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1.
Sheng Li Xue Bao ; 71(4): 527-536, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440749

RESUMO

The aim of this study was to investigate whether G protein-coupled estrogen receptor (GPER) could alleviate hippocampal neuron injury under cerebral ischemia-reperfusion injury (CIRI) by acting on endoplasmic reticulum stress (ERS). The CIRI animal model was established by middle cerebral artery occlusion (MCAO). Female ovariectomized (OVX) Sprague-Dawley (SD) female rats were randomly divided into 4 groups: control, ischemia-reperfusion injury (MCAO), vehicle (MCAO+DMSO), and GPER-specific agonist G1 (MCAO+G1) groups. The neurobehavioral score was assessed by the Longa score method, the morphological changes of the neurons were observed by the Nissl staining, the cerebral infarction was detected by the TTC staining, and the neural apoptosis in the hippocampal CA1 region was detected by TUNEL staining. The distribution and expression of GRP78 (78 kDa glucose-regulated protein 78) in the hippocampal CA1 region were observed by immunofluorescent staining. The protein expression levels of GRP78, Caspase-12, CHOP and Caspase-3 were detected by Western blot, and the mRNA expression levels of GRP78, Caspase-12, and CHOP were detected by the real-time PCR. The results showed that the neurobehavioral score, cerebral infarct volume, cellular apoptosis index, as well as GRP78, Caspase-12 and CHOP protein and mRNA expression levels in the MCAO group were significantly higher than those of control group. And G1 reversed the above-mentioned changes in the MCAO+G1 group. These results suggest that the activation of GPER can decrease the apoptosis of hippocampal neurons and relieve CIRI, and its mechanism may involve the inhibition of ERS.


Assuntos
Isquemia Encefálica , Estresse do Retículo Endoplasmático , Neurônios/citologia , Receptores Estrogênicos/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Traumatismo por Reperfusão , Animais , Apoptose , Região CA1 Hipocampal/citologia , Caspase 12/metabolismo , Caspase 3/metabolismo , Feminino , Proteínas de Choque Térmico/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Transcrição CHOP/metabolismo
2.
Mol Med Rep ; 20(2): 1593-1604, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257512

RESUMO

The present study was designed to investigate the expression and function of transmembrane protein 16 (TMEM16A), a calcium­activated chloride channel (CaCC), in the stria vascularis (SV) of the cochlea of guinea pigs at different ages, and to understand the role of CaCCs in the pathogenesis of presbycusis (age­related hearing loss), the most common type of sensorineural hearing loss that occurs with natural aging. Guinea pigs were divided into the following groups: 2 weeks (young group), 3 months (youth group), 1 year (adult group), D­galactose intervention (D­gal group; aging model induced by subcutaneous injection of D­galactose) and T16Ainh­A01 (intraperitoneal injection of 50 µg/kg/day TMEM16A inhibitor T16Ainh­A01 for 2 weeks). Differences in the hearing of guinea pigs between the various age groups were analyzed using auditory brainstem response (ABR), and immunofluorescence staining was performed to detect TMEM16A expression in the SV and determine the distribution. Reverse transcription­quantitative PCR and western blot analyses were conducted to detect the mRNA and protein levels of TMEM16A in SV in the different age groups. Morris water maze behavior analysis demonstrated that spatial learning ability and memory were damaged in the D­gal group. Superoxide dismutase activity and malondialdehyde content assays indicated that there was oxidative stress damage in the D­gal group. The ABR thresholds gradually increased with age, and the increase in the T16Ainh­A01 group was pronounced. Immunofluorescence analysis in the cochlear SV of guinea pigs in different groups revealed that expression of TMEM16A increased with increasing age (2 weeks to 1 year); fluorescence intensity was reduced in the D­gal model of aging. As the guinea pigs continued to mature, the protein and mRNA contents of TMEM16A in the cochlea SV increased gradually, but were decreased in the D­gal group. The findings indicated that CaCCs in the cochlear SV of guinea pigs were associated with the development of hearing in guinea pigs, and that downregulation of TMEM16A may be associated with age­associated hearing loss.

3.
Sheng Li Xue Bao ; 71(3): 395-404, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31218330

RESUMO

The present study was designed to examine whether Ramipril (an inhibitor of angiotensin-converting enzyme) affected spontaneous hypertension-induced injury of cerebral artery by regulating connexin 43 (Cx43) expression. Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were randomly divided into WKY, WKY + Ramipril, SHR, and SHR + Ramipril groups (n = 8). The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin-eosin (HE) staining was used to show vascular remodeling. The expression and distribution of Cx43 was determined by using immunofluorescence and immunohistochemistry analysis. The protein and mRNA levels of Cx43 were examined by Western blot and real-time PCR analysis, respectively. The results showed that chronic Ramipril treatment significantly attenuated blood pressure elevation (P < 0.01, n = 8) and blood vessel wall thickness in SHR (P < 0.01, n = 8). The cerebral artery contraction rate in the SHR group was higher than that in the WKY group (P < 0.05, n = 8). The cerebral artery contraction rate in the SHR + Ramipril group was lower than that in the SHR group (P < 0.05, n = 8). Pretreatment with 2-APB (Cx43 non-specific blocker) or Gap26 (Cx43 specific blocker) significantly decreased the vasoconstriction rate, while pretreatment with AAP10 (Cx43 non-specific agonist) significantly increased the vasoconstriction in the SHR + Ramipril group (P < 0.05, n = 8). In addition, the expression of Cx43 mRNA and protein in cerebral arteries of SHR group was higher than that of WKY group (P < 0.05, n = 8). The mRNA and protein expression of Cx43 in cerebral arteries of SHR + Ramipril group was significantly lower than that of SHR group (P < 0.05, n = 8). These results suggest that Ramipril can down-regulate the expression of Cx43 mRNA and protein in cerebral arterial cells of SHR, lower blood pressure, promote vasodilation, and improve arterial damage and vascular dysfunction caused by hypertension.


Assuntos
Artérias Cerebrais/efeitos dos fármacos , Conexina 43/metabolismo , Ramipril/farmacologia , Remodelação Vascular , Animais , Pressão Sanguínea , Artérias Cerebrais/metabolismo , Hipertensão/tratamento farmacológico , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
4.
Mol Med Rep ; 19(5): 3743-3755, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896818

RESUMO

Gap junctions (GJs) formed by connexins (Cxs) in T lymphocytes have been reported to have important roles in the T lymphocyte­driven inflammatory response and hypertension­mediated inflammation. Estrogen has a protective effect on cardiovascular diseases, including hypertension and it attenuates excessive inflammatory responses in certain autoimmune diseases. However, the mechanisms involved in regulating the pro­inflammatory response are complex and poorly understood. The current study investigated whether ß­estradiol suppresses hypertension and pro­inflammatory stimuli­mediated inflammatory responses by regulating Cxs and Cx­mediated GJs in peripheral blood lymphocytes. Male, 16­week­old spontaneously hypertensive rats (SHR) and Wistar­Kyoto rats (WKY) rats were randomly divided into the following three groups: WKY rats, vehicle (saline)­treated SHRs, and ß­estradiol (20 µg/kg/day)­treated SHRs. ß­estradiol was administered subcutaneously for 5 weeks. Hematoxylin and eosin staining was performed to evaluate target organ injury. Flow cytometry and ELISA were used to measure the populations of T lymphocyte subtypes in the peripheral blood, and expression of Cx40/Cx43 in T cell subtypes, and pro­inflammation cytokines levels, respectively. ELISA, a dye transfer technique, immunofluorescence and immunoblotting were used to analyze the effect of ß­estradiol on pro­inflammatory cytokine secretion, Cx­mediated GJs and the expression of Cxs in concanavalin A (Con A)­stimulated peripheral blood lymphocytes isolated from WKY rat. ß­estradiol significantly decreased blood pressure and inhibited hypertension­induced target organ injury in SHRs. Additionally, ß­estradiol treatment significantly improved the immune homeostasis of SHRs, as demonstrated by the decreased percentage of cluster of differentiation (CD)4+/CD8+ T­cell subset ratio, reduced serum levels of pro­inflammatory cytokines and increased the percentage of CD4+CD25+ T cells. ß­estradiol also markedly reduced the expression of Cx40/Cx43 in T lymphocytes from SHRs. In vitro, ß­estradiol significantly suppressed the production of pro­inflammatory cytokines, reduced communication via Cx­mediated gap junctions and decreased the expression of Cx40/Cx43 in Con A­stimulated lymphocytes. These results indicate that ß­estradiol attenuates inflammation and end organ damage in hypertension, which may be partially mediated via downregulated expression of Cxs and reduced function of Cx­mediated GJ.


Assuntos
Concanavalina A/efeitos adversos , Conexinas/metabolismo , Estradiol/farmacologia , Hipertensão/complicações , Inflamação/etiologia , Inflamação/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Citocinas/sangue , Citocinas/metabolismo , Junções Comunicantes/metabolismo , Expressão Gênica , Hipertensão/fisiopatologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Ratos , Remodelação Vascular/efeitos dos fármacos
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(2): 189-194, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30782286

RESUMO

OBJECTIVE: To study the effect of calcium-sensitive receptors (CaSR) on the expression of endothelial nitric oxide synthase (eNOS) and the concentration of nitric oxide (NO) in a neonatal mouse model of persistent pulmonary hypertension (PPH). METHODS: Eighty neonatal C57BL/6 mice were randomly divided into control, PPH, agonist and antagonist groups. The control group was exposed to air, and the other three groups were exposed to 12% oxygen. The agonist and antagonist groups were intraperitoneally injected with a CaSR agonist (GdCl3 16 mg/kg) and a CaSR antagonist (NPS2390, 1 mg/kg), respectively, while the PPH and control groups were intraperitoneally injected with normal saline instead. All mice were treated for 14 days. Alveolar development and pulmonary vessels were assessed by hematoxylin-eosin staining. The protein and mRNA expression of eNOS and its localization in lung tissues were determined by Western blot, qRT-PCR and immunohistochemistry. The levels of brain natriuretic peptide (BNP) and NO in lung homogenate were determined using ELISA. RESULTS: Compared with the control group, the PPH and agonist groups showed significant increases in alveolar mean linear intercept, the percent wall thickness of pulmonary arterioles, right to left ventricular wall thickness ratio (RV/LV) and BNP concentration, but a significant reduction in radial alveolar count (P<0.05). The antagonist group had significant improvements in all the above indices except RV/LV compared with the PPH and agonist groups (P<0.05). Compared with those in the control group, the protein and mRNA expression of eNOS and NO concentration were significantly increased in the PPH group and increased more significantly in the agonist group, but were significantly reduced in the antagonist group (P<0.05). CONCLUSIONS: CaSR plays an important role in the development of PPH in neonatal mice, possibly by increasing eNOS expression and NO concentration.


Assuntos
Hipertensão Pulmonar , Animais , Animais Recém-Nascidos , Cálcio , Hipóxia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico , Óxido Nítrico Sintase Tipo III , Receptores de Detecção de Cálcio
6.
Kidney Blood Press Res ; 43(5): 1607-1622, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30347394

RESUMO

BACKGROUND/AIMS: This experimental study aims to observe whether the protective effect of propofol against renal ischemia-reperfusion injury (IRI) in the rat interlobar artery occurs through altered expression of the gap junction protein connexin 43 (Cx43). METHODS: This study randomly divided male Sprague Dawley (SD) rats into an untreated control group, a sham-operated control group (sham group), an ischemia-reperfusion group (IR group), a propofol group (propofol+IR group) and a fat emulsion group (Intralipid group). The ischemia/reperfusion model was prepared through resection of the right kidney and noninvasive arterial occlusion of the left kidney. Forty-five minutes after renal ischemia-reperfusion, an automatic biochemical analyzer was employed to measure blood urea nitrogen (BUN) and serum creatinine (SCr); changes in renal tissue pathology were observed using hematoxylin and eosin (HE) staining, and the vasomotor activity of the interlobar artery was detected using a pressure mechanogram technique. The protein expression of Cx43 in renal artery cross-sections was determined through western blotting. RESULTS: The experimental study confirmed that the BUN and SCr of rats markedly increased after ischemia-reperfusion injury; additionally, we observed some coagulation necrosis and shedding of cells, some solidification of nuclear chromatin, degeneration of cytoplasmic vacuoles, high renal interstitial vascular congestion and obvious inflammatory cell infiltration, characterized by focal hemorrhages. Furthermore, the contraction activity of the renal interlobar artery greatly decreased, and the tension of the arteries in the renal lobe increased remarkably. After the gap junction blocking agents 2-APB and Gap27 were applied, the systolic velocity of blood vessels and the vascular contraction rate both decreased. In addition, the expression of Cx43 in kidney tissues increased markedly. The damage was more severe after 24 h of ischemic reperfusion than after only 4 h. However, after pretreatment with propofol, regardless of whether ischemia-reperfusion was applied for 4 h or 24 h, the previously increased expression of Cx43 decreased obviously, and all forms of renal damage were reversed. CONCLUSION: Our research suggests new ways for propofol to relieve ischemia-reperfusion injury by decreasing the abnormal expression of the gap junction protein Cx43. This study reveals a novel mechanism for the action of propofol against IRI, and we hope this finding will lead to new treatments for IRI.

7.
Cell Physiol Biochem ; 49(2): 706-716, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30165368

RESUMO

BACKGROUND/AIMS: Calcium-activated chloride channels (CaCCs) regulate numerous physiological processes including cell proliferation, migration, and extracellular matrix secretion. T16Ainh-A01 and CaCCinh-A01 are selective inhibitors of CaCCs. But it is unknown whether these two compounds have functional effects on cardiac fibroblasts (CFs). METHODS: Primary CFs were obtained by enzymatic dissociation of cardiomyocytes from neonatal rat hearts. Intracellular Ca2+ ([Ca2+]i) and Cl- ([Cl-]i) were measured using the fluorescent calcium indicators (Fluo-4 AM) and N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide respectively. The expression of anoctamin-1 (ANO1) and α-smooth muscle actin (α-SMA) was detected by quantitative RT-PCR, immunofluorescence, and western blotting. A hydroxyproline assay was used to examine collagen secretion. Cell proliferation, cell cycle distribution, and cell migration were assessed by Cell Counting Kit-8, flow cytometry, and Transwell assays, respectively. RESULTS: ANO1 was preferentially expressed on the nuclear membrane and partially within intracellular compartments around the nucleus. T16Ainh-A01 and CaCCinh-A01 displayed different inhibitory effects on [Cl-]i in CFs. T16Ainh-A01 considerably decreased [Cl-]i in the nucleus, whereas CaCCinh-A01 reduced [Cl-]i in intracellular compartments around the nucleus, and both inhibitors exhibited a minimal effect on [Ca2+]i in CFs. ANO1 and α-SMA expression levels were significantly repressed by CaCCinh-A01. T16Ainh-A01 showed a marked inhibitory effect on the mRNA levels of ANO1 and α-SMA, but had a negligible effect on ANO1 at the protein level. T16Ainh-A01 and CaCCinh-A01 led to the significant repression of cell proliferation, cell migration, and collagen secretion in CFs. CONCLUSION: Our findings indicate that T16Ainh-A01 and CaCCinh-A01 have the potential to inhibit the proliferation and collagen secretion of CFs and may serve as novel anti-fibrotic therapeutic drugs in the future.


Assuntos
Canais de Cloreto/metabolismo , Regulação para Baixo/efeitos dos fármacos , Pirimidinas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia , Actinas/genética , Actinas/metabolismo , Animais , Anoctamina-1/genética , Anoctamina-1/metabolismo , Cálcio/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Canais de Cloreto/antagonistas & inibidores , Cloretos/metabolismo , Colágeno/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Masculino , Miócitos Cardíacos/citologia , Ratos , Ratos Sprague-Dawley
8.
Cell Mol Biol Lett ; 23: 40, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30151015

RESUMO

Background: Imbalances in circulating T lymphocytes play critical roles in the pathogenesis of hypertension-mediated inflammation. Connexins (Cxs) in immune cells are involved in the maintenance of homeostasis of T lymphocytes. However, the association between Cxs in peripheral blood T lymphocytes and hypertension-mediated inflammation remains unknown. This study was designed to investigate the role of Cxs in T lymphocytes in hypertension-mediated inflammation in spontaneously hypertensive rats (SHRs). Methods: The systolic blood pressure (SBP) in Wistar-Kyoto (WKY) rats and SHRs was monitored using the tail-cuff method. The serum cytokine level was determined using ELISA. The proportions of different T-lymphocyte subtypes in the peripheral blood, the expressions of Cx40/Cx43 in the T-cell subtypes, and the gap junctional intracellular communication (GJIC) of peripheral blood lymphocytes were measured using flow cytometry (FC). The accumulations of Cx40/Cx43 at the plasma membrane and/or in the cytoplasm were determined using immunofluorescence staining. The in vitro mRNA levels of cytokines and GJIC in the peripheral blood lymphocytes were respectively examined using real-time PCR and FC after treatment with Gap27 and/or concanavalin A (Con A). Results: The percentage of CD4+ T cells and the CD4+/CD8+ ratio were high, and the accumulation or expressions of Cx40/Cx43 in the peripheral blood lymphocytes in SHRs were higher than in those of WKY rats. The percentage of CD8+ and CD4+CD25+ T cells was lower in SHRs. The serum levels of IL-2, IL-4 and IL-6 from SHRs were higher than those from WKY rats, and the serum levels of IL-2 and IL-6 positively correlated with the expression of Cx40/Cx43 in the peripheral blood T lymphocytes from SHRs. The peripheral blood lymphocytes of SHRs exhibited enhanced GJIC. Cx43-based channel inhibition, which was mediated by Gap27, remarkably reduced GJIC in lymphocytes, and suppressed IL-2 and IL-6 mRNA expressions in Con A stimulated peripheral blood lymphocytes. Conclusions: Our data suggest that Cxs may be involved in the regulation of T-lymphocyte homeostasis and the production of cytokines. A clear association was found between alterations in Cxs expression or in Cx43-based GJIC and hypertension-mediated inflammation.


Assuntos
Junções Comunicantes/patologia , Hipertensão/complicações , Hipertensão/patologia , Inflamação/etiologia , Inflamação/patologia , Linfócitos/patologia , Animais , Relação CD4-CD8 , Conexina 43/análise , Conexina 43/imunologia , Conexinas/análise , Conexinas/imunologia , Junções Comunicantes/imunologia , Hipertensão/sangue , Hipertensão/imunologia , Inflamação/sangue , Inflamação/imunologia , Interleucinas/sangue , Interleucinas/imunologia , Linfócitos/imunologia , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
9.
Biomed Res Int ; 2018: 7474207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30069477

RESUMO

Objective: The study aims to systematically evaluate the clinical effect of gabapentin in the treatment of postherpetic neuralgia (PHN). Method: Data were retrieved electronically from PubMed, Embase, CNKI, the China Biomedical Database, and the Library of Clinical Database, beginning from the time of inception to April 2017, in order to collect data on randomized controlled trials (RCTs) of gabapentin and placebo in PHN treatment. Results: A total of 11 RCTs (2376 people) were retrieved. The gabapentin group reported significantly reduced pain intensity [MD=-0.91, 95% CI -1.32 to -0.51, P<0.00001] compared with the placebo group. Those treated with gabapentin also experienced significantly improved sleep quality [SMD=-0.44, 95% CI -0.66 to -0.23, P<0.0001], but were more likely to experience incidence of adverse events, such as somnolence, dizziness, and peripheral edema. Results of the subgroup analysis showed that the source of heterogeneity may be related to the formulations of the drug. Conclusion: Gabapentin can be used to effectively and safely treat PHN.

10.
J Fluoresc ; 28(2): 561-572, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29560601

RESUMO

Significant autofluorescence (AF) of renal tissue is one of the major causes restricting the use of immunofluorescent staining. This study aimed at controlling renal tissue AF and testing an effective method for optimizing specific signals. In the present study, we observed emergence of strong AF in all renal cells under different fluorescent channels. Significant concentration-dependent reduction in AF of kidney tissue was observed with the use of sodium borohydride (NaBH4) and Sudan black B (SBB) alone (p < 0.05). Under maximum effective concentration, semi-quantitative analysis revealed that inhibitory effect of SBB on AF was superior to that of NaBH4 (P < 0.01). When the two chemicals were combined, we observed that background can be reduced, and specific staining can be optimized at optimum concentration. Intensity of renal tissue was examined by confocal λ scanning, which showed that peaks were located at the range of approximately 480 - 590 nm and similar to those of flavin and lipofuscin. These results indicated that combined use of NaBH4 and SBB, when targeted at different sources of AF in renal tissue, is the most effective means of reducing background and preserving specificity of fluorescent labels. In addition, this method does not interfere with various steps of immunofluorescence experiments.


Assuntos
Fluorescência , Rim/metabolismo , Microscopia Confocal/métodos , Animais , Artefatos , Compostos Azo/metabolismo , Boroidretos/metabolismo , Feminino , Rim/citologia , Naftalenos/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Med Sci Monit ; 24: 1205-1218, 2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29485979

RESUMO

BACKGROUND Hydrogen sulfide (H2S) has anti-inflammatory and anti-hypertensive effects, and connexins (Cxs) are involved in regulation of immune homeostasis. In this study, we explored whether exogenous H2S prevents hypertensive inflammation by regulating Cxs expression of T lymphocytes in spontaneously hypertensive rats (SHR). MATERIAL AND METHODS We treated SHR with sodium hydrosulfide (NaHS) for 9 weeks. Vehicle-treated Wistar-Kyoto rats (WKYs) were used as a control. The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin and eosin staining was used to show vascular remodeling and renal injury. The percentage of T cell subtypes in peripheral blood, surface expressions of Cx40/Cx43 on T cell subtypes, and serum cytokines level were determined by flow cytometry or ELISA. Expression of Cx40/Cx43 proteins in peripheral blood lymphocytes was analyzed by Western blot. RESULTS Chronic NaHS treatment significantly attenuated blood pressure elevation, and inhibited inflammation of target organs, vascular remodeling, and renal injury in SHR. Exogenous NaHS also improved vascular function by attenuating KCl-stimulated vasoconstrictor response in basilar arteries of SHR. In addition, chronic NaHS administration significantly suppressed inflammation of peripheral blood in SHR, as evidenced by the decreased serum levels of IL-2, IL-6, and CD4/CD8 ratio and the increased IL-10 level and percentage of regulatory T cells. NaHS treatment decreased hypertension-induced Cx40/Cx43 expressions in T lymphocytes from SHR. CONCLUSIONS Our data demonstrate that H2S reduces hypertensive inflammation, at least partly due to regulation of T cell subsets balance by Cx40/Cx43 expressions inhibition.


Assuntos
Conexinas/metabolismo , Sulfeto de Hidrogênio/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Inflamação/complicações , Inflamação/tratamento farmacológico , Animais , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/patologia , Pressão Sanguínea/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Inflamação/sangue , Inflamação/fisiopatologia , Rim/patologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiopatologia
12.
Mol Med Rep ; 17(3): 3744-3750, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29257338

RESUMO

Chronic constriction injury (CCI) of the sciatic nerve may induce dorsal root ganglion (DRG) neuronal hyperexcitability and behaviorally expressed hyperalgesia. CCI is a model of neuropathic pain. To investigate the association between the expression of protease activated receptor 2 (PAR2), TMEM16A and neuropathic pain, the expression of PAR2 and TMEM16A proteins in the DRG neurons of rats following CCI of the sciatic nerve was investigated. Following the creation of the CCI model, the thermal withdrawal latency (TWL) was examined by a hot plate test. An immunofluorescence assay and western blot assay were performed to determine the expression of PAR2 and TMEM16A proteins in the ipsilateral L4­6 DRG neurons. The concentration of inositol 1,4,5­triphosphate (IP3) in the L4­6 DRG was determined by ELISA. In the CCI­D7 (7 days after CCI) and CCI­D14 (14 days after CCI) treatment groups, the TWL of rats was significantly shorter than that in the sham operated group (P<0.01; n=12). The expression of PAR2 and TMEM16A proteins in the CCI­D7 and CCI­D14 groups were significantly upregulated compared with the sham operated group (P<0.05; n=12). Additionally, it was revealed that PAR2 and TMEM16A were co­expressed in DRG neurons. It was also observed that IP3 significantly increased in the CCI­D7 and CCI­D14 groups compared with the sham operation group (P<0.05; n=6) as PAR2 and TMEM16A also increased. These findings suggest that the upregulation of PAR2 and TMEM16A in DRG neurons, the co­expression of the two proteins and increasing IP3 are critical to the development of neuropathic pain.


Assuntos
Anoctamina-1/metabolismo , Neuralgia/patologia , Receptor PAR-2/metabolismo , Animais , Ensaio de Imunoadsorção Enzimática , Gânglios Espinais/metabolismo , Inositol 1,4,5-Trifosfato/análogos & derivados , Inositol 1,4,5-Trifosfato/análise , Masculino , Microscopia de Fluorescência , Neuralgia/metabolismo , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima
13.
Int J Mol Med ; 41(1): 13-24, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115377

RESUMO

Chronic inflammation promotes the development of hypertension and is associated with increased T cell infiltration and cytokine production in impaired organs. Gap junction protein connexin 43 (Cx43), is ubiquitously expressed in immune cells and plays an important role in T cell proliferation and activation, and cytokine production. However, the correlation between Cx43 in T cells and the hypertensive inflammatory response remains unknown. Thus, in this study, we wished to examine this correlation. First, our results revealed that hypertension caused significant thickening of the vascular wall, inflammatory cell infiltration into part of the renal interstitium and glomerular atrophy, and it increased the tubular damage scores in the kidneys of spontaneously hypertensive rats (SHRs). Moreover, the SHRs exhibited stenosis in the central artery wall ofthe spleen with increased serum levels of interleukin (IL)-2 and IL-6 compared with normotensive Wistar-Kyoto (WKY) rats. The spleens of the SHRs exhibited a significantly decreased percentage of CD4+CD25+ (Treg) T cells. However, the percentages of CD3+, CD4+ and CD8+ T cell and the levels of CD4+Cx43 and CD8+Cx43 did not differ significantly between the SHRs and WKY rats. In cultured lymphocytes from the SHRs and WKY rats, low percentages of Treg cells and reduced cytokine (IL-2 and IL-6) mRNA expression levels were observed in the lymphocytes obtained from the SHRs and WKY rats treated with the connexin blocker, Gap27, or concanavalin A (ConA) plus Gap27. The effects of ConA and Gap27 differed between the SHRs and WKY rats. On the whole, our findings demonstrate that the splenic Treg cell-mediated suppression in SHRs may be involved in hypertensive inflammatory responses. Cx43 in the gap junctional channel may regulate lymphocyte activation and inflammatory cytokine production.


Assuntos
Conexina 43/metabolismo , Hipertensão/metabolismo , Inflamação/metabolismo , Ratos Endogâmicos SHR/genética , Baço/metabolismo , Animais , Pressão Sanguínea , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/genética , Conexina 43/genética , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-6/sangue , Ratos , Ratos Endogâmicos SHR/sangue , Ratos Endogâmicos SHR/metabolismo , Baço/patologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
14.
Mol Med Rep ; 17(2): 2861-2868, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29257229

RESUMO

The present study was designed to investigate the electrophysiological properties of strial pericytes and the effect of aspirin on pericyte K+ channels. Pericytes were identified by determining their morphological characteristics and using pericyte­associated immunofluorescence techniques. The electrophysiological properties of strial pericytes were observed with a whole­cell patch­clamp technique. Alterations in the outward current of cochlear pericytes in the stria vascularis of guinea pigs were examined following the application of K+ channel retardants. The effects of aspirin on pericyte K+ channels were also evaluated with the whole­cell patch­clamp technique. The results demonstrated that pericytes were desmin positive, and their nuclei were large and surrounded by a small proportion of the cytoplasm. Cytoplasmic processes gradually declined in size as branches grew parallel to the capillary axis. Thus, capillaries were surrounded by tips. The electrophysiological properties of the cochlear pericytes in the stria vascularis of guinea pigs were also determined. The membrane capacitance of the pericytes was 5.9±0.3 pF, while the membrane resistance and resting potential were 2.2±0.3 GΩ and ­30.9±1.2 mV, respectively. The current densities of the pericytes (pA/pF) were 3.2±0.7, 10.6±1.0, 15.7±0.9 and 21.3±1.2 at command voltages of 0, +20, +40, and +60 mV, respectively. The K+ channels were activated when the pericytes were within the range of ­20 mV to +20 mV, particularly at 0 mV. The inhibition rates of the outward current of cochlear pericytes in the stria vascularis of the guinea pigs were determined by administering iberiotoxin (IBTX) and IBTX + 4­aminopyridine. Once the background leakage current was removed, the following inhibition rates were obtained with 3, 10, 30, 300 and 1,000 µmol/l aspirin: 20.8±4.8, 34.1±6.9, 48.2±6.7, 63.6±7.1 and 65.7±8.1%, respectively. The outward current of the cochlear pericytes in the stria vascularis was inhibited by aspirin with a half maximal inhibitory concentration of 24.5±4.5 µmol/l. The membranes of the pericytes in the stria vascularis are characterized by high­conductance calcium­activated K+ (BKCa) and voltage­dependent K+ (KV) channels. The outward current of the cochlear pericytes in the stria vascularis of guinea pigs was inhibited by aspirin in a concentration­dependent manner. In addition, BKCa and KV channels were inhibited by aspirin.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Antipiréticos/efeitos adversos , Aspirina/efeitos adversos , Pericitos/efeitos dos fármacos , Canais de Potássio/metabolismo , Estria Vascular/efeitos dos fármacos , Animais , Células Cultivadas , Cobaias , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Pericitos/citologia , Pericitos/metabolismo , Estria Vascular/citologia , Estria Vascular/metabolismo
15.
Exp Ther Med ; 14(3): 1999-2006, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28962116

RESUMO

The aim of the present study was to examine whether single-nucleotide polymorphisms (SNPs) of ß1 subunit of large-conductance Ca2+-activated K+ channel (KCNMB1) and inwardly rectifying K+ channel, subfamily J, member-11 (KCNJ11) are associated with essential hypertension (EH) in Xinjiang Kazak Chinese patients. A polymerase chain reaction-restriction fragment length polymorphism technique was applied to detect the distribution of selected alleles and genotype frequencies in a cohort of Xinjiang Kazak Chinese patients. Samples from 267 patients with EH and 259 normotensive (NT) controls were analyzed. An unconditional logistic regression analysis was used to estimate the odds ratio and 95% confidence interval of the risk factors that are associated with the development of EH. Genotype and allele frequency analyses revealed that the frequency of genotypes KCNJ11-rs2285676 and KCNMB1-rs11739136 was not significantly different between the EH and NT groups. Individuals carrying the GG genotype of KCNJ11-rs5219 had a 2.08 times higher risk of having EH than individuals carrying the GA+AA genotype of KCNJ11-rs5219. Furthermore, the G allele frequency of KCNJ11-rs5219 in the EH group was significantly higher than that of the NT group (P=0.048). Additionally, logistic regression analysis revealed that the body weight and GG genotype of KCNJ11-rs5219 were positively associated with EH in Xinjiang Kazak Chinese patients (P<0.01).

16.
PLoS One ; 12(9): e0184773, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28910394

RESUMO

Inflammation has been shown to play an important role in the mechanisms involved in the pathogenesis of hypertension. Connexins (Cxs)-based gap junction channels (GJCs) or hemichannels (HCs) are involved in the maintenance of homeostasis in the immune system. However, the role of Cx43-based channels in T-lymphocytes in mediating the immune response in essential hypertension is not fully understand. The present study was designed to investigate the role of Cxs-based channels in T lymphocytes in the regulation of hypertension-mediated inflammation. The surface expressions of T lymphocyte subtypes, Cx40/Cx43, and inflammatory cytokines (IFN-γ (interferon-gamma) and TNF-ɑ (tumor necrosis factor alpha)) in T cells, as well as gap junction communication of peripheral blood lymphocytes from essential hypertensive patients (EHs) and normotensive healthy subjects (NTs) were detected by flow cytometry. Expression levels and phosphorylation of Cx43 protein in peripheral blood lymphocytes of EHs and NTs were analyzed by Western blot. The proliferation rate of peripheral blood mononuclear cells (PBMCs) after treatment with a Cxs inhibitor was examined by a CCK-8 assay. The levels of inflammatory cytokines were detected using ELISA. Within the CD3+ T cell subsets, we found a significant trend toward an increase in the percentage of CD4+ T cells and CD4+/CD8+ ratio as well as in serum levels of IFN-γ and TNF-ɑ in the peripheral blood of EHs compared with those in NTs. Moreover, the peripheral blood lymphocytes of EH patients exhibited enhanced GJCs formation, increased Cx43 protein level and Cx43 phosphorylation at Ser368, and a significant increase in Cx40/Cx43 surface expressions levels in CD4+ or CD8+ T lymphocytes. Cx43-based channel inhibition by a mimetic peptide greatly reduced the exchange of dye between lymphocytes, proliferation of stimulated lymphocytes and the pro-inflammatory cytokine levels of EHs and NTs. Our data suggest that Cx40/Cx43-based channels in lymphocytes may be involved in the regulation of T lymphocyte proliferation and the production of pro-inflammatory cytokines, which contribute to the hypertensive inflammatory response.


Assuntos
Conexina 43/genética , Citocinas/metabolismo , Junções Comunicantes/metabolismo , Hipertensão/imunologia , Linfócitos T/imunologia , Regulação para Cima , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Cultivadas , Conexina 43/metabolismo , Hipertensão Essencial , Feminino , Humanos , Hipertensão/genética , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação , Fator de Necrose Tumoral alfa/metabolismo
17.
Mol Med Rep ; 16(3): 2620-2626, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28677751

RESUMO

The current study observed the effects and investigated the mechanism of remifentanil (RMF) on the isolated cerebral basilar arteries of spontaneously hypertensive rats (SHR) and Wistar­Kyoto (WKY) rats. A pressure myograph system was used to observe and compare the effects of different concentrations of RMF (10­10­10­5 mol/l) on the diameter changes of freshly isolated cerebral basilar arteries, which have been pre­shrunk by phenylephrine (PE), an endothelium­independent vasoconstrictor. Vascular smooth­muscle cells of the cerebral basilar artery (BASMCs) were freshly obtained via enzymolysis. BKCa (large­conductance calcium­activated potassium channels) current (IBKCa) and Kv (voltage­gated potassium channels) current (IKv) were recorded using a whole­cell patch­clamp technique. The changes in IBKCa and IKv produced by different concentrations of RMF (10­10 to 10­5 mol/l) on the two types of rats with the holding potential of ­40 mV were observed and compared. The cerebral basilar arteries of the SHR and WKY rats were relaxed by RMF in a concentration-dependent manner (P<0.05; n=5). At the same concentration, the diastolic effect of RMF on SHR was weaker than that observed in WKY rats (P<0.05, n=5). When the rats were pre­perfused with 10­3 mol/l of the BKCa channel blocker tetraethylammonium (TEA), the diastolic amplitudes of RMF in SHR and WKY rats were decreased, and the fitting curves shifted down (P<0.05; n=7 and 6, respectively). However, no statistically significant difference was observed with 10­3 mol/l of the Kv channel blocker 4­aminopyridine (4­AP; n=6 and 9, respectively; P>0.05). Outward currents were increased by RMF in both BASMCs of SHR and WKY rats in a voltage­ and dose­dependent manner (P<0.05; n=6). At the same concentration, the effect of RMF on the outward currents in BASMCs of WKY rats was stronger than that on SHR (P<0.05; n=6). The enhancing effect of RMF can be partially blocked by either 10­3 mol/l TEA (P<0.05; n=6) or 10­3 mol/l 4­AP (P<0.05 or 0.01; n=6 and 9, respectively) however can be totally blocked by the mixture of TEA and 4­AP (P<0.05, n=7). RMF served a diastolic role in the cerebral basilar arteries of rats in a dose­dependent manner, likely by activating the BKCa and Kv channels. However, SHR demonstrated a less pronounced diastolic reaction to RMF than that observed in WKY rats.


Assuntos
Anestésicos Intravenosos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Piperidinas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Analgésicos Opioides/farmacologia , Animais , Encéfalo/irrigação sanguínea , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiologia , Feminino , Masculino , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Técnicas de Patch-Clamp , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remifentanil
18.
Clin Exp Hypertens ; 39(4): 295-305, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28513236

RESUMO

The aim of the present study is to investigate the effects of hypertension on the gap junctions between vascular smooth muscle cells (VSMCs) in the cerebral arteries (CAs) of spontaneously hypertensive rats (SHRs). The functions of gap junctions in the CAs of VSMCs in SHRs and control normotensive Wistar-Kyoto (WKY) rats were studied using whole-cell patch clamp recordings and pressure myography, and the expression levels of connexins were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blot analyses. Whole-cell patch clamp measurements revealed that the membrane capacitance and conductance of in situ VSMCs in the CAs were significantly greater in SHRs than in WKY rats, suggesting that gap junction coupling is enhanced between VSMCs in the CAs of SHRs. Application of the endothelium-independent vasoconstrictors KCl or phenylephrine (PE) stimulated a greater vasoconstriction in the CAs of SHRs than in those of WKY rats. The EC50 value of KCl was 24.9 mM (n = 14) and 36.9 mM (n=12) for SHRs and WKY rats, respectively. The EC50 value of PE was 0.9 µM (n = 7) and 2.2 µM (n = 7) for SHRs and WKY rats, respectively. Gap junction inhibitors 18ß-glycyrrhetinic acid (18ß-GA), niflumic acid (NFA), and 2-aminoethoxydiphenyl borate (2-APB) attenuated KCl-induced vasoconstriction in SHRs and WKY rats. The mRNA and protein expression levels of the gap junction protein connexin 45 (Cx45) were significantly higher in the CAs of SHRs than in those of WKY rats. Phosphorylated Cx43 protein expression was significantly higher in the CAs of SHRs than in those of WKY rats, despite the total Cx43 mRNA and protein expression levels in the cerebral artery (CA) exhibiting no significant difference between SHRs and WKY rats. Increases in the expression of Cx45 and phosphorylation of Cx43 may promote gap junction communication among VSMCs in the CAs of SHRs, which may enhance the contractile response of the CA to vasoconstrictors.


Assuntos
Artérias Cerebrais/fisiopatologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/fisiologia , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Animais , Compostos de Boro/farmacologia , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Capacitância Elétrica , Fenômenos Eletrofisiológicos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Hipertensão/metabolismo , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Ácido Niflúmico/farmacologia , Fenilefrina/farmacologia , Fosforilação , Cloreto de Potássio/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
19.
J Huazhong Univ Sci Technolog Med Sci ; 37(2): 197-203, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28397038

RESUMO

Essential hypertension (EH) is affected by both genetic and environmental factors. The polymorphism of connexin (Cx) genes is found associated with the development of hypertension. However, the association of the polymorphism of Cxs with EH has not been investigated. This study aimed to investigate the association of the polymorphism of connexin (Cx) genes Cx37, Cx40, and Cx43 with EH in Kazak and Han Chinese in Xinjiang, China. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were used to analyze the polymorphism of Cx genes in Kazak and Han EH patients as well as their normotensive controls. The results showed that there were no significant differences in the frequencies of different three genotypes (A/A, A/G, and G/G) and A and G alleles of Cx40 rs35594137 and rs11552588 between EH patients and normotensive controls. However, in Kazak EH patients, the frequencies of three genotypes (A/A, A/G, and G/G) of Cx37 rs1630310 were 24.8%, 47.2% and 28.0%, respectively, which were significantly different from those in Han EH patients. In Han EH patients, the frequencies of the three genotypes (C/C, C/G and G/G) of Cx43 rs1925223 were 6.4%, 35.6% and 58.0%, respectively. Frequencies of the other four genotypes had no statistical differences among Kazak and Han EH patients and their normotensive controls. These results suggest polymorphisms of Cx37 rs1630310 and Cx43 rs1925223 genes may be associated with the pathogenesis of EH. Carrying Cx37 rs1630310-A or Cx43 rs1925223-G genotypes may protect against the development of EH.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Conexina 43/genética , Conexinas/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Hipertensão Essencial , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade
20.
Mol Med Rep ; 15(4): 1823-1831, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28259990

RESUMO

Hypoxic exposure results in the vascular dysfunction and reduction of vasomotor responses and thus disrupts or reduces blood flow in the resistance arteries. Connexin (Cx)-mediated gap junctional intercellular communication (GJIC) serves a critical role in the regulation of vasomotor tone and the synchronized contraction of arteries, however whether the adverse effect of hypoxia on vasomotor responses in vascular smooth muscle layer of resistance arteries is involved in changes in the GJIC and the expression of Cx43 and Cx45 remains to be elucidated. Pressure myography, whole-cell patch clamp and western blot analysis were used to investigate the differences in expression and function of gap junction (GJ) in the vascular smooth muscle cells (VSMCs) of the mesenteric resistance artery (MRA) from Sprague­Dawley (SD) rats in normoxia and acute hypoxia groups. In the present study, whole­cell patch clamp measurements demonstrated a significant reduction in the membrane capacitance and conductance in the VSMCs of the MRAs in the acute hypoxia (5 min) group (n=13) compared with the normoxia group (n=13), which suggested that exposure to acute hypoxia of 5 min decreased the coupling of the GJ between the VSMCs of MRAs in SD rats. Pressure myographic analysis demonstrated that 0.1­100 µM phenylephrine (PE)­induced MRA vasoconstriction was less sensitive under the acute hypoxic condition (n=7) compared with the normoxia condition (n=9) following treatment with 100 µM 2­aminoethoxydiphenyl borate for 20 min. Compared with SD rats under normoxia, the PE­initiated vasoconstrictive frequency and amplitude under acute hypoxia for 20, 40 and 60 min in the MRAs of SD rats was markedly attenuated (n=7). The results of western blot analysis indicated that the expression levels of Cx43 and Cx45 in MRA under acute hypoxia (1 h) were lower compared with normoxia. Cx43­and Cx45­mediated GJs serve a significant role in the regulation of the vasomotor function of MRA during hypoxia and may be essential for the adjustment of vasomotor tone in response to acute hypoxia.


Assuntos
Junções Comunicantes/patologia , Hipóxia/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Vasoconstrição , Doença Aguda , Animais , Compostos de Boro/farmacologia , Comunicação Celular , Conexina 43/metabolismo , Conexinas/metabolismo , Feminino , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Hipóxia/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
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