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1.
Cannabis Cannabinoid Res ; 7(2): 179-187, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34468198

RESUMO

Introduction: Alpha/beta-hydrolase domain 6 (ABHD6) is an enzyme that hydrolyzes 2-arachidonoylglycerol, a high-efficiency endogenous cannabinoid. Although the endocannabinoid system has been suggested to be involved in regulation of bladder function, the roles of ABHD6 in the control of micturition remain unknown. To elucidate the physiological and pathological roles of ABHD6 in vivo, we examined phenotypes of ABHD6 knockout rats (Abhd6-/-) generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins system. Materials and Methods: Age-matched knockout and wild-type (WT) rats of both sexes were used. Results: Expression of ABHD6, assessed by quantitative real-time polymerase chain reaction and Western blot analysis, was clearly diminished in Abhd6-/- rats compared with WT rats. Mutant rats had a normal appearance, and the body weight and food consumption were similar to those of WT rats. The interval between bladder contractions assessed by continuous cystometry was significantly shorter in ABHD6 knockout rats than in WT rats when the bladder was stimulated with acetic acid. Mechanical paw withdrawal thresholds measured by von Frey testing were significantly lowered in the knockout rats than in WT rats. The plasma levels of prostaglandin E2 (PGE2) and the stable metabolite of PGE2 in Abhd6-/- rats were twice as high as that in WT rats. Conclusions: Deletion of the ABHD6 gene in rats causes more frequent urination in the stimulated bladder and hyperalgesia to non-noxious mechanical stimuli along with increased plasma PGE2.


Assuntos
Endocanabinoides , Monoacilglicerol Lipases , Animais , Dinoprostona , Endocanabinoides/metabolismo , Feminino , Hidrolases , Masculino , Monoacilglicerol Lipases/genética , Fenótipo , Ratos
2.
Anticancer Res ; 40(10): 5399-5404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988859

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate whether idarubicin (IDR) induces oxidative DNA damage in the presence of copper (II). MATERIALS AND METHODS: DNA damage was evaluated by pBR322 plasmid DNA cleavage. The formation of oxidative stress markers [O2 •- and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] was analysed. RESULTS: IDR induced DNA damage and O2 •- and 8-OHdG generation in the presence of copper (II). CONCLUSION: IDR induced oxidative DNA damage in the presence of copper (II). Since it has been reported that the concentration of copper in the serum of cancer patients is higher than that in healthy groups, IDR-induced oxidative DNA damage in the presence of copper (II) may play an important role in anticancer therapeutic strategies.


Assuntos
Antraciclinas/farmacologia , Idarubicina/farmacologia , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antraciclinas/química , Cobre/química , Dano ao DNA/efeitos dos fármacos , Humanos , Idarubicina/química , Neoplasias/genética , Neoplasias/patologia , Espécies Reativas de Oxigênio/química , Superóxido Dismutase/genética
3.
Life Sci ; 234: 116772, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31422097

RESUMO

AIMS: Ligation of the urethra to create partial bladder outlet obstruction has widely been used as an animal model of bladder obstruction, although obstructive bladder dysfunction may be due to both mechanical and functional obstruction. Previous studies in rodents have demonstrated that long-term nitric oxide (NO) deficiency can lead to detrusor overactivity, and lack of NO may thus cause impairment of bladder outlet relaxation. The aim of this study was to define the characteristics of bladder and urethral dysfunction induced by chronic NO deficiency through both in vivo and in vitro investigations. MAIN METHODS: Rats were divided into two groups, and one group received an NO synthase inhibitor (Nω-nitro-L-arginine methyl ester hydrochloride: L-NAME) in the drinking water for 4 weeks. Bladder and urethral function were evaluated by continuous cystometry and isovolumetric cystometry. In vitro functional studies of detrusor strips and measurement of the mRNA and protein expression of an ischemic marker and a gap junction protein were also performed in separate rats. KEY FINDINGS: L-NAME administration raised blood pressure and decreased plasma nitrite/nitrate level compared to the control group. L-NAME treatment increased the frequency of bladder contractions and the residual volume, and elevated urethral pressure and bladder contraction pressure. In addition, carbachol-induced contraction was reduced in isolated detrusor strips from the L-NAME group, and bladder expression of HIF-1 and connexin 43 showed upregulation. SIGNIFICANCE: These findings suggest that chronic administration of L-NAME to rats induces bladder hyperactivity with residual urine, and may provide a useful model of functional bladder obstruction.


Assuntos
NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase/antagonistas & inibidores , Obstrução do Colo da Bexiga Urinária/induzido quimicamente , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Nitratos/sangue , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Ratos , Ratos Sprague-Dawley , Uretra/metabolismo , Uretra/fisiopatologia , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/sangue
4.
Am J Respir Crit Care Med ; 198(2): 232-244, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29480750

RESUMO

RATIONALE: Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains elusive. OBJECTIVES: To determine the role of NOSs in BM cells in PH. METHODS: Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS)-/-, iNOS (inducible NOS)-/-, eNOS (endothelial NOS)-/-, and n/i/eNOSs-/- mice. MEASUREMENTS AND MAIN RESULTS: In the patients, there was a significant correlation between higher pulmonary artery systolic pressure and lower nitrite plus nitrate levels in the BAL fluid. In the mice, hypoxia-induced PH deteriorated significantly in the n/i/eNOSs-/- genotype and, to a lesser extent, in the eNOS-/- genotype as compared with the WT genotype. In the n/i/eNOSs-/- genotype exposed to hypoxia, the number of circulating BM-derived vascular smooth muscle progenitor cells was significantly larger, and transplantation of green fluorescent protein-transgenic BM cells revealed the contribution of BM cells to pulmonary vascular remodeling. Importantly, n/i/eNOSs-/--BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs-/- genotype. A total of 69 and 49 mRNAs related to immunity and inflammation, respectively, were significantly upregulated in the lungs of WT genotype mice transplanted with n/i/eNOSs-/--BM compared with those with WT-BM, suggesting the involvement of immune and inflammatory mechanisms in the exacerbation of hypoxia-induced PH caused by n/i/eNOSs-/--BM transplantation. CONCLUSIONS: These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células Precursoras de Granulócitos/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Óxido Nítrico Sintase/uso terapêutico , Animais , Humanos , Masculino , Camundongos , Modelos Animais , Substâncias Protetoras/uso terapêutico
5.
J Mol Cell Cardiol ; 77: 29-41, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25265498

RESUMO

We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1α (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1α-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model.


Assuntos
Infarto do Miocárdio/enzimologia , Óxido Nítrico Sintase/genética , Animais , Modelos Animais de Doenças , Masculino , Camundongos Knockout , Infarto do Miocárdio/genética , Nefrectomia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo
6.
Circ J ; 77(7): 1827-37, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23615023

RESUMO

BACKGROUND: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model. METHODS AND RESULTS: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113. CONCLUSIONS: These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicina Kampo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Berberina , Feminino , Humanos , Proteínas Musculares/biossíntese , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo II/biossíntese , Ovariectomia , Oxirredução/efeitos dos fármacos , Ácido Peroxinitroso/metabolismo , Pós-Menopausa/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/biossíntese , Fatores de Tempo
7.
Nitric Oxide ; 25(3): 350-9, 2011 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-21767657

RESUMO

Although all three nitric oxide (NO) synthases (nNOS, iNOS, and eNOS) are expressed in injured arteries, it remains to be elucidated the role of the NOSs in their entirety in the vascular lesion formation. We addressed this issue in mice deficient in all NOS genes. Vascular injury was induced by permanent ligation of a unilateral carotid artery in wild-type (WT), singly, and triply NOS(-/-) mice. Two weeks after the procedure, constrictive vascular remodeling and neointimal formation were recognized in the ligated arteries. While constrictive remodeling was noted in the nNOS(-/-) and iNOS(-/-) genotypes, it was most accelerated in the n/i/eNOS(-/-) genotype. While neointimal formation was evident in the eNOS(-/-) and nNOS(-/-) genotypes, it was also most aggravated in the n/i/eNOS(-/-) genotype. Those lesions were reversed by long-term treatment with isosorbide dinitrate, a NO donor. Finally, we examined the involvement of bone marrow-derived cells in the vascular lesion formation. Bone marrow from the WT, singly, or triply NOS(-/-) mice was transplanted into the WT mice, and then the carotid ligation was performed. Intriguingly, constrictive remodeling and neointimal formation were both similarly most exacerbated in the case of the n/i/eNOS(-/-) bone marrow transplantation. These results indicate that the complete disruption of all the NOS genes causes markedly accelerated vascular lesion formation caused by blood flow disruption in mice in vivo, demonstrating the crucial vasculoprotective role of the whole endogenous NOS system. Our findings also suggest that the NOS system in bone marrow-derived cells may be involved in this vasculoprotective mechanism.


Assuntos
Células da Medula Óssea/enzimologia , Endotélio Vascular/enzimologia , Óxido Nítrico Sintase/metabolismo , Animais , Pressão Sanguínea , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Artérias Carótidas/cirurgia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/metabolismo , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/genética , Nitritos/metabolismo
8.
Clin Exp Pharmacol Physiol ; 34(1-2): 55-60, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17201736

RESUMO

1. The aim of the present study was to clarify the effects of landiolol, a short-acting selective beta(1)-adrenoceptor blocking agent, on mechanical and metabolic changes in postischaemic perfused hearts. 2. Rat isolated hearts (n = 30) were randomly separated into non-ischaemic or ischaemic groups. The latter group was further divided into Krebs'-Henseleit solution (KHS)- and landiolol (30, 100 or 300 micromol/L)-treated groups. Ischaemic hearts were subjected to 25 min global ischaemia and 20 min reperfusion under atrial pacing. Time-course changes in left ventricular (LV) end-diastolic pressure (LVEDP), LV developed pressure (LVDP), peak positive velocity of change of LV pressure (LVdP/dt(max)) and coronary flow were observed along with tissue contents of adenosine triphosphate (ATP), creatine phosphate, inorganic phosphate (Pi), malondialdehyde (MDA) and lactate dehydrogenase (LDH) release in coronary effluent. The effects of landiolol on rat isolated aortic preparations under KCl contraction were also investigated. 3. Ischaemia-reperfusion significantly impaired cardiodynamics, such as LVEDP, LVDP and LVdP/dt(max), decreased myocardial ATP content and increased Pi and LDH release. In the 30 micromol/L landiolol-treated group, cardiovascular parameters impaired by ischaemia-reperfusion and increased LDH release were further exacerbated and myocardial MDA content was significantly increased. In the 300 micromol/L landiolol-treated group, cardiac contractile dysfunction was improved and myocardial MDA, ATP and Pi contents were preserved. All measurements in the 100 micromol/L landiolol-treated group were similar to those in the ischaemic KHS group. Furthermore, significant relaxations of isolated aortic preparations were obtained with landiolol 30-1000 micromol/L, suggesting a possible calcium antagonism with landiolol. 4. In conclusion, landiolol, at low concentrations, aggravated myocardial ischaemia-reperfusion injuries, whereas at high concentrations it ameliorated them. The former effect may be mediated by the production of reactive oxygen species, whereas the latter may involve calcium antagonist activity.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Morfolinas/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ureia/análogos & derivados , Vasodilatadores/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Ratos , Ratos Wistar , Ureia/farmacologia , Vasodilatação/efeitos dos fármacos
9.
J Thorac Cardiovasc Surg ; 124(4): 775-84, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12324736

RESUMO

OBJECTIVE: It has recently been proposed that nitric oxide synthase, in the presence of suboptimal levels of tetrahydrobiopterin, an essential cofactor of this enzyme, might favor increased production of oxygen radicals. The aim of this study was to clarify whether supplement with tetrahydrobiopterin would exert a cardioprotective effect against ischemia-reperfusion injury. METHODS: Isolated perfused rat hearts were subjected to 30 minutes of global ischemia and 30 minutes of reperfusion at 37 degrees C. Hearts were treated with tetrahydrobiopterin or vehicle for 5 minutes just before ischemia and during the first 5 minutes of the reperfusion period. Effects of tetrahydrobiopterin on left ventricular function, myocardial contents of lipid peroxidation and high-energy phosphates, and levels of lactate dehydrogenase and nitrite plus nitrate in perfusate during ischemia and after reperfusion were estimated and further compared with those of superoxide dismutase plus catalase or L-ascorbic acid. RESULTS: Tetrahydrobiopterin and superoxide dismutase plus catalase both improved contractile and metabolic abnormalities in reperfused hearts. On the other hand, L-ascorbic acid at a dose having an equipotent radical scavenging activity with tetrahydrobiopterin did not significantly affect the postischemic changes. Although tetrahydrobiopterin and superoxide dismutase plus catalase significantly alleviated ischemic contracture during ischemia, diminished perfusate levels of nitrite plus nitrate after reperfusion were restored only with tetrahydrobiopterin. CONCLUSION: Results demonstrated that tetrahydrobiopterin lessens ischemia-reperfusion injury in isolated perfused rat hearts, probably independent of its intrinsic radical scavenging action. The cardioprotective effect of tetrahydrobiopterin implies that tetrahydrobiopterin could be a novel and effective therapeutic option in the treatment of ischemia-reperfusion injury.


Assuntos
Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Biopterinas/farmacologia , Catalase/farmacologia , Catalase/uso terapêutico , Circulação Coronária , Modelos Animais de Doenças , Sequestradores de Radicais Livres/farmacologia , Peroxidação de Lipídeos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico
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