti-fibrinogen were strong and were widespread on the tissue surface. In the second stage, granulation tissues were covered with loose fibrous connective tissue, designated as a "fibrous cap." In this stage, markedly positive staining for lipoprotein(a) [Lp(a)] was observed closer to the surface of the fibrous cap than plasminogen, suggesting that Lp(a) may prevent external fibrinolysis. Lp(a) was also found in endothelial cells and the extracellular space of small vessels underlying the fibrous cap. In the last stage of healing, apo(a) and apo B were not detectable in completely organized tissues. These findings suggest that Lp(a) plays a role in the wound healing.

Apolipoproteins B↗