The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
77 巻, 2 号
選択された号の論文の9件中1~9を表示しています
Review
Regular Papers
  • Masaki Kitahara, Tatsuro Kanaki, Kyomi Toyoda, Chie Miyakoshi, Sakuya ...
    1998 年 77 巻 2 号 p. 117-128
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress smooth muscle cell growth and arterial neointimal thickening. In this study, to elucidate the potency and mechanisms of NK-104 ((+)-monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate}, CAS 147526-32-7) in neointimal thickening, the effect of NK-104 on the neointimal thickening, Br-dU-labeled cell number and extracellular matrix immunohistochemistry were examined in balloon-injured rabbit carotid artery. NK-104 suppressed the neointimal thickening dose-dependently, and the suppression was 69.5% at 1.0 mg/kg. NK-104 suppressed the intimal total and Br-dU-labeled cell number. Fibronectin and type I collagen were observed in 81% and 38% of the total intimal area in the control arteries, respectively, and the areas occupied by fibronectin and type I collagen were significantly decreased by 1.0 mg/kg NK-104 to 39% and 22%, respectively. The decrease in fibronectin per cell was more potently demonstrated. Aortic total and activated TGF-β contents that were markedly increased in the injured artery were increased further by NK-104. NK-104 concentration-dependently suppressed fibronectin content of the basement lesion in rabbit primary cultured smooth muscle cells. These findings suggest that NK-104 suppresses balloon-injury-induced neointimal thickening through inhibition of intimal smooth muscle cell growth and extracellular matrix accumulation.
  • Kenkichi Kanno, Fumikazu Okumura, Wataru Toriumi, Noriko Ishiyama, Shi ...
    1998 年 77 巻 2 号 p. 129-135
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    We investigated nephrotoxic serum (NTS)-induced glomerulonephritis in Wistar-Kyoto (WKY) rats as a model to evaluate antinephritic agents. WKY rats required only a small amount of NTS to induce crescentic glomerulonephritis and the rats progressively lost their renal function in a few weeks. In a comparative study with WKY and Sprague-Dawley (SD) rats, WKY rats showed a normal distribution pattern in the severity of proteinuria with a small variance. While SD rats needed a much higher amount of NTS to exhibit a comparable proteinuria which was not normal and had a large variance. The effects of clinically available antinephritic drugs, methylprednisolone, cyclophosphamide and cyclosporin A, were studied in both strains. In WKY rats, these drugs significantly inhibited the proteinuria, glomerular histological changes and decrease in creatinine clearance. On the other hand, such significant inhibitory effects on proteinuria were not observed with any of these drugs in SD rats. In conclusion, NTS nephritis in WKY rats may prove to be a useful model for studying antinephritic agents.
  • Yoshihisa Nasa, Michihiko Hayashi, Hideo Sasaki, Jyun-ichi Hayashi, Sa ...
    1998 年 77 巻 2 号 p. 137-146
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    Dietary supplementation of fish oil containing eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA) has been shown to exert protective effects on ischemic/reperfused hearts. We determined whether deprivation of fish oil from the diet paradoxically enhances susceptibility of cardiomyocytes to hypoxia/reoxygenation-induced injury and whether supplementation with either EPA or DHA overcomes such alterations. Rats were fed with fish-oil-rich (FOR) diet, fish-oil-deprived (FOD) diet alone, FOD diet with EPA (1 g/kg/day), or FOD diet with DHA (1 g/kg/day) for 4 weeks. The FOD diet reduced n-3 polyunsaturated fatty acids (PUFAs) and increased n-6 PUFAs such as linoleic (C18:2) and arachidonic acids (C20:4) in myocardial phospholipids. EPA or DHA supplementation increased its incorporation into phospholipid pools. Cardiomyocytes isolated by treatment with collagenase were subjected to 150 min of hypoxia and subsequent reoxygenation for 15 min. In the FOD diet group, the number of surviving rod-shaped cells after hypoxia and reoxygenation was smaller than that of the FOR group. Supplementation with EPA did not affect the number of rod-shaped cells, but attenuated reoxygenation-induced reduction in the number of square-shaped cells. In contrast, DHA supplementation did not afford any protection. The results suggest that deprivation of fish oil from dietary intake enhances the susceptibility of cardiomyocytes to hypoxic injury, and EPA, but not DHA, is capable of salvaging cardiomyocytes from hypoxia/reoxygenation-induced damage.
  • Fukuichi Ohsawa, Miki Yamauchi, Hiroshi Nagaso, Shoichi Murakami, Jun ...
    1998 年 77 巻 2 号 p. 147-154
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    Several previous studies have demonstrated that the phosphodiesterase 4 selective inhibitor rolipram affects cellular function at a much lower concentration than the reported Ki value for phosphodiesterase 4 inhibition. In this study, we examined the inhibitory effect of rolipram on rat brain phosphodiesterase 4 to determine the heterogeneity of the enzyme activity. Partial purification of various phosphodiesterases from the rat brain was performed by anion-exchange chromatography. The eluant was pooled into four fractions, two of which manifested cAMP-selective phosphodiesterase activity that was blocked by 10 μM of rolipram, indicating the presence of phosphodiesterase 4 in these fractions. The IC50 of rolipram (racemate) of these two fractions was 492 and 79 nM, respectively. The R-(-)-enantiomer of rolipram inhibited the cAMP-phosphodiesterase activity in the latter fraction 10 times more than did S-(+)-rolipram, and the inhibition of the former fraction was less stereospecific. Dixon plot analysis revealed that the rolipram enantiomers inhibited the cAMP-phosphodiesterase in the latter fraction in a multiphasic manner, with two Ki values, one at the micromolar level and the other at the sub-micromolar level, respectively, for both of the enantiomers. These results suggest that there is a heterogeneity for phosphodiesterase 4 in the rat brain, and some of the phosphodiesterase forms are sensitive to rolipram.
  • Mutsuko Maekawa, Toshihiko Murayama, Satoshi Ono, Hirokazu Narita, Yas ...
    1998 年 77 巻 2 号 p. 155-160
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N, N-diethylamino)-ethoxy]ethanol hydrochloride (T-588), a novel cognitive enhancer, stimulated noradrenaline (NA) release from rat cerebral cortical slices. In this study, we investigated the effects of T-588 on NA uptake and release, compared to the effects of desipramine, a blocker of the NA carrier on the plasma membrane. Both T-588 and desipramine caused dose-dependent inhibition of [3H]NA uptake into the slices. Addition of 3 mM T-588 stimulated [3H]NA release from the prelabeled slices even in the presence of 10 μM desipramine, which inhibited NA uptake completely. Tyramine, which accelerates NA carrier-mediated release, also stimulated [3H]NA release, and tyramine-stimulated release was inhibited by desipramine. These findings indicated that T-588-stimulated NA release was not mediated by 1) inhibition of reuptake or 2) reverse transport mediated by NA carriers. Reserpine, which interacts with the intracellular vesicular transport system, increased [3H]NA efflux from slices. High K+-, not T-588-, stimulated [3H]NA release was shifted upward by reserpine. These findings suggest that T-588 evokes NA release by a mechanism similar to that induced by reserpine. T-588 might act as a cognitive enhancer via neurotransmitter release in the brain.
  • Takehiko Maeda, Masakazu Ibi, Seiichiro Shimazu, Akinori Akaike
    1998 年 77 巻 2 号 p. 161-167
    発行日: 1998年
    公開日: 2001/04/26
    ジャーナル フリー
    We examined the role of striatal cells in cytotoxicity induced by N-methyl-D-aspartate (NMDA) in dopamine (DA) neurons in rat mesencephalic slice culture. Coronal sections were prepared from 2- and 3-day-old rat brains and cultured using the interface culture method for 2 - 3 weeks before the NMDA cytotoxicity experiment. The exposure of mesencephalic cultures without striatum (single culture) to NMDA (10 - 300 μM) for 24 hr reduced the number of DA neurons in a concentration-dependent manner. The co-administration of the non-competitive NMDA-receptor antagonist significantly inhibited the neurotoxic effect of NMDA. When mesencephalon and striatum were kept in contact and co-cultured (contacting co-cultures), the growth of DA fibers into the striatal part was observed. In the contacting co-cultures with striatum, the minimal effective concentration for NMDA cytotoxicity was higher than that in single cultures. The contacting co-cultures with cerebellum did not alter the NMDA cytotoxicity. When the mesencephalon and striatum slices were kept apart and co-cultured, the co-cultures showed neither an outgrowth of DA fibers to the striatum nor any effect on the NMDA cytotoxicity. These results suggest that the projection of rat mesencephalic DA neurons to the striatum attenuates the NMDA cytotoxicity in DA neurons themselves.
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