Oxidative stress conditions such as oxidant stimuli, inflammation, exposure to xenobiotics and ionizing irradiation provoke cellular responses, principally involving transcriptional activation of genes encoding proteins that participate in the defense against oxidative tissue injuries. Excess of free heme, which is released from hemeproteins under these conditions, may constitute a major threat because it catalyzes the formation of reactive oxygen species. Exposure of mammalian cells to oxidative stimuli induces heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, as well as the 32-kDa heat shock protein. In various tissue injury systems, HO-1 induction has been shown to confer protection, while its abrogation has been shown to accelerate cellular injuries. In this review, recent findings concerning the role of HO-1 as a protective response against oxidative stress conditions are summarized, with a particular emphasis on its protective role in ischemic acute renal failure.
{"title":"Fundamental role of heme oxygenase in the protection against ischemic acute renal failure.","authors":"R. Akagi, Toru Takahashi, S. Sassa","doi":"10.1254/JJP.88.127","DOIUrl":"https://doi.org/10.1254/JJP.88.127","url":null,"abstract":"Oxidative stress conditions such as oxidant stimuli, inflammation, exposure to xenobiotics and ionizing irradiation provoke cellular responses, principally involving transcriptional activation of genes encoding proteins that participate in the defense against oxidative tissue injuries. Excess of free heme, which is released from hemeproteins under these conditions, may constitute a major threat because it catalyzes the formation of reactive oxygen species. Exposure of mammalian cells to oxidative stimuli induces heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, as well as the 32-kDa heat shock protein. In various tissue injury systems, HO-1 induction has been shown to confer protection, while its abrogation has been shown to accelerate cellular injuries. In this review, recent findings concerning the role of HO-1 as a protective response against oxidative stress conditions are summarized, with a particular emphasis on its protective role in ischemic acute renal failure.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"26 1","pages":"127-32"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78837473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Weinberg, M. N. Cordeiro, LimaMariaElena De, L. C. Oliveira, C. Diniz
Phoneutria nigriventer spider venom has been described as acting on several cardiovascular sites. In the present paper, a semi-purified fraction of this spider venom was studied to observe any contractile or relaxing effect in rat mesenteric arterial rings (MAR). Spider venom was first fractionated by gel filtration and subsequently by gradual isocratic steps in 0.1% trifluoroacetic acid. The first fraction of this last fractionation step is studied in the present paper and due to its main effect, it was named NORF (nitric oxide releasing fraction). No direct contractile effect was induced by NORF in relaxed MAR, suggesting no NORF-induced neurotransmitter release in this preparation. No significant influence of NORF was observed on concentration-response curves to phenylephrine on endothelium-denuded MAR, but a significant inhibitory shift of concentration-respense curves was observed on endothelium-preserved MAR (EC50 = 0.39 +/- 0.07 microM for control and EC50 = 0.68 +/- 0.14 microM with NORF). NORF induced concentration-dependent relaxation in endothelium-preserved phenylephrine pre-contracted MAR but not in endothelium-denuded MAR. NORF-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-NAME (N(omega)-nitro-arginine methyl ester). Indomethacin or HOE-140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) had no significant effect on NORF-induced relaxation. Acetylcholine- and NORF-induced relaxation of pre-contracted MAR were differently inhibited by atropine. The pA2 value for atropine-acetylcholine was 9.78 +/- 0.06 and that for atropine-NORF was 8.53 +/- 0.30 (P<0.01). These observations suggest that NORF induces concentration-dependent liberation of nitric oxide from MAR endothelium and that a non-muscarinic mechanism might be involved in this effect. Our data suggest no involvement of prostanoids or bradykinin in the relaxing mechanism.
{"title":"Endothelium-dependent relaxation of rat mesenteric arterial rings by a Phoneutria nigriventer venom fraction.","authors":"M. Weinberg, M. N. Cordeiro, LimaMariaElena De, L. C. Oliveira, C. Diniz","doi":"10.1254/JJP.88.189","DOIUrl":"https://doi.org/10.1254/JJP.88.189","url":null,"abstract":"Phoneutria nigriventer spider venom has been described as acting on several cardiovascular sites. In the present paper, a semi-purified fraction of this spider venom was studied to observe any contractile or relaxing effect in rat mesenteric arterial rings (MAR). Spider venom was first fractionated by gel filtration and subsequently by gradual isocratic steps in 0.1% trifluoroacetic acid. The first fraction of this last fractionation step is studied in the present paper and due to its main effect, it was named NORF (nitric oxide releasing fraction). No direct contractile effect was induced by NORF in relaxed MAR, suggesting no NORF-induced neurotransmitter release in this preparation. No significant influence of NORF was observed on concentration-response curves to phenylephrine on endothelium-denuded MAR, but a significant inhibitory shift of concentration-respense curves was observed on endothelium-preserved MAR (EC50 = 0.39 +/- 0.07 microM for control and EC50 = 0.68 +/- 0.14 microM with NORF). NORF induced concentration-dependent relaxation in endothelium-preserved phenylephrine pre-contracted MAR but not in endothelium-denuded MAR. NORF-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-NAME (N(omega)-nitro-arginine methyl ester). Indomethacin or HOE-140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) had no significant effect on NORF-induced relaxation. Acetylcholine- and NORF-induced relaxation of pre-contracted MAR were differently inhibited by atropine. The pA2 value for atropine-acetylcholine was 9.78 +/- 0.06 and that for atropine-NORF was 8.53 +/- 0.30 (P<0.01). These observations suggest that NORF induces concentration-dependent liberation of nitric oxide from MAR endothelium and that a non-muscarinic mechanism might be involved in this effect. Our data suggest no involvement of prostanoids or bradykinin in the relaxing mechanism.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"27 1","pages":"189-96"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80004417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.
{"title":"Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters.","authors":"K. Okumura, D. Jin, S. Takai, M. Miyazaki","doi":"10.1254/JJP.88.183","DOIUrl":"https://doi.org/10.1254/JJP.88.183","url":null,"abstract":"This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"37 1","pages":"183-8"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79381667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The present study was designed to clarify the role of angiotensin II (Ang II) in modulating renal tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) production and to investigate the effect of one dose of Ang II inhibitor on cytokines production following lipopolysaccharide (LPS) to cause endotoxemia. Two studies were performed: 1) Ang II was infused intravenously at a rate of 0.2 microg/kg per minute for 4 h in rats and then kidneys were collected to assay TNF-alpha and IL-6 mRNA levels; 2) Four-week-old Wistar rats pre-treated with angiotensin-converting enzyme inhibitor, enalapril, or type I Ang II-receptor antagonist, TCV-116, were injected with LPS (0.1, 0.5, 1.0 mg, i.p.), and then 2 or 4 h later, kidneys were collected to assay TNF-alpha, IL-6, renin and angiotensinogen mRNA levels. After a 4-h intravenous infusion of Ang II, renal TNF-alpha or IL-6 mRNA level significantly increased 1.9-fold or 2.1-fold (each P<0.05) to the control level, respectively. LPS stimulated TNF-alpha, IL-6 and angiotensinogen mRNA levels in the kidney but in rats given enalapril or TCV-116, LPS-induced IL-6 and TNF-alpha mRNA levels were completely suppressed (each P<0.05). This suggests that a single dose of renin-angiotensin system inhibitor suppressed renal IL-6 and TNF-alpha production and may prevent cytokine-induced renal damage during endotoxemia.
{"title":"Suppression of endotoxin-induced renal tumor necrosis factor-alpha and interleukin-6 mRNA by renin-angiotensin system inhibitors.","authors":"R. Niimi, A. Nakamura, Y. Yanagawa","doi":"10.1254/JJP.88.139","DOIUrl":"https://doi.org/10.1254/JJP.88.139","url":null,"abstract":"The present study was designed to clarify the role of angiotensin II (Ang II) in modulating renal tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) production and to investigate the effect of one dose of Ang II inhibitor on cytokines production following lipopolysaccharide (LPS) to cause endotoxemia. Two studies were performed: 1) Ang II was infused intravenously at a rate of 0.2 microg/kg per minute for 4 h in rats and then kidneys were collected to assay TNF-alpha and IL-6 mRNA levels; 2) Four-week-old Wistar rats pre-treated with angiotensin-converting enzyme inhibitor, enalapril, or type I Ang II-receptor antagonist, TCV-116, were injected with LPS (0.1, 0.5, 1.0 mg, i.p.), and then 2 or 4 h later, kidneys were collected to assay TNF-alpha, IL-6, renin and angiotensinogen mRNA levels. After a 4-h intravenous infusion of Ang II, renal TNF-alpha or IL-6 mRNA level significantly increased 1.9-fold or 2.1-fold (each P<0.05) to the control level, respectively. LPS stimulated TNF-alpha, IL-6 and angiotensinogen mRNA levels in the kidney but in rats given enalapril or TCV-116, LPS-induced IL-6 and TNF-alpha mRNA levels were completely suppressed (each P<0.05). This suggests that a single dose of renin-angiotensin system inhibitor suppressed renal IL-6 and TNF-alpha production and may prevent cytokine-induced renal damage during endotoxemia.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"23 1","pages":"139-45"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84710225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyloid beta (A beta) is the principal constituent of senile plaques in Alzheimer's disease patients. We investigated whether A beta and glutamate affect long-term potentiation (LTP) in rat hippocampal slices. Pretreatment with 1 microM A beta1-42 alone for 3 h slightly inhibited LTP; however, the potentiation was maintained for 60 min. Although the impairment was not observed by pretreatment with 30 microM glutamate alone for 3 h, pretreatment with A beta1-42 and glutamate impaired LTP significantly. These results raise the possibility that neurotoxicity of A beta is exacerbated by the enhancement of susceptibility to excitatory amino acids.
淀粉样蛋白(A β)是阿尔茨海默病患者老年斑的主要成分。我们研究了A β和谷氨酸是否影响大鼠海马切片的长期增强(LTP)。1 μ m A β 1-42单独预处理3 h，对LTP有轻微抑制作用;然而，增强作用维持了60分钟。尽管单独用30微米谷氨酸预处理3小时未观察到损伤，但A β 1-42和谷氨酸预处理显著损害了LTP。这些结果提出了A β的神经毒性通过增强对兴奋性氨基酸的敏感性而加剧的可能性。
{"title":"Glutamate exacerbates amyloid beta1-42-induced impairment of long-term potentiation in rat hippocampal slices.","authors":"Y. Nakagami, T. Oda","doi":"10.1254/JJP.88.223","DOIUrl":"https://doi.org/10.1254/JJP.88.223","url":null,"abstract":"Amyloid beta (A beta) is the principal constituent of senile plaques in Alzheimer's disease patients. We investigated whether A beta and glutamate affect long-term potentiation (LTP) in rat hippocampal slices. Pretreatment with 1 microM A beta1-42 alone for 3 h slightly inhibited LTP; however, the potentiation was maintained for 60 min. Although the impairment was not observed by pretreatment with 30 microM glutamate alone for 3 h, pretreatment with A beta1-42 and glutamate impaired LTP significantly. These results raise the possibility that neurotoxicity of A beta is exacerbated by the enhancement of susceptibility to excitatory amino acids.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"1 1","pages":"223-6"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89136053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tomonori Nakamura, A. Sakai, I. Isogami, K. Noda, K. Ueno, S. Yano
As a way of alleviating severe constipation in cancer patients taking morphine to relieve pain, effects of Dai-kenchu-to (DKT), a traditional Japanese herbal medicine (Kampo medicine), on gastrointestinal transit in mice or on the isolated guinea pig ileum were studied in special reference to morphine. Without altering the anti-nociceptive effect of morphine, DKT was significantly effective against morphine-induced disorder of gastrointestinal transit in mice as assessed by the charcoal meal test for the intestine and measurement of transit time for the colon tract. The results of in vitro studies with guinea pig ileum suggest that abatement of morphine-induced disorder of transit by DKT is caused by both moderate contraction of morphine-treated longitudinal muscle and relaxation of morphine-induced tonic contraction of circular muscle.
{"title":"Abatement of morphine-induced slowing in gastrointestinal transit by Dai-kenchu-to, a traditional Japanese herbal medicine.","authors":"Tomonori Nakamura, A. Sakai, I. Isogami, K. Noda, K. Ueno, S. Yano","doi":"10.1254/JJP.88.217","DOIUrl":"https://doi.org/10.1254/JJP.88.217","url":null,"abstract":"As a way of alleviating severe constipation in cancer patients taking morphine to relieve pain, effects of Dai-kenchu-to (DKT), a traditional Japanese herbal medicine (Kampo medicine), on gastrointestinal transit in mice or on the isolated guinea pig ileum were studied in special reference to morphine. Without altering the anti-nociceptive effect of morphine, DKT was significantly effective against morphine-induced disorder of gastrointestinal transit in mice as assessed by the charcoal meal test for the intestine and measurement of transit time for the colon tract. The results of in vitro studies with guinea pig ileum suggest that abatement of morphine-induced disorder of transit by DKT is caused by both moderate contraction of morphine-treated longitudinal muscle and relaxation of morphine-induced tonic contraction of circular muscle.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"9 1","pages":"217-21"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77737130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ohkita, M. Takaoka, Yutaka Kobayashi, Eriko Itoh, Hiroko Uemachi, Y. Matsumura
We examined whether the proteasome could regulate endothelin (ET)-1 production in vascular endothelial cells (ECs). A proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal (PSI) significantly decreased ET-1 release from ECs by about 25% of the basal release. PSI also suppressed tumor necrosis factor (TNF)-alpha-induced ET-1 release from ECs in a dose-dependent manner. Similar inhibitory effects were observed using another proteasome inhibitor lactacystin, whereas a calpain inhibitor calpeptin had no apparent effect on ET-1 release. Furthermore, PSI significantly attenuated prepro ET-1 mRNA expression under basal and TNF-alpha-stimulated conditions. Electrophoretic mobility shift assay showed that proteasome inhibitors diminished TNF-alpha-stimulated nuclear factor-kappa B (NF-kappaB) activation in ECs. Pretreatment with antioxidants, pyrrolidine dithiocarbamate and alpha-lipoic acid, both of which are known to be suppressors of NF-kappaB activation, effectively attenuated basal and TNF-alpha-induced ET-1 release. Thus, a proteasome-dependent proteolytic pathway is at least partly involved in ET-1 production under basal conditions, and this proteolytic pathway seems to have a crucial role in ET-1 production enhanced by TNF-alpha. The reduction of NF-kappaB activation may be involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression and ET-1 release.
{"title":"Involvement of proteasome in endothelin-1 production in cultured vascular endothelial cells.","authors":"M. Ohkita, M. Takaoka, Yutaka Kobayashi, Eriko Itoh, Hiroko Uemachi, Y. Matsumura","doi":"10.1254/JJP.88.197","DOIUrl":"https://doi.org/10.1254/JJP.88.197","url":null,"abstract":"We examined whether the proteasome could regulate endothelin (ET)-1 production in vascular endothelial cells (ECs). A proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal (PSI) significantly decreased ET-1 release from ECs by about 25% of the basal release. PSI also suppressed tumor necrosis factor (TNF)-alpha-induced ET-1 release from ECs in a dose-dependent manner. Similar inhibitory effects were observed using another proteasome inhibitor lactacystin, whereas a calpain inhibitor calpeptin had no apparent effect on ET-1 release. Furthermore, PSI significantly attenuated prepro ET-1 mRNA expression under basal and TNF-alpha-stimulated conditions. Electrophoretic mobility shift assay showed that proteasome inhibitors diminished TNF-alpha-stimulated nuclear factor-kappa B (NF-kappaB) activation in ECs. Pretreatment with antioxidants, pyrrolidine dithiocarbamate and alpha-lipoic acid, both of which are known to be suppressors of NF-kappaB activation, effectively attenuated basal and TNF-alpha-induced ET-1 release. Thus, a proteasome-dependent proteolytic pathway is at least partly involved in ET-1 production under basal conditions, and this proteolytic pathway seems to have a crucial role in ET-1 production enhanced by TNF-alpha. The reduction of NF-kappaB activation may be involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression and ET-1 release.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"16 1","pages":"197-205"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73705634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Both retrospective and prospective clinical studies have demonstrated positive associations of smoking with psychiatric disorders such as schizophrenia, depression and anxiety. Neuronal nicotinic acetylcholine receptors (nAChR) belong to a family of ligand-gated ion channels that are widely distributed in the brain. The pre-synaptically located nAChR, which are composed of alpha3 or alpha4 subunits in combination with beta2 subunit on axon terminals, modulate the multiple transmission release. Several studies indicated which individual nicotinic receptor subtype is responsible for mediating each of the behavioral effects of nicotine. A reduced number of alpha7 nicotinic receptor subtypes in the hippocampus were reported in schizophrenic patients. In addition, it was assumed that nicotine provided useful therapeutic treatment for a variety of cognitive impairments including those found in Alzheimer's disease, schizophrenia and attention deficit hyperactive disorder. Both alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are involved in these phenomena. In the genetic depressive rats, nicotine showed antidepressant-like effects in forced swim models of depression, suggesting the involvement of alpha4beta2 nicotinic receptor in this phenomenon. Thus, it appears likely that pre-synaptic nAChR on monoaminergic fibers are composed of alpha3 or alpha4 subunits in combination with the beta2 subunit, and these subunit compositions mediate dopaminergic and noradrenergic release, and glutamate is mainly controlled by the alpha7 subunit. All these findings suggest that nicotine and other nicotinic drugs warrant further study for possible clinical prescription to psychiatric disorders.
{"title":"Neuronal nicotinic receptor and psychiatric disorders: functional and behavioral effects of nicotine.","authors":"H. Araki, K. Suemaru, Y. Gomita","doi":"10.1254/JJP.88.133","DOIUrl":"https://doi.org/10.1254/JJP.88.133","url":null,"abstract":"Both retrospective and prospective clinical studies have demonstrated positive associations of smoking with psychiatric disorders such as schizophrenia, depression and anxiety. Neuronal nicotinic acetylcholine receptors (nAChR) belong to a family of ligand-gated ion channels that are widely distributed in the brain. The pre-synaptically located nAChR, which are composed of alpha3 or alpha4 subunits in combination with beta2 subunit on axon terminals, modulate the multiple transmission release. Several studies indicated which individual nicotinic receptor subtype is responsible for mediating each of the behavioral effects of nicotine. A reduced number of alpha7 nicotinic receptor subtypes in the hippocampus were reported in schizophrenic patients. In addition, it was assumed that nicotine provided useful therapeutic treatment for a variety of cognitive impairments including those found in Alzheimer's disease, schizophrenia and attention deficit hyperactive disorder. Both alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are involved in these phenomena. In the genetic depressive rats, nicotine showed antidepressant-like effects in forced swim models of depression, suggesting the involvement of alpha4beta2 nicotinic receptor in this phenomenon. Thus, it appears likely that pre-synaptic nAChR on monoaminergic fibers are composed of alpha3 or alpha4 subunits in combination with the beta2 subunit, and these subunit compositions mediate dopaminergic and noradrenergic release, and glutamate is mainly controlled by the alpha7 subunit. All these findings suggest that nicotine and other nicotinic drugs warrant further study for possible clinical prescription to psychiatric disorders.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"35 1","pages":"133-8"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79048305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Golbidi, H. Moriuchi, T. Irie, T. Ghafghazi, V. Hajhashemi
We examined which of the known properties of trifluoperazine, including calmodulin inhibition, are involved in its analgesic effect. Furthermore, we tried to find any possible interaction between opioidergic system and calmodulin inhibition-induced analgesia. Intrathecal trifluoperazine (1, 10, 100 microg) showed a biphasic effect in the formalin test; i.e., analgesia at relatively low doses (1, 10 microg) and hyperalgesia at a high dose (100 microg). No analgesic effects were observed after intrathecal injection of sulpiride (1, 10, 100 microg), atropine (0.1, 1, 10 microg), phentolamine (0.1, 1, 10 microg) and brompheniramine (0.1, 1, 10 microg). Meanwhile, intrathecal calmidazolium (10, 50, 250 microg) induced a dose-dependent analgesia. Histamine (1 microg), physostigmine (1 microg), bromocriptine (1 microg) and norepinephrine (1 microg) did not affect trifluoperazine-induced analgesia. Calcium (20 microg) attenuated the antinociceptive effect of trifluoperazine and inhibited the analgesic effect of calmidazolium. Finally, naloxone (2 mg/kg) decreased trifluoperazine-induced antinociception but did not have any effects on calmidazolium-induced analgesia. We concluded that calmodulin inhibition may be involved in the analgesia produced by trifluoperazine. With increasing doses of trifluoperazine, the algesic effect seems to overcome the analgesic effect. It is also suggested that the opioidergic system does not interact with calmodulin inhibition-induced analgesia even though this system has a possible role in trifluoperazine-induced analgesia.
{"title":"Involvement of calmodulin inhibition in analgesia induced with low doses of intrathecal trifluoperazine.","authors":"S. Golbidi, H. Moriuchi, T. Irie, T. Ghafghazi, V. Hajhashemi","doi":"10.1254/JJP.88.151","DOIUrl":"https://doi.org/10.1254/JJP.88.151","url":null,"abstract":"We examined which of the known properties of trifluoperazine, including calmodulin inhibition, are involved in its analgesic effect. Furthermore, we tried to find any possible interaction between opioidergic system and calmodulin inhibition-induced analgesia. Intrathecal trifluoperazine (1, 10, 100 microg) showed a biphasic effect in the formalin test; i.e., analgesia at relatively low doses (1, 10 microg) and hyperalgesia at a high dose (100 microg). No analgesic effects were observed after intrathecal injection of sulpiride (1, 10, 100 microg), atropine (0.1, 1, 10 microg), phentolamine (0.1, 1, 10 microg) and brompheniramine (0.1, 1, 10 microg). Meanwhile, intrathecal calmidazolium (10, 50, 250 microg) induced a dose-dependent analgesia. Histamine (1 microg), physostigmine (1 microg), bromocriptine (1 microg) and norepinephrine (1 microg) did not affect trifluoperazine-induced analgesia. Calcium (20 microg) attenuated the antinociceptive effect of trifluoperazine and inhibited the analgesic effect of calmidazolium. Finally, naloxone (2 mg/kg) decreased trifluoperazine-induced antinociception but did not have any effects on calmidazolium-induced analgesia. We concluded that calmodulin inhibition may be involved in the analgesia produced by trifluoperazine. With increasing doses of trifluoperazine, the algesic effect seems to overcome the analgesic effect. It is also suggested that the opioidergic system does not interact with calmodulin inhibition-induced analgesia even though this system has a possible role in trifluoperazine-induced analgesia.","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"34 1","pages":"151-7"},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77036789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effect of antisense oligodeoxynucleotides (ODNs) of plasma membrane Ca2+-pumping ATPase (PMCA) on rat aortic vascular smooth muscle cells (VSMCs) in primary culture was examined. More than 80% of the PMCA expressed in cultured VSMCs was the PMCA-1B subtype. Exposed to antisense ODNs against PMCA-1, not only the expression of the PMCA protein but also mRNA of PMCA-1B was diminished in a concentration-dependent manner. Extracellular Na+-independent 45Ca2+ efflux catalyzed via PMCA was inhibited with antisense ODNs. Both the resting and ionomycin- or ATP-stimulated levels of intracellular Ca2+ were increased by antisense ODNs. Furthermore, prolonged treatment with antisense ODNs caused apoptosis in VSMCs. The occurrence of apoptosis was inhibited by FK506, a potent immunosuppressant. These results demonstrate that the PMCA was specifically inhibited by antisense ODNs and suggest that PMCA plays an important role in regulation of intracellular Ca2+ concentrations, especially at the resting condition to prevent an occurrence of apoptosis that may be induced through the activation of calcineurin.
{"title":"Antisense-Inhibition of Plasma Membrane Ca2+ Pump Induces Apoptosis in Vascular Smooth Muscle Cells","authors":"Satoshi Sasamura , Ken-Ichi Furukawa , Miwa Shiratori , Shigeru Motomura , Yasushi Ohizumi","doi":"10.1254/jjp.90.164","DOIUrl":"10.1254/jjp.90.164","url":null,"abstract":"<div><p>The effect of antisense oligodeoxynucleotides (ODNs) of plasma membrane Ca<sup>2+</sup>-pumping ATPase (PMCA) on rat aortic vascular smooth muscle cells (VSMCs) in primary culture was examined. More than 80% of the PMCA expressed in cultured VSMCs was the PMCA-1B subtype. Exposed to antisense ODNs against PMCA-1, not only the expression of the PMCA protein but also mRNA of PMCA-1B was diminished in a concentration-dependent manner. Extracellular Na+-independent <sup>45</sup>Ca<sup>2+</sup> efflux catalyzed via PMCA was inhibited with antisense ODNs. Both the resting and ionomycin- or ATP-stimulated levels of intracellular Ca<sup>2+</sup> were increased by antisense ODNs. Furthermore, prolonged treatment with antisense ODNs caused apoptosis in VSMCs. The occurrence of apoptosis was inhibited by FK506, a potent immunosuppressant. These results demonstrate that the PMCA was specifically inhibited by antisense ODNs and suggest that PMCA plays an important role in regulation of intracellular Ca<sup>2+</sup> concentrations, especially at the resting condition to prevent an occurrence of apoptosis that may be induced through the activation of calcineurin.</p></div>","PeriodicalId":14750,"journal":{"name":"Japanese journal of pharmacology","volume":"90 2","pages":"Pages 164-172"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1254/jjp.90.164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22100874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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