RESUMEN
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adult central nervous system (CNS) synapses, but it excites immature CNS neurons as well as neurons in the myenteric plexus. The present work aimed to determine whether GABA-induced nonadrenergic, noncholinergic (NANC) neuronal-mediated relaxation of the rat duodenum is dependent on the activity of Na+ K+ Cl- cotransporters (NKCC) and requires calcium influx. In the presence of guanethidine (3 µmol/L), atropine (3 µmol/L), and indomethacin (1 µmol/L), relaxations induced by GABA (100 µmol/L), KCl (5-10 mmol/L) and electrical field stimulation (1-8 Hz, 2 ms, 60 V), but not those induced by bradykinin (10-100 nmol/L) were abolished by lidocaine (300 µmol/L). However, only GABA-induced relaxations were reduced in a concentration-dependent manner by the NKCC1/2 inhibitors bumetanide (0.1-1 µmol/L) and furosemide (1-10 µmol/L). GABA-induced NANC neuronal relaxation was abolished by bicuculline (30 µmol/L) and inhibited by N-nitroarginine methyl ester (l-NAME, 300 µmol/L). The ω-conotoxin GVIA (1 µmol/L), which acts exclusively on neuronal CaV2 channels, but not on smooth muscle voltage-gated Ca2+ CaV1 channels, and nonselective blockers of these channels (verapamil 100 nmol/L and ruthenium red 10 µmol/L), reduced GABA-induced relaxations. These results showed that the activation of GABAA receptors induces NANC nitrergic neuronal relaxations in the rat duodenum, which depend on NKCC activity and CaV2 channel activation, suggesting that this phenomenon results from neuronal depolarization promoted by Cl- efflux through GABAA receptors, with subsequent Ca2+ influx and nitric oxide release.
Asunto(s)
Relajación Muscular , Músculo Liso , Animales , Duodeno , Estimulación Eléctrica , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico , Ratas , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Evaluate the anti-inflammatory activity in vivo and in vitro of cis-(±)-acetate of 4-chloro-6-(naphtalene-1-yl)-tetrahydro-2H-pyran-2-yl) methyl 2-(2-(2,6-diclorofenylamine) phenyl (LS19). Male Swiss mice were analyzed in the paw edema, ear edema, and air pouch tests, and in vitro COX inhibition, cytotoxicity evaluation, and cytokine and nitric oxide determination tests. The compound showed effect on the carrageenan- and bradykinin-induced paw edema and capsaicin-induced ear edema tests. In addition, the compound was able to inhibit leukocyte migration to decrease the levels of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) and to increase the levels of the anti-inflammatory cytokine IL-10. The compound was also able to reduce levels of TNF-α, IL-6, and nitric oxide in the RAW 264.7 cell line and to inhibit COX activity. LS19 did not induce any significant changes in the viability of RAW 264.7 cells, demonstrating safety for these cell lines. The compound LS19 did not reduce the production of gastric mucus and induced a smaller increase in the extent of gastric lesions than that developed by the administration of diclofenac. In summary, the new compound proved to be safer and it had additional mechanisms compared to diclofenac.
Asunto(s)
Antiinflamatorios no Esteroideos , Antiinflamatorios , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Carragenina/efectos adversos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Masculino , Ratones , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
The Frank-Starling response of the heart is known to be mediated by nitric oxide (NO) signaling, which is regulated by reduced glutathione (GSH) and hydrogen sulfide (H2S). We hypothesized that stimulation of endogenous H2S or GSH synthesis would improve the Frank-Starling response. Wistar male rats were injected with propargylglycine (PAG; 11.3 mg/kg, 40 min, n = 12), an inhibitor of H2S-producing enzyme (cystationine-γ-lyase), and l-cysteine (121 mg/kg, 30 min, n = 20), a precursor of H2S and GSH. Pretreatment with PAG or l-cysteine separately slightly improved the pressure-volume (P-V) dependence of the isolated rat heart, but the combination of PAG and l-cysteine (n = 12) improved heart contractile activity. H2S content, Ca2+-dependent NOS activity (cNOS) activity, nitrate reductase activity, and nitrite content increased by 2, 3.83, 2.5, and 1.3 times in cardiac mitochondria, and GSH and oxidized glutathione (GSSG) levels increased by 2.24 and 1.86 times in the heart homogenates of the PAG + l-cysteine group compared with the control (all P < 0.05). Inhibition of glutathione with DL-buthionine-sulfoximine (BSO; 22.2 mg/kg, 40 min, n = 6) drastically decreased Frank-Starling response of the heart and prevented PAG + l-cysteine-induced increase of GSH and GSSG levels (BSO + PAG + l-cysteine, n = 9). Inhibition of NOS, N-nitro-l-arginine-methylester hydrochloride (l-NAME; 40 min, 27 mg/kg) abolished positive inotropy induced by PAG+l-cysteine pretreatment (l-NAME + PAG + l-cysteine, n = 7). Thus, PAG + l-cysteine administration improves the Frank-Starling response by upregulating mitochondrial H2S, glutathione, and NO synthesis, which may be a promising approach in the treatment of myocardial dysfunction.
Asunto(s)
Glutatión/metabolismo , Sulfuro de Hidrógeno/metabolismo , Mitocondrias/metabolismo , Contracción Miocárdica/efectos de los fármacos , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal/fisiología , Alquinos/farmacología , Animales , Cisteína/farmacología , Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Técnicas In Vitro , Masculino , Ratas Wistar , Estimulación Química , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Renal ischemia-reperfusion injury (RIRI) as a pathological process induces remote organ injury such as lung complications and it is regulated in a hormone-dependent manner. This study investigates the effect of estrogen on RIR-induced pulmonary injury in ovariectomized (OV) rats. A total of 60 female Wistar rats were divided into six groups: (i) intact sham, (ii) OV sham, (iii) OV sham + estradiol valerate (E), (iv) intact ischemia, (v) OV ischemia, and (vi) OV ischemia + E. Bilateral ischemia was performed for 45 min in all groups except sham. Before the ischemia, OV groups received an intramuscular (i.m.) injection of E. After reperfusion, blood samples were collected for serum analysis and kidney and lung tissue were separated for pathological experiment and malondialdehyde (MDA) and nitrite measurement. The left lung was weighed to measure pulmonary edema. Estrogen deficiency caused a greater increase in blood urea nitrogen and creatinine levels during IRI. Ischemia reduced nitrite of serum and lung tissue. The increased level of MDA during ischemia, returned to normal levels via estrogen injection. The severity of renal and lung damage in ischemic groups increased significantly, and estrogen improved this injury. Estrogen as an antioxidant agent can reduce oxidative stress and may improve renal function and ameliorating lung damage caused by RIR.
Asunto(s)
Estradiol/administración & dosificación , Isquemia/complicaciones , Riñón/irrigación sanguínea , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/etiología , Ovariectomía , Daño por Reperfusión/complicaciones , Animales , Antioxidantes , Nitrógeno de la Urea Sanguínea , Creatinina/metabolismo , Estradiol/farmacología , Femenino , Inyecciones Intramusculares , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Riñón/metabolismo , Lesión Pulmonar/metabolismo , Malondialdehído/metabolismo , Nitritos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
The aim of this study was to examine if the peripheral antinociception of α-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, NG-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-Bisabolol produced antinociception during both phases of the formalin test. α-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-Bisabolol was able to active the NO-cGMP-K+ channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.
Asunto(s)
Analgésicos/farmacología , GMP Cíclico/metabolismo , Sesquiterpenos Monocíclicos/farmacología , Óxido Nítrico/metabolismo , Nocicepción/efectos de los fármacos , Canales de Potasio/metabolismo , Receptores Opioides/metabolismo , Animales , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/química , Canales de Potasio/genética , Ratas , Ratas Wistar , Receptores Opioides/química , Receptores Opioides/genéticaRESUMEN
Human arterial endothelial cells (HAECs) regulate their phenotype by integrating signals encoded in the frictional forces exerted by flowing blood, fluid shear stress (FSS). High laminar FSS promotes establishment of adaptive HAEC phenotype protective against atherosclerosis, whereas low or disturbed FSS cause HAECs to adopt atheroprone phenotypes. A vascular endothelial cadherin (VE cadherin)-based mechanosensory complex allows HAECs to regulate barrier function, cell morphology,/ and gene expression in response to FSS. Previously, we reported that this mechanosensor integrated exchange protein activated by cAMP (EPAC1) and a PDE4D gene derived cyclic nucleotide phosphodiesterase (PDE), but had not identified the PDE4D variant involved. Our hypothesis here was that only one of the two â¼100 kDa PDE4D variants expressed in HAECs coordinated these responses. Now, we show one unique PDE4D splice variant, PDE4D7, controls transcriptional responses of HAECs to FSS while another, PDE4D5, does not. Adaptive transcriptional responses of HAECs subjected to laminar FSS in vitro were blunted in cells in which PDE4D7 was silenced, but unaffected in cells with silenced PDE4D5. This work identifies a specific therapeutic target for the treatment or prevention of atherosclerosis and improves our understanding of the role of cAMP signaling in modulating mechanosensory signal transduction in the vascular endothelium.
Asunto(s)
Arterias/citología , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Células Endoteliales/metabolismo , Perfilación de la Expresión Génica , Resistencia al Corte , Estrés Mecánico , HumanosRESUMEN
Human immunodeficiency virus (HIV) is associated with lower nitric oxide (NO) bioavailability and vascular dysfunction. Nitrate-rich beetroot juice (BJ) has been shown to acutely increase NO availability and vascular function in healthy and individuals at high risk for cardiovascular disease. Thus, we tested the effects of BJ ingestion on flow-mediated dilation (FMD) and pulse wave velocity (PWV) measurements in healthy and HIV-infected patients. Thirteen HIV-infected individuals (age, 36 ± 10 years) and 18 healthy (age, 27 ± 8 years) participated in the study. Individuals were submitted to vascular tests such as FMD and pulse PWV at pre (T0) and at 120 min (T120) after BJ and placebo (PLA) ingestion. The %FMD at T0 of the control group was significantly higher than the %FMD at T0 of the HIV individuals in both interventions. BJ improved the %FMD at T120 when compared with T0 in the HIV and control groups. There was no change in %FMD after PLA ingestion in the control and HIV groups. There were no differences between groups (control vs HIV), time points (T0 vs T120), and interventions (BJ vs PLA) for PWV. Our findings showed that nitrate-rich BJ ingestion acutely improved vascular function in healthy and HIV-infected patients. Clinical Trials Registry no. NCT03485248. Novelty: HIV is associated with lower NO bioavailability and vascular dysfunction. Acute supplementation with nitrate-rich BJ has been shown to acutely increases NO bioavailability. We showed for the first time that BJ acutely improves endothelial function in HIV-infected patients.
Asunto(s)
Suplementos Dietéticos , Endotelio Vascular/fisiología , Jugos de Frutas y Vegetales , Infecciones por VIH/terapia , Nitratos/administración & dosificación , Adulto , Beta vulgaris , Presión Sanguínea , Estudios de Casos y Controles , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico , Análisis de la Onda del Pulso , Rigidez Vascular , Adulto JovenRESUMEN
Chronic Chlorella intake and aerobic exercise training reduce arterial stiffness and increase circulating nitric oxide (NO) levels, which has beneficial effects. This study aimed to clarify the combined aortic NO-mediated effects of chronic Chlorella intake and aerobic exercise training on endothelial vasorelaxation in aged mice. In this study, 38-week-old male senescence-accelerated mouse prone 1 (SAMP1) mice were divided into aged sedentary control (Con), aerobic exercise training (AT; voluntary wheel running for 12 weeks), Chlorella intake (CH; 0.5% Chlorella powder in normal diet), and AT and CH combined (AT+CH) groups. Endothelium-dependent vasorelaxation by addition of acetylcholine to the isolated mouse aortic rings was significantly higher in the AT, CH, and AT+CH groups than in the Con group; a significantly greater effect was seen in the AT+CH group than in the AT and CH groups. Similarly, plasma and arterial nitrite/nitrate levels and arterial endothelial NO synthase phosphorylation were significantly higher in the AT, CH, and AT+CH groups than in the Con group; the AT+CH group had higher values than the AT and CH groups. Thus, chronic Chlorella intake combined with aerobic exercise training had pronounced effects on endothelial vasorelaxation in aged mice via an additive increase in arterial NO production. Novelty: Endothelium-dependent vasorelaxation was improved by Chlorella intake and exercise. Chlorella intake and exercise increased arterial Akt/eNOS/NO signaling. This combination approach further improved vasorelaxation via arterial NO production.
Asunto(s)
Envejecimiento/fisiología , Chlorella , Endotelio Vascular/fisiología , Alimentos Fortificados , Óxido Nítrico/fisiología , Condicionamiento Físico Animal/fisiología , Vasodilatación/fisiología , Animales , Aorta/fisiología , Masculino , Ratones , Óxido Nítrico/sangre , Transducción de SeñalRESUMEN
The present study was designed to evaluate the cardioprotective effects of melatonin (a single dose of 50 mg·kg-1), a naturally occurring polypharmacological molecule, in Wistar rats acutely exposed to carbon tetrachloride (CCl4). This was done for the first time by tracking different biochemical parameters that reflect rat heart antioxidative and oxidative capacities, nitric oxide and arginine metabolism, and the glutathione cycle. Additionally, the extrinsic apoptosis pathway related parameters were studied. Acute exposure to CCl4 led to an increase in the studied tissue oxidant parameters (hydrogen peroxide, malondialdehyde, and carbonylated protein content), as well as the activity alteration of antioxidant (catalase, superoxide dismutase, and peroxidase) and glutathione-metabolizing (glutathione peroxidase, S-transferase, and reductase) enzymes. Furthermore, CCl4 caused a disturbance in the tissue myeloperoxidase, nitric oxide, citrulline, arginase, and inducible nitric oxide synthase content and activities and in two apoptosis-related parameters, caspase-3 and FAS ligand. Melatonin as a post-treatment prevented the changes induced by CCl4 to a differing extent, and in some cases, it was so potent that it completely abolished any tissue disturbances. This study is a promising starting point for further research directed to the development of melatonin treatment in cardiac tissue associated diseases.
Asunto(s)
Arginina/metabolismo , Tetracloruro de Carbono/efectos adversos , Glutatión/metabolismo , Melatonina/farmacología , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Miocardio/patología , Ratas , Ratas WistarRESUMEN
The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 µg/paw) or buprenorphine (1-5 µg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1-2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1-3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.
Asunto(s)
Analgésicos Opioides/farmacología , Antagonistas de Narcóticos/farmacología , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Buprenorfina/farmacología , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Gliburida/administración & dosificación , Humanos , Inyecciones Subcutáneas , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , Nalbufina/farmacología , Óxido Nítrico/metabolismo , Nocicepción/fisiología , Dolor/inducido químicamente , Dolor/diagnóstico , Dimensión del Dolor , Bloqueadores de los Canales de Potasio/administración & dosificación , Ratas , Receptores Opioides/metabolismo , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Red blood cell (RBC), which is the most commonly transfused blood component, due to its ability to save a life in absence of any other blood components, can be stored up to maximum 6 weeks by following standard preservation procedure. During storage, RBC undergoes various biophysical and biochemical changes (commonly known as storage lesion) for which blood transfusion with "old RBC" shows a lot of clinical problems especially relevant to critically ill patients. Recent research on S-nitrosylation of haemoglobin to improve oxygen delivery of banked blood revealed the important role of nitric oxide (NO) in protecting storage lesion. MATERIALS AND METHODS: In the present study, we used various "NO donating" chemicals with different NO release dynamics and chemistries in RBC storage cocktails to test the effects of NO on storage lesion. Changes in different storage markers were evaluated after 7 days storage of pre-treated RBC. RESULTS: All the NO donors have shown protection against hemolysis. However, S-nitroso glutathione (GSNO) ranks first in shielding RBCs from storage lesion and additionally, it helps in elevating the value of 2, 3-di phosphoglycerate (2, 3-DPG), improving the RBC membrane fluidity and decreasing the adhesion towards endothelial monolayer. DISCUSSION: Present study reveals that NO released from NO donors confers protection against storage lesions of the RBC. Further, the study confirms that pre-treatment with GSNO, a NO donor and a nitrosylating agent, ensures the best protection to RBC during low temperature storage, when compared to other NO donor treatments.
Asunto(s)
Conservación de la Sangre , Donantes de Óxido Nítrico , Membrana Eritrocítica , Eritrocitos , Hemólisis , Humanos , Donantes de Óxido Nítrico/farmacologíaRESUMEN
When controlling for baseline diameter, males have greater brachial flow-mediated dilation (BA-FMD) responses than females. It is unclear whether sex differences in baseline diameter also influences popliteal FMD (POP-FMD), which may be impacted by cardiorespiratory fitness and physical activity levels. We hypothesized that males would exhibit greater BA-FMD and POP-FMD when allometrically scaled to baseline diameter. FMD (ultrasonography), cardiorespiratory fitness (indirect calorimetry), and objectively measured physical activity were assessed in males (n = 13; age, 23 ± 3 years; peak oxygen consumption, 48.0 ± 7.1 mL·kg-1·min-1) and females (n = 13; age, 24 ± 2 years; peak oxygen consumption, 36.8 ± 6.0 mL·kg-1·min-1). Both groups had similarly high levels of moderate-to-vigorous intensity physical activity (503 ± 174 vs. 430 ± 142 min·week-1, p = 0.25). However, males were more aerobically fit (p < 0.001) and females accumulated more light-intensity physical activity (182 ± 67 vs. 127 ± 53 min·week-1, p = 0.03). Relative and allometrically scaled BA-FMD were similar (both, p ≥ 0.09) between sexes. In contrast, relative (6.2% ± 1.0% vs. 4.6% ± 1.4%, p = 0.001) and scaled (6.8% ± 1.7% vs. 4.7% ± 1.7%, p = 0.03) POP-FMD were greater in females. Relative POP-FMD was related to light-intensity physical activity in the pooled sample (r = 0.43; p = 0.04). However, the enhanced relative POP-FMD in females remained after adjusting for higher light-intensity physical activity levels (p = 0.01). Young females have enhanced popliteal, but not brachial, endothelial health than males with similar moderate-to-vigorous intensity physical activity levels and higher cardiorespiratory fitness. Novelty In physically active adults, females had greater POP-FMD but not BA-FMD than males. The enhanced POP-FMD in females was not related to greater vascular smooth muscle sensitivity to nitric oxide or their smaller baseline diameters. POP-FMD was associated with light physical activity levels in the pooled sample.
Asunto(s)
Capacidad Cardiovascular , Ejercicio Físico , Flujo Sanguíneo Regional , Factores Sexuales , Adulto , Arteria Braquial/fisiología , Dilatación , Femenino , Humanos , Masculino , Consumo de Oxígeno , Arteria Poplítea/fisiología , Adulto JovenRESUMEN
Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO-cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose-response curves were 8303 and 2080 µg/kg, respectively. The experimental ED50 values of morphine and tadalafil in their mixture were 4800 and 1210 µg/kg, respectively. Those results showed an additive interaction between morphine and tadalafil presented by a total fraction value for the mixture of 1160 µg/kg. This outcome can be interpreted by the fact that both drugs share common pathways, namely, NO-cGMP and opioid receptors. As a conclusion, the morphine and tadalafil combination showed an additive effect against acute pain, which is mediated through the central nervous system, thus providing a rationale for combining them to decrease morphine dose and thus minimizing its side effects.
Asunto(s)
Analgesia/métodos , Morfina/farmacocinética , Dolor/tratamiento farmacológico , Tadalafilo/farmacocinética , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Morfina/administración & dosificación , Dolor/diagnóstico , Dimensión del Dolor , Tadalafilo/administración & dosificaciónRESUMEN
OBJECTIVES: Recently, numerous studies have renewed attention to the hematologic profile in the early identification of diabetic inflammation and complications. The objective of this study was to investigate the relationship between hematologic indices abnormalities and oxidative stress among children with type 1 diabetes mellitus (T1DM). METHODS: This study included 70 children diagnosed with T1DM and 30 healthy control subjects. The children with T1DM were divided into 2 groups according to the duration of diabetes: children with newly diagnosed T1DM and children with established T1DM. RESULTS: Erythrocyte count and platelet count were decreased significantly in children with established T1DM, whereas leukocyte count and neutrophil count were increased significantly in children with newly diagnosed T1DM compared with healthy control subjects. Moreover, hemoglobin and hematocrit values revealed a significant depletion in both T1DM groups; however, values of red blood cell distribution width, mean platelet volume and platelet distribution width were significantly elevated in both T1DM groups compared with healthy control subjects. Also, microalbuminuria levels showed a significant increase in children with established T1DM, whereas lipid peroxidation biomarker (malondialdehyde) and nitric oxide levels were elevated markedly in both T1DM groups compared with the healthy group. CONCLUSIONS: The data demonstrated that the hematologic profile showed noticeable alterations in children with T1DM, and the inflammation and oxidative stress markers were contributed to the hematologic abnormalities. The results revealed that some hematologic indices can be used in the early detection of children with T1DM at risk for diabetic complications.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Enfermedades Hematológicas/sangre , Estrés Oxidativo , Adolescente , Albuminuria/metabolismo , Glucemia/análisis , Niño , Preescolar , Complicaciones de la Diabetes , Diabetes Mellitus Tipo 1/complicaciones , Recuento de Eritrocitos , Femenino , Hematócrito , Enfermedades Hematológicas/etiología , Hemoglobinas/análisis , Humanos , Recuento de Leucocitos , Peroxidación de Lípido , Masculino , Malondialdehído/sangre , Óxido Nítrico/sangre , Recuento de PlaquetasRESUMEN
Renal ischemia/reperfusion (I/R) injury is a common pathological condition. Studies reported renal toxicity following administration of triptans, which are commonly used for treating migraine headaches. To investigate the effects of sumatriptan and the molecular mechanisms involved in renal I/R injury in rats, ischemia was induced by bilateral clamping of renal pedicles followed by 24 h of reperfusion. Sumatriptan was administered in three different doses (5, 10, and 20 mg/kg) before I/R injury induction. Biochemical and histopathological changes were evaluated. The contribution of nitric oxide in modulating the effects of sumatriptan was determined by administrating aminoguanidine at 50 mg/kg 60 min before I/R injury. The tissue level of nitrite, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. Sumatriptan at 10 and 20 mg/kg increased the serum level of creatinine (Cr) and blood urea nitrogen (BUN) significantly. There was also a significant increase in nitrite level of animals that received 10 mg/kg sumatriptan. Co-administration of sumatriptan with aminoguanidine significantly decreased the BUN and Cr. Depletion of SOD level (P < 0.05) and elevation of serum levels of MDA (P < 0.001) indicated the involvement of oxidative stress in sumatriptan adverse effects. Overall, the administration of sumatriptan intensified renal I/R injury through activation of inducible nitric oxide synthase and oxidative responses in rats.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Riñón/efectos de los fármacos , Óxido Nítrico/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Sumatriptán/farmacología , Lesión Renal Aguda/metabolismo , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/metabolismo , Riñón/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Skeletal muscle is highly vascularized, with perfusion being tightly regulated to meet wide-ranging metabolic demands. For decades, the capillary supply has been explored mainly in terms of evaluating the capillary numbers and their function in the supply of oxygen and substrates and the removal of metabolic byproducts. This review will focus on recent discoveries concerning the role played by capillaries in facilitating other aspects of cell regulation and maintenance, in health and disease, as well as alterations during the aging process. Novelty Capillaries play a central role in the coordination of the vascular response that controls blood flow during contraction and the cellular responses to which they feed into. Nitric oxide is an important regulatory compound within the cardiovascular system, and a significant contributor to skeletal muscle capillary angiogenesis and vasodilatory response to agonists. The microvascular network between muscle fibres may play a critical role in the distribution of signalling factors necessary for optimal muscle satellite cell function.
Asunto(s)
Capilares/fisiología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiología , Capilares/ultraestructura , Humanos , Músculo Esquelético/ultraestructura , Óxido Nítrico/metabolismoRESUMEN
This study aimed to clarify whether muscle-derived irisin secretion induced by aerobic exercise training is involved in reduction of arterial stiffness via arterial nitric oxide (NO) productivity in obesity. In animal study, 16 Otsuka Long-Evans Tokushima Fatty (OLETF) rats with obesity were randomly divided into 2 groups: sedentary control (OLETF-CON) and 8-week aerobic treadmill training (OLETF-EX) groups. In human study, 15 subjects with obesity completed 8-week aerobic exercise training for 45 min at 60%-70% peak oxygen uptake intensity for 3 days/week. As a result of animal study, carotid-femoral pulse wave velocity (cfPWV) was decreased, and arterial phosphorylation levels of AMP-activated protein kinase (AMPK), protein kinase B (Akt), and endothelial NO synthase (eNOS), circulating levels of nitrite/nitrate (NOx) and irisin, and muscle messenger RNA expression of fibronectin type III domain containing 5 (Fndc5) were increased in the OLETF-EX group compared with OLETF-CON group. In a human study, regular aerobic exercise reduced cfPWV and elevated circulating levels of NOx and irisin. Furthermore, change in circulating irisin levels by regular exercise was positively correlated with circulating NOx levels and was negatively correlated with cfPWV. Thus, aerobic exercise training-induced increase in irisin secretion may be related to reduction of arterial stiffness achieved by NO production via activated arterial AMPK-Akt-eNOS signaling pathway in obesity. Novelty Aerobic exercise training promoted irisin secretion with upregulation of muscle Fndc5 gene expression in rats with obesity. Irisin affected the activation of arterial AMPK-Akt-eNOS signaling by aerobic exercise training. Increased serum irisin level by aerobic exercise training was associated with reduction of arterial stiffness in obese adults.
Asunto(s)
Ejercicio Físico/fisiología , Fibronectinas/biosíntesis , Óxido Nítrico/metabolismo , Obesidad/fisiopatología , Rigidez Vascular/fisiología , Adulto , Animales , Modelos Animales de Enfermedad , Fibronectinas/genética , Humanos , Masculino , Ratas , Ratas Endogámicas OLETFRESUMEN
Hydrogen sulfide (H2S) is an endogenous gas transmitter with profound effects on the cardiovascular system. We hypothesized that stimulation of H2S synthesis might alleviate age-associated changes in vascular reactivity. Pyridoxal-5-phosphate (PLP), the coenzyme of H2S-synthesizing enzymes, was administrated to old male Wistar rats per os at a dose of 0.7 mg/kg body mass once a day for 2 weeks. H2S content in the aortic tissue, markers of oxidative stress, inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS), arginase activities, and endothelium-dependent vasorelaxation of the aortic rings were studied. Our results showed that PLP restored endogenous H2S and low molecular weight S-nitrosothiol levels in old rat aorta to the levels detected in adults. PLP significantly reduced diene conjugate content, hydrogen peroxide and peroxynitrite generation rates, and iNOS and arginase activity in the aortic tissue of old rats. PLP also greatly improved acetylcholine-induced relaxation of old rat aorta (47.7% ± 4.8% versus 18.4% ± 4.1% in old rats, P < 0.05) that was abolished by NO inhibition with N-nitro-l-arginine methyl ester hydrochloride (L-NAME) or H2S inhibition with O-carboxymethylhydroxylamine (O-CMH). Thus, PLP might be used for stimulation of endogenous H2S synthesis and correction of oxidative and nitrosative stress and vessel tone dysfunction in aging and age-associated diseases.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Sulfuro de Hidrógeno/metabolismo , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Fosfato de Piridoxal/farmacología , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To investigate the effects of thyroid-stimulating hormone (TSH) on the expression of endothelial nitric oxide synthase (eNOS) in human microvascular endothelial cells (HMEC-1) and explore the potential mechanism. MATERIALS AND METHODS: Expression of thyroid-stimulating hormone receptor (TSHR) in HMEC-1 cells was determined by immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Cell proliferation and the production of nitric oxide (NO) and superoxide anion (SA) were measured after TSH treatment. eNOS expression and AKT phosphorylation were detected by Western blotting. RESULTS: TSHR was expressed in HMEC-1 cells. TSH promoted HMEC-1 cell proliferation and SA production, but inhibited NO generation by dose-dependent blocking of mRNA and protein expression of eNOS. Mechanism studies demonstrated that TSH promoted AKT phosphorylation (P<0.05), and that LY294002 inhibited the reduction of eNOS expression by TSH. Moreover, TSH activated the AKT signaling pathway through binding to TSHR on HMEC-1 cells. CONCLUSIONS: TSH inhibits NO production via the TSHR/AKT signaling pathway.
Asunto(s)
Células Endoteliales/enzimología , Óxido Nítrico Sintasa de Tipo III/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Tirotropina/metabolismo , Tirotropina/farmacología , Línea Celular , Células Endoteliales/química , Expresión Génica/efectos de los fármacos , Humanos , Microvasos/citología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , ARN Interferente Pequeño , Receptores de Tirotropina/antagonistas & inhibidores , Receptores de Tirotropina/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
This study aimed to investigate the effects of propofol through evaluating its interaction with nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Wistar male rats were divided in 4 groups: (1) bolus injection of propofol (1% 10 mg/mL, 100 mg/kg bw, i.p.); (2) Nω-nitro-l-arginine methyl ester (L-NAME; NO synthase inhibitor, 60 mg/kg bw, i.p.) + bolus injection of propofol (1% 10 mg/mL, 100 mg/kg bw, i.p.); (3) DL-propargylglycine (DL-PAG; H2S synthase inhibitor, 50 mg/kg bw, i.p.) + bolus injection of propofol (1% 10 mg/mL, 100 mg/kg bw, i.p.); (4) zinc protoporphyrin IX (ZnPPIX; CO synthase inhibitor, 50 µmol/kg bw, i.p.) + bolus injection of propofol (1% 10 mg/mL, 100 mg/kg bw, i.p.). Increased levels of albumins, low-density lipoproteins, alkaline phosphatase, amylase, high-sensitivity Troponin T, and fibrinogen were found in L-NAME + propofol group. Platelet crit, platelet count, total cholesterol, and high-density lipoproteins were elevated in ZnPPIX + propofol group. Hydrogen peroxide was increased in all groups treated with gasotransmitters inhibitors. Reduced glutathione was reduced in all groups, superoxide dismutase activity only in L-NAME + propofol. The effect of propofol on various biochemical, haematological, and oxidative stress markers may be at least in part mediated through interaction with 3 estimated gasotransmitters.