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Biomedical subjects

T Kariya

Publications and source records attributed to T Kariya.

At least 73 records · Page 4Linked to original sources
PubMed1989

Effects of five anion channel blockers on thrombin- and ionomycin-activated platelet functions.

The inhibitory effects of anion channel blockers were evaluated on aggregation, intracellular Ca2+ rises, and the production of arachidonic acid metabolites in human platelets. Inhibitors included five anion channel blockers: phloretin, probenecid, pyridoxal phosphate, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The degree of inhibition by each of these agents was dose-dependent on thrombin-activated platelet function. These agents generally had no significant inhibitory effects on ionomycin-activated platelet functions. It is suggested that anion mobilization plays a major role in the receptor-mediated activation of platelet functions, but only a minor role in Ca2+ ionophore-induced platelet activation. It is also suggested that several agents may have properties unrelated to anion channel blockers. Phloretin may be a selective cyclooxygenase inhibitor, and probenecid may inhibit phospholipase A2. DIDS and SITS may interfere with certain aggregation-inducing mechanisms.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Correlation of intracellular and extracellular calcium ion concentrations with synergy between 1,2-dioctanoyl-sn-glycerol and ionomycin in platelet arachidonic acid mobilization.

The potentiation by 1,2-dioctanoyl-sn-glycerol (DiC8) of ionomycin-induced platelet production of 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) was investigated in correlation with extracellular Ca2+ concentrations and increases in [Ca2+]i, as detected with aequorin and fura-2. Extracellular Ca2+ concentrations greatly influenced the production of arachidonic acid metabolites induced by DiC8 and ionomycin, while that induced by ionomycin alone was minimally affected by variation of the extracellular Ca2+ concentration. In the synergy between ionomycin and 20 microM DiC8, the optimal concentrations of ionomycin shifted from high to low with increasing concentrations of extracellular Ca2+, suggesting that there might be a range of optimal [Ca2+]i for the production of the arachidonic acid metabolites. This hypothesis was confirmed by simultaneous measurements of [Ca2+]i increases, and the production of the arachidonic acid metabolites. With the aequorin method, the optimal concentrations of [Ca2+]i fell to between 10 microM and 20 microM, and with the fura-2 method, it fell to between 800 nM and 1800 nM. Direct measurements of [14C]arachidonic acid release suggested that the DiC8-potentiated production of arachidonic acid metabolites induced by ionomycin was attributable to increased arachidonic acid release. Since ionomycin and DiC8 induced relatively low levels of phosphatidic acid production, an indicator of phospholipase C activation, it was suggested that the increased arachidonic acid release was largely dependent upon phospholipase A2. Synergy between DiC8 and ionomycin was also observed with aggregation and serotonin release. Aggregation was induced by lower concentrations of ionomycin, and appeared to be more dependent upon extracellular Ca2+, while serotonin release required higher concentrations of ionomycin, and variations in extracellular Ca2+ affected the response minimally. These findings suggest that the mechanisms underlying the synergy between protein kinase C activation and Ca2+ mobilization differ among the three functions evaluated in this study.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Anion channels contribute to the regulation of intracellular pH in human platelets.

The presence of extracellular bicarbonate potentiated platelet intracellular pH rises induced by thrombin. The effect was most remarkable in sodium-depleted buffers. This effect of bicarbonate was dose-dependent and was inhibited by anion channel blockers. Bicarbonate also potentiated the pHi recovery after acid loading, but had no effect on alkali loading. It was suggested that anion exchange, most probably that of bicarbonate/chloride, contributes to the regulation of intracellular pH in human platelets.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Does kallikrein improve the brain function in dementia?

Forty biological units of Kallikrein were administered intramuscularly to nine persons suffering from multi-infarct dementia. With automatic analysis equipment, the wave-form recognition method was used to analyze EEG before injection, immediately after injection, and 30, 60, 90, and 120 minutes after injection. The results of analysis done the five times after injection were then compared with the analysis results before injection. With the passage of time after injection, delta and theta waves showed a gradually decreasing tendency, while alpha and beta waves showed a gradual increase. It was inferred that these changes in the EEG were caused by an increase in the flow of cerebral blood, which in turn was the effect of the dilatation of cerebral blood vessels resulting from the action of the Kallikrein.

Aged↗
PubMed1989

Acetyltransferase activity and production of platelet-activating factor by human neutrophils activated with various stimuli.

The acetyltransferase activity and biosynthesis of platelet-activating factor (PAF) were assessed in human neutrophils activated by 4 microM A23187, 20 ng/ml phorbol myristate acetate (PMA), and 10(-6) M n-formyl-methionyl-leucyl-phenylalanine (fMLP). All three agents elevated the acetyltransferase activity dose-dependently. There were no significant differences in the Km values for acetyl CoA between non-stimulated and stimulated cells. All three stimuli gave a similar Vmax value of acetyltransferase determined 10 min after stimulation, being more than twice as high as the control value. By contrast, the amount of PAF produced by the neutrophils differed with the stimuli, A23187 being by far the most potent. The time course of PAF synthesis, particularly when activated by PMA, did not parallel that of acetyltransferase activity; PMA-induced PAF production was negligible for the first 20 min and gradually increased to reach its plateau 60 min after stimulation, while enzyme activity was at its highest level 5 min after stimulation. These results suggest that the different stimuli activated the same acetyltransferase, and that there was an increase in the number of the enzyme molecules in the activated state. It is unlikely that a change in the biological activity of a preexisting enzyme without a change in the number of active enzyme molecules could be the cause. Certain factors other than acetyltransferase may also regulate the PAF biosynthesis induced by these stimuli.

Acetyltransferases↗
PubMed1989

[Genetic markers and thrombin reaction in a family of Bernard-Soulier syndrome].

A family with Bernard-Soulier syndrome (BSS) was investigated with reference to the genetic markers and thrombin reactions. The proband was a 24-year-old man with a life-long history of epistaxis and gingival bleeding. His parents were first cousins; furthermore, his father was born to parents of second cousins. His father also had bleeding tendency and was also diagnosed as having BSS. However, his mother and elder brother were normal. Genetic marker analysis among the family members suggested that the 16th chromosome was associated with the development of BSS, because only the haptoglobin genotype coded on the 16th chromosome was the marker in both the proband and his father. In addition, they both exhibited decreased thrombin-induced platelet aggregation at a low dose, but an almost normal reaction at a high dose of thrombin.

Adult↗
PubMed1988

Tissue distribution and selective inhibition of subtypes of high affinity cAMP phosphodiesterase.

High affinity cAMP phosphodiesterase (PDE), also referred to as PDE III, or low Km PDE occurs as two subtypes. One subtype is sensitive to inhibition by cGMP while the other is relatively insensitive. To be consistent with previously recommended nomenclature, these subtypes were designated Types IV and V PDEs respectively. Tissue distribution of these subtypes of high affinity cAMP PDE was investigated using comparative potencies of specific inhibitors. Of the tissues examined, dog heart contained the highest proportion of the cGMP inhibitable form (Type IV PDE), whereas dog kidney cortex and brain were composed almost entirely of the cGMP non-inhibitable form (Type V PDE). Enoximone and other new cardiotonic drugs that inhibit high affinity cAMP PDE were shown to be specific for the cGMP inhibitable form, whereas rolipram was specific for the cGMP non-inhibitable form. The apparently partially competitive kinetics shown by one of these drugs, enoximone, was due to the presence of both subtypes of the enzyme. When the activity of the cGMP non-inhibitable form was suppressed by rolipram, competitive inhibition of the cGMP inhibitable subtype by enoximone was observed. Rat heart high affinity cAMP PDE activity contained a higher proportion of the cGMP non-inhibitable subtype than did the enzyme from dog heart. It is suggested that this may account for the relative insensitivity of rats to the cardiotonic PDE inhibitors.

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

Studies on the physical states of human platelet myosin in crude extracts.

The physical properties of human platelet myosin in crude extracts were studied by means of Sepharose 4B gel filtration and sucrose density gradient centrifugation in the presence or absence of Mg-ATP. Platelet myosin extracted with a buffer containing 0-0.15 M KCl gave a Stokes radius of about 12.0-12.5 nm irrespective of the presence or absence of Mg-ATP. The sedimentation coefficients obtained in the presence of Mg-ATP were about 10-11 and 8.5S at 0.05-0.10 and 0.15 M KCl, respectively, whereas the values obtained in the absence of Mg-ATP were about 16, 9-12, and 8.5S at 0.05, 0.10, and 0.15 M KCl, respectively. The apparent molecular weight in the presence of Mg-ATP, therefore, was about 500,000 and 420,000 at 0.05-0.10 and 0.15 M KCl, respectively, while the molecular weight in the absence of Mg-ATP was about 790,000, 460,000-620,000, and 440,000 at 0.05, 0.10, and 0.15 M KCl, respectively. The purified monomeric platelet myosin that had been solubilized with Mg-ATP at 0.10 M KCl had a Stokes radius of about 12.5 nm, a sedimentation coefficient of about 9S, and an apparent molecular weight of 460,000. On the other hand, while crude platelet myosin extracted at 0.6 M KCl with Mg-ATP gave a Stokes radius of about 20 nm, a sedimentation coefficient of about of 6S, and an apparent molecular weight of about 490,000, each of these physical parameters obtained in the absence of Mg-ATP was much larger than that obtained in the presence of Mg-ATP because the myosin was associated with F-actin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

Characterization of growth hormone-releasing hormone receptors in pituitary adenomas from patients with acromegaly.

GHRH receptors in pituitary adenoma cell membranes from five patients with acromegaly were characterized using [125I] [His1,Nle27]GHRH-(1-32)NH2 ([125I]GHRHa) as a ligand. Specific binding of [125I]GHRHa to adenoma cell membranes was maximal within 20 min at 24 C, remained stable for 60 min, and was reversible in the presence of 500 nmol/L human GHRH-(1-44)NH2 (hGHRH). The specific binding increased linearly with 10-160 micrograms cell membrane protein. This binding was inhibited by 10(-11)-10(-6) mol/L hGHRH in a dose-dependent manner, with an ID50 of 0.20 nmol/L, but not by 10(-7) mol/L vasoactive intestinal peptide, glucagon, somatostatin-14, somatostatin-28, TRH, LHRH, and CRH. The specific binding of [125I]GHRHa to the membranes was saturable, and Scatchard analysis of the data revealed an apparent single class of high affinity GHRH receptors in five adenomas from acromegalic patients; the mean dissociation constant was 0.30 +/- 0.07 (+/- SE) nmol/L, and the mean maximal binding capacity was 26.7 +/- 7.0 (+/- SE) fmol/mg protein. In three nonfunctioning pituitary adenomas, GHRH receptors were not detected. The plasma GH response to hGHRH (100 micrograms) injection was studied in four acromegalic patients before surgery. Plasma GH levels increased variably in response to hGHRH injection in all four patients. However, there was no correlation between the characteristics of the tumor GHRH receptors and plasma GH responsiveness in these patients. We conclude that pituitary GH-secreting adenomas have specific GHRH receptors. Exogenously administered GHRH presumably acts via these receptors, but the variations in plasma GH responsiveness to hGHRH in these patients cannot be directly related to the variations in binding characteristics of the GHRH receptors on the GH-secreting adenoma cells.

Acromegaly↗
PubMed1987

Pharmacology of enoximone.

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Characterization of serum cholinesterase in familial hyper-cholinesterasemia associated with an isozyme variant band.

An investigation of the properties and kinetics of serum cholinesterase (chE) was conducted in familial cases of serum hyper-chE activity. An inhibition study with specific pseudo-chE inhibitor (ethopropazine), or with anti-human pseudo-chE sera, has produced evidence that this genetically variant chE is pseudo-chE. The Km or relative activity of the variant chE against enzyme protein turns out to be the same as that of the normal serum chE. However, the variant serum chE shows more basic pK in addition to the main pK of the normal pseudo-chE on isoelectrofocusing analysis. The serum chE isozyme analysis has revealed two different extrabands in the variant: one demonstrated as a sharp line between bands 3 and 4, which we described previously, and the other as slow migrating broad band in the cathodic region close to the origin. Both prove to be pseudo-chE. Although there have been some similar descriptions about the latter type of extraband, no reports are found about the former type. It is noteworthy that the use of heparin as an anti-coagulant caused the total disappearance of the first type of extraband. It should be remembered that only heparinized plasma was used in the earlier studies. Since the detection of the former type of band seems to be specific and is simple, our findings would probably help clinicians diagnose a familial case of hyper-chE.

Cholinesterases↗
PubMed1987

Effects of enoximone and isobutylmethylxanthine on contractile tension and cyclic nucleotide levels in isolated blood-perfused dog papillary muscle.

The effects of enoximone (MDL 17,043) and 3-isobutyl-1-methylxanthine (IBMX) on developed tension, blood flow, and cyclic nucleotide levels were investigated in the isolated blood-perfused dog papillary muscle preparation. Intraarterial infusion of each agent, over 15 s, in doses ranging from 0.001 to 3 mg, produced a dose-dependent positive inotropic effect accompanied by increases in rate of contraction, rate of relaxation, and blood flow. The dose-response relationships for enoximone were always less steep than those for IBMX. Enoximone did not enhance automaticity at any dose, whereas the higher doses of IBMX (0.3, 1, and 3 mg) enhanced automaticity and produced arrhythmic preparations. Both agents produced increases in cyclic AMP during the peak positive inotropic effect (45 s); however, only IBMX produced an increase in cyclic GMP. The increase in cyclic AMP produced by enoximone lagged behind tension development by at least 15 s, whereas the increases in cyclic nucleotides produced by IBMX occurred concurrently with the development of the positive inotropic effect. The evaluation in cyclic AMP produced by enoximone is consistent with the reported property of this agent to inhibit specifically and selectively the particulate high-affinity cyclic AMP phosphodiesterase from dog heart, and supports a cyclic AMP-dependent mechanism of positive inotropism for enoximone.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Separable function of platelet release reaction and clot retraction.

Amiloride, a known Na+/H+ exchange inhibitor, inhibited platelet serotonin release in a dose-dependent manner (100 microM for 50% inhibition, and 1mM for the nearly complete inhibition), although amiloride (1mM) accelerated clot retraction when it was measured at decreased platelet concentration. On the contrary, cytochalasin B (10 micrograms/ml) accelerated platelet serotonin release, but it inhibited clot retraction. These results demonstrate that release reaction and clot retraction, both of which are important processes involved in platelet activation, can be functionally separated.

Actins↗