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1.
Cells ; 9(8)2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784475

RESUMO

A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32718702

RESUMO

OBJECTIVE: Acute kidney injury (AKI) is a serious complication of cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study was to evaluate the effects of nitric oxide (NO) supplementation to the CPB circuit on the development of cardiac surgery-associated AKI. METHODS: This prospective randomized controlled study included 96 patients with moderate risk of renal complications who underwent elective cardiac surgery with CPB. The study protocol was registered at ClinicalTrials.gov (identifier NCT03527381). Patients were randomly allocated to either NO supplementation to the CPB bypass circuit (NO treatment group; n = 48) or usual care (control group; n = 48). In the NO treatment group, 40-ppm NO was administered during the entire CPB period. The primary outcome was the incidence of AKI. RESULTS: NO treatment was associated with a significant decrease in AKI incidence (10 cases [20.8%] vs 20 cases [41.6%] in the control group; relative risk, 0.5; 95% confidence interval, 0.26-0.95; P = .023) and a higher median urine output during CPB (2.6 mL/kg/h [interquartile range (IQR), 2.1-5.08 mL/kg/h] vs 1.7 mL/kg/h [IQR, 0.80-2.50 mL/kg/h]; P = .0002). The median urinary neutrophil gelatinase-associated lipocalin level at 4 hours after surgery was significantly lower in the NO treatment group (1.12 ng/mL [IQR, 0.75-5.8 ng/mL] vs 4.62 ng/mL [IQR, 2.02-34.55 ng/mL]; P = .005). In the NO treatment group, concentrations of NO metabolites were significantly increased at 5 minutes postclamping, at 5 minutes after declamping, and at the end of the operation. Concentrations of proinflammatory and anti-inflammatory mediators and free plasma hemoglobin did not differ significantly between the 2 groups. CONCLUSIONS: NO administration in patients at moderate risk of renal complications undergoing elective cardiac surgery with CPB was associated with a lower incidence of AKI.

4.
Hypertens Res ; 43(10): 1068-1078, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32382155

RESUMO

c-Jun N-terminal kinases (JNKs) are involved in the myocardial and aortic remodeling, increased arterial tone, and arterial blood pressure elevation associated with hypertension. The aim of the present study was to investigate the antihypertensive effect of a new JNK inhibitor, 1H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), on spontaneously hypertensive rats (SHRs). Experiments were performed using normotensive Wistar-Kyoto (WKY) rats and SHRs. Experimental groups of SHRs received IQ-1S intragastrically for 6 weeks in daily doses of 5 and 50 mg/kg; experimental groups of WKY rats received 50 mg/kg IQ-1S according to the same regimen. The IQ-1S administration regimen induced decreases in systolic blood pressure, mean arterial blood pressure, total peripheral resistance, blood viscosity, hematocrit, myocardial cell cross-sectional area, and aortic wall thickness in SHRs vs untreated SHRs. There were no significant differences in systolic blood pressure values between the control and experimental groups of WKY rats during the treatment period. A concentration-dependent decrease in the tone of carotid arterial rings isolated from SHRs was observed after JNK inhibitor application in vitro. Application of the JNK inhibitor diminished endothelin-1 secretion by human umbilical vein endothelial cells in vitro. The main mechanisms of the antihypertensive effect of IQ-1S included the attenuation of blood viscosity due to decreased hematocrit, a vasodilatory effect on arterial smooth muscle cells, and a decrease in endothelin-1 production by endothelial cells.

5.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058815

RESUMO

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 µM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.


Assuntos
Isquemia Encefálica/prevenção & controle , Citidina Difosfato Colina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oximas/administração & dosagem , Quinoxalinas/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/metabolismo , Circulação Cerebrovascular , Citidina Difosfato Colina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Oximas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento
6.
J Thorac Cardiovasc Surg ; 157(6): 2328-2336.e1, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30447958

RESUMO

OBJECTIVES: The aim of this pilot study was to elucidate the effects of exogenous nitric oxide (NO) supply to the extracorporeal circulation circuit for cardioprotection against ischemia-reperfusion injury during coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). METHODS: A total of 60 patients with coronary artery disease scheduled for CABG with CPB were enrolled in a prospective randomized study. Patients were allocated randomly to receive treatment according to standard or modified CPB protocol where 40-ppm NO was added to the CPB circuit during cardiac surgery. The primary endpoint was the measurement of cardiac troponin I (cTnI). The secondary end points consisted in the measurements of creatine kinase-muscle/brain fraction (CK-MB) and vasoactive inotropic score (VIS). RESULTS: NO delivered into the CPB circuit had a cardioprotective effect. The level of cTnI was significantly lower in NO-treated group compared with the control group 6 hours after surgery: 1.79 ± 0.39 ng/mL versus 2.41 ± 0.55 ng/mL, respectively (P = .001). The CK-MB value was significantly lower in NO-treated group compared with the control group 24 hours after surgery: 47.69 ± 8.08 U/L versus 62.25 ± 9.78 U/L, respectively (P = .001); and the VIS was significantly lower in the NO-treated group 6 hours after the intervention. CONCLUSIONS: NO supply to the CPB circuit during CABG exerted a cardioprotective effect and was associated with lower levels of VIS and cardiospecific blood markers cTnI and CK-MB.


Assuntos
Ponte Cardiopulmonar/métodos , Cardiotônicos/uso terapêutico , Ponte de Artéria Coronária/métodos , Óxido Nítrico/uso terapêutico , Biomarcadores/sangue , Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/cirurgia , Creatina Quinase Forma MB/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/prevenção & controle
7.
Cell Physiol Biochem ; 21(1-3): 29-36, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18209469

RESUMO

Previously, we reported that hyposmotic swelling evoked transient vascular smooth muscle cell (SMC) contraction that was completely abolished by L-type Ca(2+) channel blockers. In contrast, sustained contraction revealed in hyper- and isoosmotically-shrunken SMCs was insensitive to L-type channel blockers and was diminished in Ca(2+)-free medium by only 30-50%. Several research groups reported cell volume-dependent cytoskeleton network rearrangements. This study examines the role of cytoskeleton proteins in cell volume-dependent contraction of endothelium-denuded vascular smooth muscle rings (VSMR) from the rat thoracic aorta. Hyperosmotic shrinkage and hyposmotic swelling were triggered by modulation of medium osmolality; isosmotic shrinkage was induced by VSMR transfer from hypo- to isosmotic medium. The relative content of globular (G) and fibrillar (F) actin was estimated by fluorescence microscopy. Hyperosmotic shrinkage and hyposmotic swelling led to elevation of the F-actin/G-actin ratio by 2.5- and 1.8-fold respectively. Contraction of shrunken and swollen VSMR was insensitive to modulators of microtubules such as vinblastine, colchicine and docetaxel. Microfilament disassembly by cytochalasin B resulted in dramatic attenuation of the maximal amplitude of contraction of hyperosmotically-shrunken and hyposmotically-swollen VSMR, and almost completely abolished the contraction triggered by isosmotic shrinkage. These data suggest that both L-type Ca(2+) channel-mediated contraction of swollen vascular SMC and Ca(2+)(o)-insensitive contractions of shrunken cells are triggered by reorganization of the microfilament network caused by elevation of the F-actin/G-actin ratio.


Assuntos
Tamanho Celular , Citoesqueleto/metabolismo , Contração Muscular , Músculo Liso Vascular/citologia , Actinas/metabolismo , Animais , Tamanho Celular/efeitos dos fármacos , Citocalasina B/farmacologia , Citoesqueleto/efeitos dos fármacos , Contração Isométrica/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Concentração Osmolar , Ratos , Ratos Wistar , Vimblastina/farmacologia
8.
Pflugers Arch ; 449(1): 42-55, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15293051

RESUMO

This study elucidates the role of cell volume in contractions of endothelium-denuded vascular smooth muscle rings (VSMR) from the rat aorta. We observed that hyposmotic swelling as well as hyper- and isosmotic shrinkage led to VSMR contractions. Swelling-induced contractions were accompanied by activation of Ca2+ influx and were abolished by nifedipine and verapamil. In contrast, contractions of shrunken cells were insensitive to the presence of L-type channel inhibitors and occurred in the absence of Ca2+ o. Thirty minutes preincubation with bumetanide, a potent Na+, K+, CI- cotransport (NKCC) inhibitor, decreased Cl(-)i content, nifedipine-sensitive 45Ca uptake and contractions triggered by modest depolarization ([K+]o = 36 mM). Elevation of [K+]o to 66 mM completely abolished the effect of bumetanide on these parameters. Bumetanide almost completely abrogated phenylephrine-induced contraction, partially suppressed contractions triggered by hyperosmotic shrinkage, but potentiated contractions of isosmotically shrunken VSMR. Our results suggest that bumetanide suppresses contraction of modestly depolarized cells via NKCC inhibition and Cl(-)i-mediated membrane hyperpolarization, whereas augmented contraction of isosmotically shrunken VSMR by bumetanide is a consequence of suppression of NKCC-mediated regulatory volume increase. The mechanism of bumetanide inhibition of contraction of phenylephrine-treated and hyperosmotically shrunken VSMR should be examined further.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Tamanho Celular , Cloretos/metabolismo , Contração Muscular/fisiologia , Músculo Liso Vascular , Potássio/metabolismo , Sódio/metabolismo , Animais , Aorta/anatomia & histologia , Aorta/metabolismo , Células Cultivadas , Meios de Cultura/química , Soluções Hipertônicas , Soluções Hipotônicas , Técnicas In Vitro , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Isoformas de Proteínas/metabolismo , Ratos , Ratos Wistar , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Membro 2 da Família 12 de Carreador de Soluto
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