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Volume 71 (1996)
- Issue 4 Pages 273-
- Issue 3 Pages 187-
- Issue 2 Pages 89-
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Volume 71, Issue 3
Displaying 1-12 of 12 articles from this issue
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Philip Seeman, Roy Corbett, Diane Nam, Hubert H.M. Van Tol1996 Volume 71 Issue 3 Pages 187-204
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThis review summarizes the amino acid sequences of the human dopamine and serotonin receptors and their human variants. The review also examines the receptor basis of the atypical antipsychotic drugs that elicit less parkinsonism than the typical antipsychotics. Because the dissociation constant of a drug varies with the radioligand, the dissociation constants of many neuroleptics are here summarized for the dopamine D2-, D4- and serotonin S2A-receptors using different radioligands. Radioligands of low solubility in the membrane (having low tissue/buffer partition) result in lower values for the neuroleptic dissociation constants, compared to radioligands of high membrane solubility. Such studies yield the intrinsic K value for a neuroleptic in the absence of a competing ligand. Clozapine, for example, has an intrinsic K value of 1.6 nM at the D4-receptor, in agreement with the value of 1.6 nM when directly measured with [3H]clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo clozapine concentration to occupy 75% of the dopamine D4-receptors is derived to be ?? 13 nM. This agrees with the value of 12 to 20 nM in the plasma water (or spinal fluid) observed in treated patients. Moreover, in L-DOPA psychosis (in Parkinson''s disease), the clozapine concentration for 75% blockade of D4 is predicted to be ?? 3 nM. This agrees with the value of ?? 1.2 nM observed by Meltzer et al. in plasma water (Neuropsychopharmacology, 12, 39-45 (1995)). This analysis supports the concept and practical value of the intrinsic K values. Some atypical neuroleptics (remoxipride, clozapine, perlapine, seroquel and melperone) have high intrinsic K values (ranging from 30 to 88 nM) at the D2-receptor, making them displaceable by high levels of endogenous dopamine in the caudate/putamen. In contrast, however, typical neuroleptics (i.e., those that typically cause parkinsonism) have intrinsic K values of 0.3 to 6 nM, making them less displaceable by endogenous dopamine. A relationship exists between the neuroleptic doses for rat catalepsy and the D2/D4 ratio of the intrinsic K values. Thus, the atypical neuroleptics appear to fall into two groups, those that bind loosely to D2 and those that are selective at D4.View full abstractDownload PDF (1444K) -
Miwa Toyoda, Hiroshi Saito, Norio Matsuki1996 Volume 71 Issue 3 Pages 205-211
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe aim of the present study was to elucidate the role of carbon monoxide (CO) in learning and to compare it with that of nitric oxide (NO). Effects of an inhibitor of heme oxygenase which produces CO, Zn-protoporphyrin IX, on passive avoidance learning and spatial learning in mice were examined using step through, step down and water maze tests. Zn-protoporphyrin IX (10, 20 nmol, i.c.v.) affected neither type of learning. In contrast, N-ω-nitro-L-arginine (40 nmol, i.c.v.), an inhibitor of NO synthase, impaired spatial learning, but not passive avoidance learning. These results suggest that NO but not CO is involved in spatial learning.View full abstractDownload PDF (479K) -
Takeshi Matsuura, Tokihito Yukimura, Shokei Kim, Katsuyuki Miura, Hiro ...1996 Volume 71 Issue 3 Pages 213-222
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSBy using BQ-788 as a selective endothelin ETB-receptor antagonist and FR139317 as a selective endothelin ETA-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist (succinyl-[G1u9, A1a11.5]-endothelin-1(8-21)), in anesthetized rats. Bolus intravenous injection of endothelin-1 (0.5 nmol/kg) and IRL1620 (1.65 nmol/kg) produced a transient fall in systemic blood pressure followed by a sustained increase. The initial fall in blood pressure observed after endothelin-1 and IRL1620 administration was completely blocked by BQ-788 (0.5 μmol/kg, i.v.), whereas the pressor response was blocked by FR139317 (0.8, μmol/kg, i.v.). Renal blood flow was decreased and calculated renal vascular resistance was dramatically increased by endothelin-1 and IRL1620. The reduction of renal blood flow by endothelin-1 was significantly suppressed by FR139317 but potentiated by BQ-788. Both BQ-788 and FR139317 partially blocked the renal vasoconstriction by IRL1620. Pretreatment by BQ-788 itself decreased renal blood flow by 14.1%. These results indicate that the systemic depressor responses induced by endothelin-1 and IRL 1620 are mediated through the endothelin ETB-receptor, and the pressor responses are mediated through the endothelin ETA-receptor. In the renal vasculature of anesthetized rats, it is suggested that vasoconstriction is mediated through both endothelin ETA and ETB-receptors and that endothelin ETB-receptors may be also involved in vasodilating responses to endothelin peptides.View full abstractDownload PDF (632K) -
Akito Nishida, Ayumi Uchida-Kobayashi, Yukihiro Takemoto, Shinobu Akuz ...1996 Volume 71 Issue 3 Pages 223-230
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe determined the relative contributions of endogenous gastrin, histamine and cholinergic tone to basal acid secretion in chronic fistula rats. Results were compared with those for acid secretion in pylorus-ligated rats. In chronic fistula rats, YM022 {(R)-1-[2, 3-dihydro-l-(2''-methylphenacyl)-2-oxo5-phenyl-lH-1, 4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea} dose-dependently inhibited pentagastrinstimulated acid secretion and abolished this secretion at 1 μmol/kg, s.c., but did not affect histamine- and carbachol-induced acid secretion even at 10 μmol/kg. In contrast, famotidine at 1 μmol/kg completely inhibited not only the acid secretion induced by histamine but also those by pentagastrin and carbachol. Furthermore, atropine abolished carbachol- and pentagastrin-stimulated acid secretion and significantly suppressed histamine-stimulated acid secretion at 0.1 μmol/kg. YM022 dose-dependently inhibited basal acid secretion. The YM022 dosage required to inhibit basal acid secretion is consistent with that required to suppress pentagastrin-induced acid secretion. Famotidine (1 μmol/kg) and atropine (0.1 μmol/kg) also abolished basal acid secretion. In pylorus-ligated rats, YM022 inhibited acid secretion in a dose-dependent manner; the inhibition at 1 μmol/kg, i.v. was 65%. No additional effect was observed when rats were dosed at 30 μmol/kg. Famotidine partially inhibited acid secretion in these rats, whereas atropine abolished this secretion. These results indicate that the major part of basal acid secretion in rats is attributable to endogenous gastrin via histamine and cholinergic tone-dependent pathways. Moreover, pylorus ligation reduces the relative contribution of gastrin to acid secretion due to the activation of cholinergic tone.View full abstractDownload PDF (520K) -
Hiroshi Ozaki, Asaki Abe, Yusuke Uehigashi, Masayoshi Kinoshita, Masat ...1996 Volume 71 Issue 3 Pages 231-237
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSIn the isolated guinea pig aorta, the prostaglandin 12 analog iloprost (0.01-10 μM) inhibited the contractions induced by the thromboxane A2 analog U46619 (9, 11-dideoxy-llα, 9α-epoxymethanoprostaglandin F2α; 30 nM) and prostaglandin F2α (PGF2α, 1 μM) in a concentration-dependent manner. In contrast, iloprost only partially inhibited the high K+ (65.4 mM)-induced contraction. In the muscle stimulated with high K+, verapamil (0.3 and 10 μM)inhibited [Ca2+]i and muscle tension in parallel, whereas iloprost (1 μM) inhibited muscle tension with only a small decrease in [Ca2+]i. In the muscle stimulated with U46619 (30 nM), verapamil and iloprost decreased both [Ca2+]i and muscle tension. However, as compared with the effect of verapamil, iloprost more strongly inhibited muscle tension than [Ca2+]i. The iloprost (0.1—1 μM)-induced relaxation was accompanied by a concentration-dependent increase in cAMP content. It was further demonstrated that inhibition of the U46619-contractions was augmented in the presence of cycloxygenase inhibitors, such as indomethacin (10 μM), ibuprofen (10 μM) and aspirin (10 μM). In contrast, the inhibition of PGF2α-induced contraction was not affected by indomethacin. Similarly, the inhibitory effect of forskolin on U46619-induced contractions, but not on PGF2α-induced contraction, was enhanced by indomethacin. These results suggest that iloprost inhibits vascular smooth muscle contraction by decreasing [Ca2+]i and the Ca2+ sensitivity of contractile elements through a cAMP-dependent mechanism. The results also suggest that in U46619-stimulated muscle, vasoactive prostaglandins that counterbalance the relaxing action of cAMP may be generated.View full abstractDownload PDF (402K) -
Hiroyuki Motoie, Hiroyuki Kanoh, Stig Ogata, Kosei Kawamuki, Hisataka ...1996 Volume 71 Issue 3 Pages 239-246
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe have evaluated the effects of YM175 {disodium dihydrogen (cycloheptylamino) methylenebisphosphonate monohydrate}, a novel bisphosphonate, on bone mineral densities (BMD) at the lumbar spine and forelimb in ovariectomized beagles with dietary calcium restriction. Groups 1 and 2 were given a sham operation and Groups 3—6 were ovariectomized. One month later (month 0), a low calcium diet was given to Groups 2—6. Groups 4—6 were orally treated with YM175 at doses of 0.01, 0.1 and 1.0 mg/kg, respectively, for 18 months. Changes in BMD at the lumbar spine and left forelimb were determined serially by dual energy X-ray absorptiometry. Calcium restriction decreased lumbar BMD by 19% at month 2 and by up to 30% at month 17 compared to its baseline value, but ovariectomy itself had a minimal effect on bone mass in dogs with restricted calcium intake. YM175 (1 mg/kg) prevented the bone loss at month 2 and YM 175 at 0.1 mg/kg or more inhibited the BMD reduction at month 17. The magnitude of BMD reduction of the forelimb was less remarkable as compared to that of the lumbar spine. Urinary hydroxyproline excretion and plasma osteocalcin levels were increased by calcium restriction, indicating a high turnover of bone. YM 175 reduced hydroxyproline excretion but not osteocalcin levels. These results indicate that YM 175 prevents bone loss induced by calcium restriction and ovariectomy through partially normalizing high bone turnover.View full abstractDownload PDF (521K) -
Tsuneyuki Ebara, Katsuyuki Miura, Takeshi Matsuura, Masahito Imanishi, ...1996 Volume 71 Issue 3 Pages 247-253
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSThe present experiments were conducted to elucidate the role of platelet-activating factor (PAF) and cyclooxygenase products in the cardiovascular responses to endotoxin in anesthetized rats. Endotoxin (10 mg/kg, i.v.) induced hypotension that was accompanied by a decrease in cardiac output and an increase in calculated total peripheral resistance, suggesting that this hypotension mainly resulted from the reduced cardiac output. The endotoxin-induced decrease in cardiac output and hemoconcentration was significantly attenuated by TCV-309 (a PAF receptor antagonist), ibuprofen (a cyclooxygenase inhibitor) or S-1452 (a thromboxane A2/prostaglandin H2-receptor antagonist). During the 3-hr observation period following endotoxin administration, ibuprofen and S-1452 showed only early protection and TCV-309 showed late attenuation of the endotoxin-induced hypotension. Tachycardiac responses to endotoxin were only blocked by ibuprofen but not by TCV-309 or S-1452. These results suggest that both PAF and cyclooxygenase product(s), including thromboxane A2, mediate the decrease in cardiac output and hypotension in rat experimental endotoxic shock. Cyclooxygenase product(s) other than thromboxane A2 or prostaglandin endoperoxide may be involved in the endotoxin-induced increase in heart rate.View full abstractDownload PDF (478K) -
Shin-ichi Iwata, Takao Shimizu, Masahiro Nomoto, Takeo Fukuda1996 Volume 71 Issue 3 Pages 255-258
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe measured the number of D1-receptors (Bmax) in the striatum whose dopaminergic terminals were destroyed to various degrees by 6-hydroxydopamine (6-OHDA) to clarify the relationship between the degree of denervation and the change in Bmax for D1-receptor. Rats were sacrificed 28 days after 6-OHDA treatment, and [3H]SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine) binding capacity and monoamine content were measured in striatal homogenate. Bmax was significantly upregulated when dopamine content was reduced to less than 5% of that in the vehicletreated striatum. In contrast, it was significantly decreased when dopamine content was 5—25% of that in the vehicle-treated striatum. The D1-receptors showed either upregulation or downregulation depending on the degree of denervation.View full abstractDownload PDF (275K) -
Masahiro Nishibori, Naoki Nakaya, Shuji Mori, Masahiro Kawabata, Akihi ...1996 Volume 71 Issue 3 Pages 259-262
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSWe purified macrophage migration inhibitory factor/glycosylation inhibiting factor (MIF/GIF) from bovine brain by using an affinity column with the C-terminal region peptide of a novel serpin as a ligand. The affinity purified preparation showing a single band on SDS-PAGE contained four peptides on RP-HPLC, which were converged into two peptides time-dependently. Sequence analysis and Western blotting revealed that one was identical to bovine MIF/GIF and the other was an N-terminally modified form of MIF/GIF. These results indicated that there exist at least two forms of MIF/GIF in the bovine brain and that they have an affinity for the C-terminal portion of the serpin.View full abstractDownload PDF (245K) -
Masato Sasaki, Akio Fujimura1996 Volume 71 Issue 3 Pages 263-264
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSTo examine the renal tubular transport pathways of lomefloxacin, a new quinolone antibiotic, the agent was injected intravenously with or without pretreatment with probenecid, an organic anion, or ranitidine, an organic cation, in rats. Urinary excretion of lomefloxacin significantly decreased in the probenecid-treated animals. However, no significant decrease was observed in this parameter by pretreatment with ranitidine. These results suggest that lomefloxacin is mainly secreted in urine by the organic anion transport system, while the pathway mediated by the organic cation transport system is negligible.View full abstractDownload PDF (130K) -
Hitoshi Ohmori, Ken-ichi Haruna, Atsushi Okumura, Tatsuya Kishimoto, M ...1996 Volume 71 Issue 3 Pages 265-268
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSSubconjunctival immunization of mice with dinitrophenyl (DNP)-Ascaris plus alum led to the induction of a local anti-DNP IgE response in 8 days. Anti-DNP IgE was found to be secreted from isolated lymphocytes in the parotic lymph node neighboring the immunization site but not from those in the spleen and the mesenteric lymph node. The IgE response was also confirmed by the detection of Cε transcript in the parotic lymph node cells. Ocular topical application of betamethazone resulted in considerable suppression of the IgE response in the parotic lymph node, thus suggesting that this immunization protocol is useful for evaluating ocular topical anti-allergic drugs that are expected to suppress local IgE responses.View full abstractDownload PDF (260K) -
Kaoru Nakao, Masakatsu Takahashi, Hiroshi Kaneto1996 Volume 71 Issue 3 Pages 269-272
Published: 1996
Released on J-STAGE: April 06, 2006
JOURNAL FREE ACCESSExposure to footshock (2 mA, 1-sec duration, 0.2 Hz for 15 min; FS), forced swimming (water at 20°C for 3 min, SW) or psychological stress (using a communication box for 5 min, PSY) produced antinociceptive effects (stress-induced analgesia, S1A). Intracerebroventricular (i.c.v.) injection of glibenclamide (10-40 μg/mouse), an ATP-sensitive K+ (KATP) channel blocker, antagonized FS-SIA, while SW- and PSY-SIA were unaffected by the compound. Cromakalim (0.1-10 μg/mouse, i.c.v.), a KATP-channel opener, did not affect FS-, SW- or PSY-SIA. Thus, we provided evidence that central KATP channels participate in the production of FS-SIA but not production of SW or PSY-SIA; and we suggest that glibenclamide, through closing of KATP channels, suppresses μ-opioid receptor functions, which subsequently leads to the inhibition of FS-SIA since antinociception is produced by the activation of μ-receptors.View full abstractDownload PDF (248K)
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