Alterations in reactivity to acetylcholine in myasthenia gravis and carcinomatous myopathy.
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Biomedical subjects
Publications and source records attributed to T Namba.
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In previous studies of muscle fatigue, tension was monitored from whole muscle, while action potentials were recorded from a few muscle fibers. To compare more accurately changes in these responses, an in vitro fluid electrode technique was employed to record the action potential of whole muscle simultaneously with tension during fatigue induced by nerve stimulation in the rat extensor digitorum longus (EDL), soleus, and diaphragm muscles. In each muscle, tension declined from the start of stimulation, while action potential amplitude initially increased slightly and then declined most rapidly in EDL, more slowly in diaphragm, and most slowly in soleus. Direct stimulation of the fatigued muscle produced the greatest increase in tension in EDL, next in diaphragm, and least in soleus. These results indicate that while failure of excitation-contraction coupling or of the contractile mechanism is the initial cause of fatigue in all the muscles studied, and remains the predominant cause throughout in the soleus muscle, failure of neuromuscular transmission plays an important role in fatigue after the first 15 seconds in EDL, and to a lesser extent, after the first 90 seconds in diaphragm.
Glycyrrhizin (GL), a main constituent of liquorice, was hydrolysed to 18 beta-glycyrrhetic acid mono-beta-D-glucuronide (GAMG, glycyrrhetyl monoglucuronide) by rat liver homogenate, and the hydrolytic activity was localized in the lysosomes among the same subcellular fractions as acid beta-D-glucuronidase activity (p-nitrophenyl beta-D-glucuronide (pNPG)-hydrolysing activity). Rat liver lysosomes hydrolysed GAMG to 18 beta-glycyrrhetic acid (GA) at only 30% rate compared with the rate of GL to GAMG. GA was also produced slowly from GL after time lag by the lysosomes. Thus, GL seems to be first hydrolysed to GAMG, which was successively hydrolysed slowly to GA. GL-hydrolysing activity was released together with acid beta-D-glucuronidase activity from the lysosomes by sonication. Both activities from the sonicated lysosomes were eluted coincidentally on Sephacryl S-300 and butyl-Toyopearl 650M column chromatography, indicating that both activities are exhibited by the same enzyme. Moreover, GL-hydrolysing activity was inhibited strongly with D-saccharic acid 1,4-lactone, a specific inhibitor beta-D-glucuronidases of various origins. pH optimum of GL-hydrolysing activity was found to be 5.6, different from that (less than 4.0) of pNPG-hydrolysing activity. Km for GL was found to be 2 x 10(-5) M. Although hepatic lysosomes from mouse and cattle hydrolysed GAMG to GA similarly to those from rat, the hydrolysis of GAMG was not detected in lysosomes of human and porcine livers. Accordingly, lysosomal beta-D-glucuronidases from human and porcine livers converted GL to GAMG only.
Twenty-four tannins and related compounds were examined for inhibition against reverse transcriptase from RNA tumor virus. Hydrolyzable tannins showed a potent inhibitory effect comparable to nitidine, in the presence of polyadenylic acid-oligothymidylic acid as a template-primer. A lesser inhibitory activity was observed for the monomeric ellagitannins, gallotannins, and nitidine using polycytidylic acid-oligodeoxyguanylic acid as a template-primer, whereas the inhibitory activity of dimeric ellagitannins was almost as potent as that observed for these compounds in the polyadenylic acid-oligothymidylic acid directed reaction. Inhibition by tannins was reversed by the addition of either template-primer or enzyme, suggesting that the inhibition is due to the interaction of tannins with both of them.
As a part of our studies on the metabolism of bioactive compounds from oriental medicines by intestinal flora, homoorientin, a C-glycosylflavonoid, was anaerobically incubated with a human intestinal bacterial mixture. Homoorientin was transformed to 6-C-glucosyleriodictyol, (+/-)-eriodictyol, luteolin, 3,4-dihydroxyphenylpropionic acid, and phloroglucinol. A novel cleavage of the C-glycosyl bond was discovered for the first time by using intestinal bacteria.
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We have recently cloned cDNAs for the human and mouse TXA2/PGH2 receptors and a cDNA for the mouse PGE receptor. Sequencing, homology and hydrophobicity analyses revealed that they are proteins of 343, 341 and 365 amino acid residues, respectively, and all are rhodopsin-type receptors with putative seven transmembrane domains. Homology between the human and mouse TXA2 receptors is 76% in total and that between the human TXA2 and mouse PGE receptors is 38%. The homology increases in the putative transmembrane regions to 85 and 45%, respectively, and there observed several features common to the three receptors. These results indicate that the prostanoid receptors constitute a family of receptors of similar structure. The cloned PGE receptor showed binding activity specific to so-called EP3 agonists, which verified for the first time that pharmacologically defined PGE receptor subtypes consist of different molecules. This receptor also displayed different efficiency in signal transduction to an EP3 agonist, M & B-28767, and PGE2, providing an interesting model for the analysis of receptor-G protein coupling. In addition to the above biochemical results, these studies have revealed the characteristic tissue distribution of these receptors, which will open up a new biology of these prostanoids.