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Volume 73 (1997)
- Issue 4 Pages 263-
- Issue 3 Pages 185-
- Issue 2 Pages 105-
- Issue 1 Pages 1-
Volume 73, Issue 2
Displaying 1-10 of 10 articles from this issue
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Hiroyuki Taniguchi, Eiji Yomota, Eisuke Kume, Toshirou Shikano, Toshio ...1997 Volume 73 Issue 2 Pages 105-112
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSEffects of a new cholecystokinin (CCK)A-receptor antagonist, T-0632 [sodium (S)-I-(2-flu orophenyl)-2, 3-dihydro-3-[(3-isoquinolinylcarbonyl)amino]-6-methoxy-2-oxo-1H-indole-3-propanoate], on caerulein-induced and pancreatic duct ligation-induced pancreatitis models were studied and compared with the CCKA-receptor antagonist loxiglumide and the orally active protease inhibitor camostate, respectively. In rats, orally administered T-0632 potently prevented the caerulein-induced increases in pancreatic digestive enzymes in plasma and suppressed the histological changes in the pancreas. The estimated ED50 values of T-0632 and loxiglumide were 0.0092 and 8.9 mg/kg, respectively. In dogs, T-0632 (0.1, 1 mg/kg, i.d.)prevented the caerulein-induced increase in plasma amylase activity in a dose-dependent manner. Loxiglumide (100 mg/kg, i.d.)did not show any preventive effects. In pancreatic duct ligation (6 hr)induced pancreatitis of the rat, T-0632 (0.001-0.1 mg/kg, p.o.)partially prevented both the increase in plasma amylase activity and the histological changes in the pancreas, whereas camostate (10, 100 mg/kg, p.o.)did not show any preventive effects. In pancreatic duct ligation (3 hr)-induced pancreatitis, caerulein injection (1 μg/kg, s.c.)caused a further increase in plasma amylase activity, and T-0632 (0.01, 0.1 mg/kg, p.o.)dose-dependently decreased the aggravation by caerulein. We conclude that T-0632 showed preventive effects on all of these pancreatitis models by oral or intraduodenal administration. These results suggest that CCK plays an important role in progression and aggravation of acute pancreatitis, and T-0632 may have a therapeutic value in these disease states.View full abstractDownload PDF (653K) -
Kumiko Shibasaki, Kenji Takizawa, Wataru Uchida, Toichi Takenaka1997 Volume 73 Issue 2 Pages 113-124
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2, 6-dimethyl-((S)-4-(m-nitrophenyl))-1, 4-dihydropyridine-3, 5-dicarboxylate)were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg)produced a dose-dependent decrease in mean blood pressure (MBP)with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the β1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10 mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and β1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.View full abstractDownload PDF (639K) -
Miwa Misawa, Junya Sato1997 Volume 73 Issue 2 Pages 125-132
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe involvement of endogenous nitric oxide (NO)in bronchial cholinergic neurotransmission was compared between normal rats and airway hyperresponsive (AHR)rats. Male Wistar rats were sensitized and repeatedly challenged with dinitrophenylated (DNP)-Ascaris antigen. Twenty-four hours after the last antigenic challenge, enhancements of both the electrical field stimulation (EFS)-induced bronchoconstriction and acetylcholine (ACh)release were observed. NG-Monomethyl-L-arginine (L-NMMA; NO synthase inhibitor, 0.1 mM)augmented the EFS-induced bronchoconstriction and ACh release without affecting exogenously applied ACh-induced bronchoconstriction in normal rats. Interestingly, the augmentative effects of L-NMMA seen in normal rats were not manifested in AHR rats. Sodium nitroprusside inhibited the EFS-induced bronchoconstriction in a concentration-dependent manner; the inhibition was much larger than that of exogenously applied ACh-induced constriction in both normal and AHR rats. Furthermore, dibutyryl cGMP (3 mM)inhibited the EFS-induced bronchoconstriction with no effect on the ACh-induced bronchoconstriction in both normal and AHR rats. These findings suggest that endogenous NO may have a modulatory role in bronchial cholinergic neurotransmission in normal rats and that the augmented ACh release in the AHR rats may result from the defect of endogenous NO-induced modulation of cholinergic nerve transmission.View full abstractDownload PDF (496K) -
Naoki Ashizawa, Motoyuki Yoshida, Yoshiko Sugiyama, Nobuhide Akaike, S ...1997 Volume 73 Issue 2 Pages 133-144
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSGP-1447 {3-[(4, 5, 7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylacetic acid}, a novel aldose reductase (AR)inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, human muscle, porcine and rat lens with IC50 values ranging from 3 to 10 nM. Lineweaver-Burk plots revealed non-competitive inhibition between DL-glyceraldehyde or β-NADPH and inhibition of AR by GP-1447. In contrast to epalrestat, AR activity inhibited by GP-1447 did not recover after dialysis for 24 hr. Administration of GP-1447 to streptozotocin (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ injection effectively inhibited the accumulation of sorbitol in the sciatic nerve, lens and retina with ED50 values of 0.25, 1.6 and 2.9 mg/kg/day, respectively. The motor nerve conduction velocity (MCV)in STZ-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 weeks dose-dependently restored the decreased MCV with an ED50 value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 weeks beginning 3 days after STZ injection)completely prevented cataract formation and was accompanied by marked inhibition of sorbitol accumulation in the lens. Furthermore, partial reversibility of cataract formation and morphological changes of the lens was observed in diabetic rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 weeks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic complications. Potent inhibition of cataract formation will be one of the characteristics of this compound.View full abstractDownload PDF (834K) -
Kazunori Yoneda, Tetsuya Yamamoto, Eisaku Ueta, Tokio Osaki1997 Volume 73 Issue 2 Pages 145-153
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe influence of the anti-allergy agent azelastine hydrochloride (Azeptin®)on NF-κB activation associated with the. generation of cytokines and nitric oxide (NO)was investigated in various kinds of human and mouse cells. Azeptin dose-dependently suppressed both DNA and protein synthesis in human gingival fibroblasts (HF)and also suppressed blastogenesis of human peripheral blood lymphocytes (PBL). Generation of tumor necrosis factor-alpha, interleukin 1-beta, granulocyte-macrophage colony-stimulating factor and interleukin-6 from 10-5 M Azeptin-treated PBL and human monocytes (HM)was decreased to approximately 1/3 to 2/3 of the control levels. In parallel with the decreased cytokine generation, each cytokine mRNA was less expressed in the presence of 10-5 M Azeptin. In addition, both inducible nitric oxide synthase-mRNA level and NO generation in mouse peritoneal macrophages were suppressed by 10-5 M Azeptin. Being compatible with those results, Azeptin (10-5 M)suppressed activation of NF-κB in PBL, HM and HF. These results appear to indicate that suppression of cytokine and NO generation by Azeptin results at least partially from the inhibition of NF-κB activation.View full abstractDownload PDF (569K) -
Satomi Niioka, Tadayoshi Takeuchi, Masami Kishi, Toshiaki Ishii, Hidea ...1997 Volume 73 Issue 2 Pages 155-161
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe mediators of nonadrenergic, noncholinergic (NANC)relaxation in the longitudinal muscle of rat jejunum were studied in vitro. Electrical field stimulation (EFS)of segments of rat jejunum induced a rapid transient relaxation followed by a subsequent contraction in the presence of atropine and guanethidine. NG-Nitro-L-arginine (L-NOARG, 10 μM)inhibited the EFS-induced NANC relaxation by about 25%, and L-arginine (1 mM)completely reversed this inhibition. Exogenously added nitric oxide (0.1-10 μM)induced relaxation of the segment. Treatment of the segment with a-chymotrypsin resulted in about 50% inhibition of the EFS-induced relaxation. Several peptide candidates for the mediator of NANC relaxation were examined by using selective antagonists of their receptors or by a receptor-desensitization method. Results indicated that vasoactive intestinal peptide, pituitary adenylate cyclase activating peptide, peptide histidine isoleucine, atrial natriuretic peptide and neurotensin are not associated with NANC relaxation of the segments. On the other hand, apamin at 1 μM inhibited the EFS-induced relaxation by 74%. Inhibitory effects of L-NOARG and, apamin or α-chymotrypsin treatment on the EFS-induced relaxation were additive and almost complete. Exogenous nitric oxide-induced relaxation was not affected by apamin. Inhibitory junction potentials (i.j.p.''s)were recorded from longitudinal muscle cells of rat jejunum. Apamin at 200 nM abolished i.j.p.''s induced by two pulses of EFS. These results suggest that NANC relaxation in longitudinal muscle of rat jejunum involves two independent components: one is a nitric oxide-mediated minor component, and the other is an unknown substance-mediated apamin-sensitve major component that is inhibited by α-chymotrypsin treatment.View full abstractDownload PDF (518K) -
Yoichiro Isohama, Yukie Kumanda, Katsuyuki Tanaka, Hirofumi Kai, Kazuo ...1997 Volume 73 Issue 2 Pages 163-169
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSInsufficient production of pulmonary surfactant in alveolar type II cells is relevant to many lung diseases. To cure its deficiency, glucocorticoid is commonly used in clinical areas. In the present study, we investigated the effect of dexamethasone on the secretion of phosphatidylcholine, a major phospholipid of pulmonary surfactant, in a primary culture of rat alveolar type II cells. Dexamethasone had no effect on the basal secretion rate of phosphatidylcholine. Dexamethasone augmented both the phosphatidylcholine secretion and the cyclic AMP formation increased by terbutaline. Furthermore, dexamethasone increased the number of β-adrenoceptors and mRNA expression of β2-adrenoceptors in type II cells. These findings indicate that dexamethasone increases pulmonary surfactant secretion through an enhancement of β2-adrenoceptor gene expression.View full abstractDownload PDF (488K) -
Kiyotaka Nishikawa, Satoshi Yamamoto, Haruna Nagumo, Ryuichi Kato1997 Volume 73 Issue 2 Pages 171-174
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSIn primary cultured mouse epidermal cells, protein kinase C (PKC) ζconsists of multiple forms: a low salt-eluted PKCζ (1-PKCζ, 79 and 85 kDa) and a high salt-eluted PKCC (h-PKCζ, 79 and 85 kDa) by anion-exchange column chromatography (K. Nishikawa et al., Cell. Signal. 7, 491-504, 1995). In the present study, PKC isozyme-specific responses during terminal differentiation of epidermal cells, which were induced by the increase of Ca2+ -concentration in culture medium, were examined. After 24 hr-treatment with 1.8 mM Ca2+, 79-kDa 1-PKCζ in the particulate fraction was apparently shifted to the 85-kDa form. The phosphatidylserine-dependent kinase activity of this 1-PKCζ was increased in association with the shift. These results suggest the pivotal role of 1-PKCζ in the particulate fraction in the Ca2+ -induced epidermal cell differentiation processes.View full abstractDownload PDF (356K) -
Tohru Masukawa, Kunio Nakanishi1997 Volume 73 Issue 2 Pages 175-177
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSSusceptibility to enoxacin (80 mg/kg, p.o.)-induced convulsions was examined in mice coadministered with fenbufen (100 mg/kg, p.o.) over 24 hr at 3-hr intervals (light 7:00-19:00 hr). There was a marked circadian variation in the incidence of clonic and tonic convulsions and mortality. The susceptibility to enoxacin was higher around 15:00-18:00 hr and lower around 3:00-9:00 hr; the 50% clonic convulsive dose (CD50) at 9:00 and 15:00 hr was 95.0 and 56.5 mg/kg, respectively, its ratio being 1.64. Under these conditions, brain enoxacin level at 15:00 hr was increased 2.43-fold over that at 9:00 hr 30 min after enoxacin administration. Thus, the change of brain enoxacin may contribute to one of the causes of the above circadian variation.View full abstractDownload PDF (222K) -
Hiroshi Kuromi, Susumu Seino1997 Volume 73 Issue 2 Pages 179-182
Published: 1997
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSIt is reported that glucose releases ATP with insulin from pancreatic βcells. Nuramin (50-200μM), a purinoceptor blocker, reversibly and dose-dependently inhibited the rise in cytoplasmic calcium concentration ([Ca2+]i) induced by glucose and by ATP in single β cells. Suramin did not inhibit the glucose-induced increase in NAD(P)H fluorescence. The rise in [Ca2+]i induced by tolbutamide (an inhibitor of ATP-sensitive K+ channels), arginine (a cationic amino acid) and acetylcholine was unaffected by suramin (50-200 μM). This suggests that suramin inhibits the glucose-induced Ca2+ response without an inhibitory effect on glucose metabolism, K+ channels, voltage-dependent Ca2+ influx or Ca2+ release from internal Ca2+ stores and that a purinergic mechanism is involved in the glucose response in β cells.View full abstractDownload PDF (293K)
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