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Biomedical subjects

H Kasai

Publications and source records attributed to H Kasai.

At least 289 records · Page 16Linked to original sources
PubMed1989

Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator.

The mechanism by which nongenotoxic peroxisome proliferators induce hepatocellular carcinomas in rats and mice remains intriguing. The available experimental evidence suggests that the proliferation of peroxisomes and induction of peroxisome-associated enzymes results in oxidative stress which then leads to tumorigenesis. However, so far no direct evidence for oxidative DNA damage in livers of peroxisome proliferator-treated animals has been established. In the present study we have examined the DNA obtained from the livers of rats treated with ciprofibrate, a potent peroxisome proliferator, for variable periods of time for 8-hydroxydeoxyguanosine (8-OH-dG), an adduct that results from the damage of DNA caused by hydroxyl radical. Administration of ciprofibrate in diet at a concentration of 0.025% for 16, 28, 36, or 40 weeks resulted in progressive increases in the levels of 8-OH-dG. At 16, 28, and 40 weeks of ciprofibrate treatment, the 8-OH-dG in the liver DNA was significantly increased as compared to controls. This increase in 8-OH-dG levels is attributed to persistent peroxisome proliferation resulting from chronic ciprofibrate treatment as no increase in 8-OH-dG was found in liver DNA of rats that received a single large dose of ciprofibrate. The results of this study clearly demonstrate, for the first time, that persistent proliferation of peroxisomes leads to specific oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1989

Modulation of Ca-channel current by an adenosine analog mediated by a GTP-binding protein in chick sensory neurons.

Inhibitory modulation of the high-voltage-activated (HVA) Ca-channel current by 2-chloroadenosine (2CA) was studied in chick sensory neurons using the whole-cell clamp method. 2CA reduced the omega CTX-sensitive HVA-current (Aosaki and Kasai 1989) in a dose-dependent manner with a Kd of 0.8 microM. The inhibition by 2CA was also voltage-dependent, being maximal at hyperpolarized potentials, and completely removed at potentials more positive than 30 mV. This voltage-dependence of 2CA action was also evident as a progressive increase in Ca-channel current magnitude during a depolarization which could be described by a single exponential function and which became faster at larger depolarizations. The concentration of 2CA affected the steady-state reduction in Ca-channel current, but did not alter the time-course of current increase during depolarization. The voltage-dependent effect of 2CA was mimicked by intracellular application of GTP-gamma S, but not by phorbol ester, arachidonic acid or nitroprusside. These results are consistent with model in which 2CA activates a G-protein, which then unmasks an additional activation gate on the Ca-channel.

2-Chloroadenosine↗
PubMed1989

Characterization of two kinds of high-voltage-activated Ca-channel currents in chick sensory neurons. Differential sensitivity to dihydropyridines and omega-conotoxin GVIA.

High-voltage-activated (HVA) Ca-channel currents in chick sensory neurons were characterized by dihydropyridine compounds (DHPs) and omega-conotoxin GVIA (omega CTX) using patch-clamp methods. In single-channel recordings, two HVA-currents were identified by their single-channel conductances, 13 pS and 25 pS in 110 mM BaCl2. DHPs selectively affected the large-conductance channel. omega CTX (5 microM), on the other hand, irreversibly eliminated only the small-conductance channel, while the large-conductance channel was either unaffected or only transiently blocked. In whole-cell recordings the macroscopic HVA-current was completely and irreversibly blocked by omega CTX but insensitive to DHPs in 60% of the cells. This current presumably was carried by the 13 pS channel. In the remaining cells, a part of the HVA-current (10%, SD = 11%) was either unaffected or transiently blocked by omega CTX and was sensitive to DHPs. This current presumably was carried by the 25 pS channel. Inactivation of both macroscopic current component was incomplete during a 150 ms long depolarization. Our data suggest that the HVA-currents in chick sensory neurons are carried by two distinct Ca-channels that are differentially affected by omega CTX and DHPs.

Animals↗
PubMed1989

Methylreductic acid and hydroxymethylreductic acid: oxygen radical-forming agents in heated starch.

Two compounds forming oxygen radicals were isolated from heated starch by monitoring the potency to form 8-hydroxydeoxyguanosine from deoxyguanosine during purification procedures. These compounds were identified as hydroxymethylreductic acid and methylreductic acid. The former compound was mutagenic to Salmonella strains TA100, TA102 and TA104 and the latter compound induced sister-chromatid exchanges in human NL3 cells. Hydroxymethylreductic acid was found to be a novel compound. Considerable amounts of these compounds were detected in various heat-processed foods.

Animals↗
PubMed1989

Technetium-99m pertechnetate and gallium-67 imaging in salivary gland disease.

Thirty-two patients with salivary gland tumors or sialadenitis were studied with Tc-99m pertechnetate and Ga-67 imaging and, in some instances, sialography. The diagnostic algorithm presented allows the correct categorization of the salivary gland pathology in the vast majority of patients. The patients were studied serially with Tc-99m pertechnetate, Ga-67 and in certain situations sialography (or CT-sialography). Use of the algorithm can distinguish benign salivary tumors from malignant tumors and malignant tumors from inflammatory disease. The limitations and pitfalls of interpretation are discussed.

Adult↗
PubMed1989

Deoxyribonucleic acid (DNA) damage induced by bleomycin-Fe(II) in vitro: formation of 8-hydroxyguanine residues in DNA.

Treatment of calf thymus deoxyribonucleic acid (DNA) with bleomycin-Fe(II) at 0 degree C for 5 min resulted in the formation of 8-hydroxyguanine (8-OH-Gua) residues in DNA in a dose dependent manner, in addition to the formation of base propenal, a DNA-degradation product. The amount of 8-OH-Gua was about one-hundredth of that of base propenal. Treatment of cellular DNA with bleomycin did not result in any increase of 8-OH-Gua even under conditions of 100% cell killing.

Bleomycin↗
PubMed1989

Immunopharmacological studies on TBX, a new antiallergic drug (3). Inhibitory effects on histamine release from lung fragments and bronchoconstriction in guinea pigs.

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.

Animals↗
PubMed1989

Immunopharmacological studies on TBX, a new antiallergic drug (4). Effects on type II to IV allergic reactions and immunological functions in animal models.

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) on type II to IV allergic reactions and immunological functions were investigated in animal models. Types II to IV allergic reactions in rodents were unaffected in vivo by TBX, even at higher doses than those capable of completely inhibiting the type I allergic reaction. However, both complement-mediated hemolysis via the classical pathway and hypotonic shock-induced hemolysis were slightly inhibited in vitro only by a high concentration of the drug (10(-4) g/ml). In the mouse system, TBX had no ability to suppress anti-hapten IgE antibody formation as well as hemagglutinin formation and to inhibit the proliferation of spleen cells induced by non-specific T and B cell mitogens. The results obtained indicate that TBX is an antiallergic drug essentially devoid of inhibitory actions on types II to IV allergic reactions and immunological functions, thus indicating that it is a specific inhibitor of type I allergic reactions.

Animals↗
PubMed1989

[DNA damage by oxygen radicals and carcinogenesis].

Oxygen radicals are produced by ionizing radiation and many other environmental carcinogens. They are also produced in cells endogenously by the oxygen metabolism. Therefore it appears to be important to study DNA damage by oxygen radicals and its relation with mutagenesis and carcinogenesis. During a study on DNA damage caused in vitro by heated carbohydrates, which were being used as a model of cooked foods, a new type of DNA modification was discovered, the formation 8-hydroxyguanine (8-OH-Gua). Various oxygen radical forming carcinogenic agents (radiation, cigarette smoke components, asbestos + H2O2 etc.) have been found to be effective in the formation of 8-OH-Gua in DNA in vitro. The formation of 8-OH-Gua was also observed in cellular DNA in vivo after mice or cultured cells were irradiated by ionizing radiation. The 8-OH-Gua residue in DNA may cause mutagenesis and carcinogenesis, since 8-OH-Gua in DNA induces misreading during DNA synthesis in vitro. Among the various types of DNA damage induced by oxygen radicals, 8-OH-Gua can be most readily measured at high sensitivity by high-pressure liquid chromatography coupled to an electrochemical detector. Recently, we found that oral administration of several chemical carcinogens, which are known to produce oxygen radicals, induce 8-OH-Gua in rat target organ DNA. Therefore, 8-OH-Gua can be used as a marker for monitoring oxidative DNA damage as a means of evaluating the carcinogenic potency of various oxygen radical forming agents. We are also measuring 8-OH-Gua levels in human lymphocyte DNA in order to investigate the relation between oxidative DNA damage and the incidence of cancer.

Animals↗
PubMed1988

Identification of thromboxane A2 receptor in cultured vascular endothelial cells of rat aorta.

The binding site for [3H]SQ29,548, a potent and selective thromboxane A2 (TXA2) receptor antagonist, was studied in cultured vascular endothelial cells (VEC) of the rat aorta. Specific binding of [3H]SQ29,548 to rat VEC at 24 degrees C was saturable, displaceable and of high affinity. Scatchard analysis of equilibrium binding studies indicated that rat VEC contain a single class of binding sites with a Kd of 2.7 nM. The number of maximum binding sites (25.8 fmol/10(6) cells) for [3H]SQ29,548 on rat VEC was respectively 23 and 3.2 times more than that on rat platelets and rat vascular smooth muscle cells. Four TXA2 receptor antagonists and U46619 completely suppressed [3H]SQ29,548 binding to rat VEC, whereas other prostanoids, such as PGD2, PGF2 alpha, PGE1 and Iloprost, displaced the ligand binding only at considerably higher concentrations. These results suggest that the specific receptor for TXA2 is present in rat vascular endothelial cells.

Animals↗
PubMed1988

Specific receptors for thromboxane A2 in cultured vascular smooth muscle cells of rat aorta.

The specific binding site for thromboxane A2 (TXA2) was studied in cultured vascular smooth muscle cells (VSMC) of the rat aorta. [3H]SQ29,548, a potent and selective TXA2 receptor antagonist, displayed high-affinity and specificity, as well as saturable and displaceable binding to rat VSMC in culture. Scatchard analysis of equilibrium binding at 24 degrees C revealed a single class of binding sites with a Kd of 1.7 nM and a Bmax of 8.0 fmol/10(6) cells. A series of TXA2 receptor antagonists completely suppressed [3H]SQ29,548 binding to rat VSMC, and the rank order of their inhibitory potencies (Ki) correlated well with the potencies for suppression of the U46619-induced contraction of rat thoracic aorta. These results suggest that specific binding sites for [3H]SQ29,548 represent the TXA2 receptor in rat VSMC.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Divalent cation dependent inactivation of the high-voltage-activated Ca-channel current in chick sensory neurons.

We have used the whole-cell clamp technique to investigate inactivation of the omega-conotoxin sensitive high-voltage-activated Ca-channel current (HVA current [2]) carried either by Ca, Ba or Sr (2.5 mM) in chick sensory neurons. At a low internal EGTA concentration (0.1 mM), Ca-channel currents clearly inactivated irrespective of the species of divalent cation carrying the current. During 150 ms pulses, current inactivated to 0.57, 0.67 and 0.75 of the peak current in Ca, Ba and Sr solution, respectively. Time constants of inactivation (26 +/- 10 ms and 280 +/- 50 ms, mean +/- S.D., in Ba) were largely independent of the membrane potential. Double-pulse experiments showed that the amount of inactivation left by a pre-pulse was proportional to the amplitude of the current evoked by the pre-pulse. No inactivation was induced by an outward current elicited by a strong depolarization to +60 mV. With an internal EGTA concentration of 20 mM, the amount of inactivation was significantly smaller. In conclusion, the inactivation of the HVA Ca-channel currents during current flow depends mostly on the entry of divalent cations irrespective of their species.

Animals↗
PubMed1988

Immunopharmacological studies on TBX, a new antiallergic drug (2). Inhibitory effects on histamine release from peritoneal mast cells and lung fragments of rats.

The ability of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) to inhibit histamine release from both peritoneal exudate cells (PEC) containing mast cells and lung fragments of rats was investigated in vitro. Low concentrations of TBX dose-dependently inhibited IgE-mediated histamine release from PEC of passively sensitized animals; its IC50 was 5.1 x 10(-9) g/ml. When TBX was added simultaneously with the antigen challenge, the highest inhibition was obtained. In contrast, extension of preincubation time with the agent resulted in a marked decrease in the inhibition of histamine release. The potent inhibition of histamine release by TBX was observed equally in glucose-free as well as complete Tyrode's solution, whereas TBX reduced its inhibitory action in Ca2+-free or D2O-supplemented medium. In addition, TBX inhibited compound 48/80- but not calcium ionophore A23187-induced histamine release from normal PEC. With regard to the intracellular cyclic AMP level in normal PEC, it was significantly enhanced by a high concentration of TBX (10(-3) g/ml). TBX also inhibited antigen-induced histamine release from lung fragments of actively immunized animals. Interestingly, TBX displayed non-competitive inhibition of cyclic AMP-dependent phosphodiesterase derived from lung homogenates; its K1 value was 8.70 x 10(-4) M.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Immunopharmacological studies on TBX, a new antiallergic drug (1). Inhibitory effects on passive cutaneous anaphylaxis in rats and guinea pigs.

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on passive cutaneous anaphylaxis (PCA) mediated by homologous IgE or IgG antibody were investigated in rats and guinea pigs. TBX (i.v. and p.o.) clearly inhibited IgE- and IgGa-mediated homologous PCAs in rats, without showing any inhibition of the skin reactions caused by histamine, serotonin and bradykinin in contrast to the inhibition of prostaglandin E1-induced skin reaction. Neither adrenalectomy nor propranolol treatment modified TBX's inhibition of the former PCA. With regard to tachyphylaxis to TBX, it was demonstrable in IgE-mediated homologous PCA in rats when they were pretreated with TBX (0.5 mg/kg, i.v.), followed 60 min later by a second dose of the drug (0.05 mg/kg, i.v.). There was no cross-tachyphylaxis between disodium cromoglycate (DSCG) and TBX. Homologous PCA caused by guinea pig IgE was also inhibited in a dose-dependent fashion by i.v. and p.o. administrations of TBX, although higher doses of TBX were needed to inhibit guinea pig PCA than the rat one. Interestingly, TBX showed more potent inhibition of both rat and guinea pig homologous PCAs than DSCG or tranilast. The results obtained indicate that TBX is an orally effective antiallergic agent displaying no antagonistic actions on the chemical mediators released.

Animals↗
PubMed1987

Formation of 8-hydroxyguanine residues in DNA treated with 4-hydroxyaminoquinoline 1-oxide and its related compounds in the presence of seryl-AMP.

The mechanism whereby treatment of DNA with 4-hydroxyaminoquinoline 1-oxide (4HAQO) in the presence of seryl-AMP leads to the formation of 8-hydroxyguanine (8-OH-Gua) residues in DNA (Kohda et al., this journal, 139, 626, 1986) has been studied. In the survey of other N-arylhydroxylamines, only 4HAQO analogues which could bind to DNA produced 8-OH-Gua. The amount of 8-OH-Gua varied depending on the structure of 4HAQO analogues and that of DNA. The formation of 8-OH-Gua was not inhibited by active oxygen scavengers. Possible mechanisms are discussed.

4-Hydroxyaminoquinoline-1-oxide↗