RESUMO
The aim of this study was to investigate the effects of melatonin on the serum asymmetric dimethylarginine (ADMA) levels and the expressions of vaspin, visfatin, dimethylarginine dimethylaminohydrolase (DDAH), and signal transducer and activator of transcription-3 (STAT-3) for evaluation of endothelial function and inflammation in the hypercholesterolemic rats. Rats were divided into 5 groups: (1) control, (2) hypercholesterolaemia, (3) melatonin administrated concurrently with cholesterol diet, (4) melatonin administrated only last 2 weeks and fed with cholesterol diet, (5) atorvastatin administered only last 2 weeks fed with cholesterol diet. Although an increase was observed in the expressions of visfatin and STAT-3 and the serum ADMA levels, the vaspin and DDAH protein expressions were found to decrease with hypercholesterolemic diets. Melatonin was determined to restore all the parameters to the normal levels. In conclusion, melatonin may have protective and therapeutic effects on hypercholesterolaemia by regulating vaspin, STAT-3, DDAH, and ADMA signalling pathways and create similar effects with atorvastatin.
Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipidemias , Melatonina , Ratos , Animais , Melatonina/farmacologia , Melatonina/uso terapêutico , Nicotinamida Fosforribosiltransferase , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Inflamação/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Óxido Nítrico/metabolismoRESUMO
Abstract This study aimed to investigate the role and signaling pathways of β3-AR in myocardial ischemia/reperfusion (I/R) injury, which is one of the leading causes of death worldwide. 47 male rats were randomly divided into two main groups to evaluate infarct size and molecular parameters. Rats in both groups were randomly divided into 4 groups. Control (sham), I/R (30 min ischemia/120 min reperfusion), BRL37344 (BRL) (A) (5 µg/kg single-dose pre-treatment (preT) before I/R) and BRL (B) (5 µg/kg/day preT for 10 days before I/R). Infarct size was determined with triphenyltetrazolium chloride staining and analyzed with ImageJ program. The levels of AMPK, SIRT1, mTOR, and p70SK6 responsible for cellular energy and autophagy were evaluated by western blot. Infarct size increased in the I/R group (44.84 ± 1.47%) and reduced in the single-dose and 10-day BRL-treated groups (32.22 ± 1.57%, 29.65 ± 0.55%; respectively). AMPK and SIRT1 levels were decreased by I/R but improved in the treatment groups. While mTOR and p70S6K levels increased in the I/R group, they decreased with BRL preT. BRL preT protects the heart against I/R injury. These beneficial effects are mediated in part by activation of AMPK and SIRT1, inhibition of mTOR and p70S6K, and consequently protected autophagy.
RESUMO
BACKGROUND: High blood pressure effects heart and vessels. Development of pathogenesis is the result of oxidative stress. We aimed to investigate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE), and pollen on the hearts of rats which chronic nitric oxide synthase (NOS) inhibited through Nω-nitro-L-arginine methyl ester (L-NAME). Paraoxonase 1 (PON1), total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), asymmetric dimethylarginine (ADMA), and nuclear factor-κB (NF-κB) were analyzed on the heart. MATERIAL AND METHODS: Sprague-Dawley rats were divided five groups of seven rats in every group; Group I: Control, Group II: L-NAME, Group III: L-NAME+propolis, Group IV: L-NAME+CAPE and Group V: L-NAME+pollen. L-NAME become dissolved in regular saline (0.9% NaCl w/v). The ethanolic extract of propolis (200 mg/kg/days, gavage), pollen (100 mg/kg/days, by gavage), CAPE (50 µM/kg/days, intraperitoneally), and the NOS inhibitor L-NAME (40 mg/kg, intraperitoneally) had been administered. RESULTS: Blood pressure (BP) of rats treated with propolis, CAP,E and pollen statistically significant decreased. Decreasing in BP of the rats of pollen group was more than CAPE and propolis groups (P < .05). PON1 and TAS levels decreased in L-NAME-treated groups (P < .05), but ranges have been better in propolis, CAPE and pollen groups. TOS, ADMA and NF-κB levels increased (P < .05) in L-NAME group; however, these parameters were lower (P < .05) in propolis and CAPE groups (P < .05). CONCLUSIONS: Vasorelaxant properties and free radical scavenging actions of propolis, CAPE, and pollen may reduce the oxidative stress and blood pressure in the rats chronic NOS inhibited through L-NAME.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Miocárdio/metabolismo , Álcool Feniletílico/análogos & derivados , Pólen , Própole/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Arginina/análogos & derivados , Arginina/metabolismo , Arildialquilfosfatase/metabolismo , Masculino , NF-kappa B/metabolismo , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase/antagonistas & inibidores , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Protective effects of ischemic postconditioning (PostC) decrease/disappear with age and chronic heart diseases. Similarly, low serum melatonin levels have been reported in the same risk groups. The aims of this study were to investigate the effects of melatonin on the protection of PostC in ischemia-reperfusion (I/R)-induced infarct size and roles of uncoupling protein (UCP) 3, irisin, and nuclear factor kappa B (NFkB) levels. METHODS: Rats were pinealectomized (Px) or sham operated (non-Px) 2 months before the I/R studies. The left main coronary artery was occluded for 30 min followed by 120 min reperfusion. PostC was induced with three cycles of R/I (10 s each) after ischemia. RESULTS: The infarct size was found to be significantly higher in Px rats (54.68±1.5%) than in the control group (35.1±2.5%). PostC and melatonin administrations to non-Px rats significantly reduced the infarct size. On the other hand, PostC did not create a significant effect in Px rats, but protection was provided when PostC was co-administrated with melatonin. While significant decreases were detected in the UCP3 levels, irisin and NFkB levels increased with I/R and Px. Treatment with PostC and melatonin in non-Px groups and their co-administration in Px groups were found to return all the genes close to normal levels. CONCLUSION: The physiological and pharmacological concentrations of melatonin may play a role in the protection of PostC. In cases when physiological melatonin is reduced, such as aging and heart diseases, this protection may decrease, and this effect may be restored by melatonin replacement. PostC and melatonin may regulate energy metabolism and inflammatory mediators and protect mitochondria by affecting the UCP3, irisin, and NFkB levels.
Assuntos
Pós-Condicionamento Isquêmico , Melatonina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteína Desacopladora 3/sangue , Animais , Modelos Animais de Doenças , Masculino , Melatonina/administração & dosagem , Traumatismo por Reperfusão Miocárdica/sangue , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIM OF THE STUDY: Ischemic postconditioning (PostC) is considered to be one of the strongest mechanisms limiting the extent of myocardial infarction, and reducing ischemia-reperfusion (I/R) injury. I/R-induced myocardial injury results in apoptosis, autophagy, and necrosis. The aim of the present study was to investigate the roles of the necrotic gene cytochrome b-245 beta chain (Cybb); Cybb-related microRNA miR139-3p; the autophagy gene Beclin-1 (Becn1); proapoptotic genes Fas, Faslg and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a); and apoptosis-related microRNA miR181a-1 levels on I/R injury, as well as, the potential protective effects of PostC through this gene and microRNAs. METHODS: The left main coronary artery was subjected to ischemia for 30 minutes, followed by reperfusion for 120 minutes. PostC involved three cycles of I/R, each lasting 10 seconds. Gene and microRNA levels were analyzed using a quantitative reverse transcription-polymerase chain reaction. RESULTS: Although an increase was observed in the expression levels of the Cybb, Fas, Faslg and Gadd45a genes, the miR139-3p, miR181a-1, and Becn1 expression levels were found to decrease with I/R injury. PostC was determined to restore the expression of all the genes to the normal levels. CONCLUSIONS: The abovementioned genes can be used as important prognostic markers in the diagnosis of reperfusion injury and in the evaluation of treatment efficacy. It was further noted that increased expression of CYBB, which is one of the target genes for miR139-3p, and a decreased expression of miR181a-1 may cause apoptosis by affecting Fas and Faslg signaling. PostC can inhibit apoptosis by increasing miR139-3p and miR181a-1 levels.
Assuntos
Apoptose/genética , Vasos Coronários , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Pós-Condicionamento Isquêmico , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , NADPH Oxidase 2/genética , NADPH Oxidase 2/fisiologia , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Receptor fas/genética , Receptor fas/metabolismo , Vasos Coronários/metabolismo , Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais/genéticaRESUMO
It has been found that remote organ/limb temporary ischemia, known as remote ischemic conditioning, can provide protection against the formation of lethal ischemic outcome. Current evidence suggests that aging and age-releated comorbidities impair the cardioprotective effects of conditionings. In conjuction with aging, decrease in melatonin synthesis from pineal gland can have role in the pathogenesis of aging and age-related cardiovascular diseases. In this study, we investigated the effects of remote ischemic perconditioning (RIPerC) and physiological and pharmacological concentrations of melatonin on the infarct size, Fas gene, cytochrome b-245 beta chain (Cybb) gene, nuclear factor-kappa B (NfκB), and irisin using an in vivo model of myocardial ischemia/reperfusion (I/R) injury. Sprague-Dawley rats that were divided into two groups first as non-pinealectomized (Non-Px) and pinealectomized (Px), and then (a) Control; (b) I/R (30-minute ischemia, 120-minute reperfusion caused by left coronary artery ligation); (c) I/R + RIPerC (when myocardial ischemia initiated, three cycles of 5-minute occlusion followed by 5-minute reperfusion); (d) I/R + Mel; (e) Px; (f) Px + I/R; (g) Px + I/R + RIPerC; (h) Px + I/R + RIPerC + Mel groups. The infarct size was determined by TTC staining and analyzed by the ImageJ program. Molecular parameters were evaluated by qRT-PCR and Western blot. Results showed that increased infarct size in Non-Px groups decreased with RIPerC and melatonin. However, increased infarct size in Px groups was decreased minimally with RIPerC and significantly decreased with RIPerC + Melatonin. Fold change in Fas gene was associated with the infarct size. RIPerC and melatonin reduced expressions of Cybb, NfκB, and irisin genes. The physiological release and pharmacological concentration of melatonin may improve protective effect of RIPerC against I/R-induced infarct size by modulating Cybb, Fas, NfκB, Irisin signaling pathways.
Assuntos
Fibronectinas/metabolismo , Precondicionamento Isquêmico , Melatonina/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-DawleyRESUMO
The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nω -nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index (OSI), total antioxidant status (TAS), total oxidant status (TOS), asymmetric dimethylarginine (ADMA), and nuclear factor kappa B (NF-κB). TAS levels and PON1 activity were significantly decreased in kidney tissue samples in the L-NAME-treated group (P < 0.05). The levels of TAS and PONI were higher in the L-NAME plus propolis, CAPE, and pollen groups compared with the L-NAME-treated group. TOS, ADMA, and NF-κB levels were significantly increased in the kidney tissue samples of the L-NAME-treated group (P < 0.05). However, these parameters were significantly lower in the L-NAME plus propolis, CAPE, and pollen groups (P < 0.05) compared with rats administered L-NAME alone (P < 0.05). Furthermore, the binding energy of CAPE within catalytic domain of glutathione reductase (GR) enzyme as well as its inhibitory mechanism was determined using molecular modeling approaches. In conclusion, experimental and theoretical data suggested that oxidative alterations occurring in the kidney tissue of chronic hypertensive rats may be prevented via active compound of propolis, CAPE administration.
Assuntos
Ácidos Cafeicos/farmacologia , Nefropatias/etiologia , Simulação de Dinâmica Molecular , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Própole/farmacologia , Animais , Antioxidantes , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/toxicidade , Arildialquilfosfatase/metabolismo , Sítios de Ligação , Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Glutationa Redutase/química , Glutationa Redutase/metabolismo , Meia-Vida , Hipertensão/metabolismo , Hipertensão/patologia , Nefropatias/metabolismo , Masculino , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Álcool Feniletílico/química , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacologia , Pólen/química , Pólen/metabolismo , Própole/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-DawleyRESUMO
The present study aims to explore the effects of chronic and acute zinc sulfate supplementation on myocardial ischemia-reperfusion injury in rats. The study registered 50 adult male rats which were divided into five groups in equal numbers as follows: group 1, normal control; group 2, sham; group 3, myocardial ischemia reperfusion (My/IR): the group which was fed on a normal diet and in which myocardial I/R was induced; group 4, myocardial ischemia reperfusion + chronic zinc: (5 mg/kg i.p. zinc sulfate for 15 days); and group 5, myocardial ischemia reperfusion + acute zinc: the group which was administered 15 mg/kg i.p. zinc sulfate an hour before the operation and in which myocardial I/R was induced. The collected blood and cardiac tissue samples were analyzed using spectrophotometric method to determine levels of MDA, as an indicator of tissue injury, and GSH, as an indicator of antioxidant activity. The highest plasma and heart tissue MDA levels were measured in group 3 (p < 0.05). Group 5 had lower MDA values than group 3, while group 4 had significantly lower MDA values than groups 3 and 5 (p < 0.05). The highest erythrocyte GSH values were found in group 4 (p < 0.05). Erythrocyte GSH values in group 5 were higher than those in group 3 (p < 0.05). The highest GSH values in heart tissue were measured in group 4 (p < 0.05). The results of the study reveal that the antioxidant activity inhibited by elevated oxidative stress in heart ischemia reperfusion in rats is restored partially by acute zinc administration and markedly by chronic zinc supplementation.
Assuntos
Suplementos Nutricionais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Zinco/farmacologia , Animais , Eritrócitos/metabolismo , Glutationa/sangue , Masculino , Malondialdeído/sangue , Traumatismo por Reperfusão Miocárdica/sangue , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND/AIM: The effects of AT2 receptor agonist novokinin on blood pressure, eNOS, NADPH oxidase, protein arginine methyltransferases (PRMTs), and Rho kinase in hypertension were investigated. Furthermore, in isolated thoracic aorta rings, contractile and dilator responses were studied. MATERIALS AND METHODS: To develop hypertension, L-NAME was administered intraperitoneally and salt was given with tap water (1%) for 4 weeks. Novokinin was administered intraperitoneally for the last 2 weeks. Blood pressures were measured using the tail-cuff method and enzyme levels by real-time polymerase chain reaction in aortic tissues. RESULTS: Blood pressure increased significantly in hypertensive rats. Novokinin reduced the blood pressure in the hypertensive group. While the contractile responses to increasing doses of angiotensin II were increased, vascular reactivity (Emax) and sensitivity (EC50) to acetylcholine were decreased in hypertensive rats. In novokinin-treated hypertensive groups, the EC50 value decreased and the Emax value for acetylcholine significantly increased. The levels of Rho kinase and PRMT expression increased and the level of eNOS expression decreased in the hypertensive group. In novokinin-treated rats, ADMA, NADPH oxidase, and Rho kinase tended to decreased, but these changes did not reach statistical significance. CONCLUSION: Although further studies are needed to determine its effectiveness, the AT2 agonist novokinin may be a novel agent that is promising in terms of protective effects for the treatment of hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Hipertensão , NADPH Oxidases , Óxido Nítrico Sintase , Oligopeptídeos , Ratos , Quinases Associadas a rhoRESUMO
AIM: The biological and pharmacological properties of vessels used in coronary artery bypass graft (CABG) surgery are as important as their mechanical properties. The aim of this study was to investigate the possible role of protein kinase C (PKC)-dependent mechanisms in leptin-induced relaxation in the human internal mammary artery (IMA). METHODS: IMA rings, obtained from patients undergoing CABG surgery, were suspended in isolated tissue baths containing Krebs-Henseleit solution, which were continuously gassed with 95% O2 and 5% CO2 at 37(°)C. RESULTS: The IMA rings were pre-contracted with increasing concentrations of norepinephrine (NE 10(-9)-10(-4) mol/l) and the relaxation responses to sodium nitroprusside (SNP), a nitrosovasodilator, and leptin were studied in the presence and absence of a PKC inhibitor. Leptin (1 µM) caused a dose-dependent relaxation in NE pre-contracted IMA rings. Pre-treatment with a PKC inhibitor significantly attenuated this vasorelaxatory response to leptin in human isolated IMA. CONCLUSION: It was found that SNP and leptin caused significant relaxation of the NE pre-contracted human IMA rings, and PKC was probably the sub-cellular mediator for this effect. Our findings may have clinical or pharmacological importance as it could be hypothesised that obese subjects who have a left IMA bypass graft would have better myocardial perfusion.
Assuntos
Leptina/farmacologia , Artéria Torácica Interna/efeitos dos fármacos , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Anastomose de Artéria Torácica Interna-Coronária , Artéria Torácica Interna/enzimologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Coleta de Tecidos e ÓrgãosRESUMO
OBJECTIVE: The purpose of the present study was to evaluate the effects of melatonin on biochemical and cardiovascular changes resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a polychlorinated dibenzo-para-dioxin. METHODS: A total of 24 Sprague-Dawley rats were divided equally into the following four groups: (1) control group was administered with 0.5 mL corn oil by gavage and 0.5 cc vehicle of melatonin (proportionally nine parts physiological serum + one part ethyl alcohol) intraperitoneally for 4 weeks, (2) the melatonin group was given 5 mg/kg/day melatonin intraperitoneally for 4 weeks, (3) the TCDD group was given 500 ng/kg/day TCDD by gavage for 4 weeks and (4) the TCDD + melatonin group was given TCDD (500 ng/kg/day) by gavage and melatonin (5 mg/kg/day) intraperitoneally simultaneously for 4 weeks. Systolic blood pressure was evaluated by the tail-cuff method. Vascular responses to phenylephrine and acetylcholine were evaluated in the isolated thoracic aortas. RESULTS: TCDD not only augmented the systolic blood pressure but also increased the contractile responses to phenylephrine in aorta. Melatonin reversed the blood pressure augmented by TCDD and decreased the contractile responses to phenylephrine in aorta. TCDD induced an increase in the malondialdehyde levels in kidney tissue and melatonin did not change it. Therefore, TCDD caused a decrease in glutathione levels in kidney tissues and melatonin reversed it. CONCLUSION: Present data demonstrated that TCDD may lead to an increase in blood pressure via increased renal oxidative stress and vascular reactivity. However, melatonin might ameliorate the blood pressure disturbed by TCDD in part by decreasing the oxidant activity induced by TCDD.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Hipertensão/induzido quimicamente , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Acetilcolina/farmacologia , Animais , Antioxidantes/farmacologia , Glutationa/sangue , Masculino , Malondialdeído/sangue , Fenilefrina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The aim of this study is to investigate the effects of caffeic acid phenethyl ester (CAPE) on isoproterenol (ISO)-induced myocardial injury in hypertensive rats. METHODS: Rats were divided into 4 groups (n=29): Control group (n=8), L-NNA (NG-Nitro-L-arginine) group (n=8), L-NNA+ISO (L-NNA+isoproterenol) group (n=7) and L-NNA+ISO+CAPE (L-NNA+ISO + caffeic acid phenethyl ester) group (n=6). ISO (150 mg/kg/day) was given intraperitoneally (i.p.) once a day for 2 consecutive days (at the 12th and 13th days of L-NNA treatment). NG-Nitro-L-arginine (L-NNA) was given orally (25 mg/kg/day) in drinking water for 14 days. CAPE (10 µmol/kg/day) was given (i.p.) for 7 days after the first week. Systolic blood pressure (SBP) was evaluated by the tail-cuff method and biochemical analysis were performed using an autoanalyzer and a spectrophotometer. RESULTS: SBP in all L-NNA-treated groups was found to be increased at seventh day. AST and LDH levels in LNNA+ISO group were significantly increased compared to control (AST: 125±5 vs. 105±2; LDH: 861±154 vs. 571±46 U/L respectively) (p<0.05). Also, ISO caused to extensive necrosis and mononuclear cell infiltration in hypertensive rat myocardium. CAPE application reversed the enhanced AST and LDH levels as well as the extensive necrosis and the mononuclear cell infiltration in LNNA+ISO+CAPE group compared LNNA+ISO. CONCLUSION: According to our findings, it might be suggested that CAPE may be a favorable agent to protect the hypertensive myocardium from the injury induced by isoproterenol via mechanisms such as the induction of the antioxidant enzymes and the inhibition of lipid peroxidation.
Assuntos
Antioxidantes/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Hipertensão/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ácidos Cafeicos/administração & dosagem , Ácidos Cafeicos/farmacologia , Modelos Animais de Doenças , Injeções Intraperitoneais , Isoproterenol/efeitos adversos , Peroxidação de Lipídeos , Infarto do Miocárdio/induzido quimicamente , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , RatosRESUMO
AIM: Endothelial dysfunction, oxidative stress and inflammation are among the most important mechanisms of ischaemia-reperfusion (I/R) injury. Besides their cholesterol-lowering effects, statins are known to provide protection against myocardial dysfunction and vascular endothelial injury via nitric oxide-dependent mechanisms. The aim of this study was to investigate the effects of rosuvastatin on certain intermediates involved in the generation of nitric oxide (asymmetrical dimethyl arginin, ADMA, caveolin-1 and hsp 90), oxidative stress (rhokinase, NADPH oxidase) and inflammation (NFkB), using an in vivo model of myocardial infarction in the rat. METHODS: Adult male Sprague Dawley rats were divided into three groups (control, I/R and I/R after 15 days of rosuvastatin administration). Reperfusion was applied for 120 min following left anterior descending coronary artery ischaemia for 30 min. Caveolin-1, hsp 90 and NFkB levels were evaluated with the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and ADMA, rhokinase and NADPH oxidase levels were evaluated with ELISA. RESULTS: While NFkB and hsp 90 levels were higher in the I/R group, their levels were significantly lower in the rosuvastatin group. While ADMA and NADPH oxidase levels significantly increased with I/R, they were lower in the rosuvastatin-treated group, but not statistically significant. Rhokinase levels were significantly lower in the rosuvastatin group. Caveolin-1 levels were not different between the groups. CONCLUSION: Our results suggest that ADMA, rhokinase, NADPH oxidase, hsp 90 and NFkB could facilitate I/R injury, and rosuvastatin significantly reduced levels of these parameters. These results indicate that rosuvastatin may have a protective role in I/R injury via mechanisms targeting inflammation, endothelial dysfunction and oxidative stress.
Assuntos
Fluorbenzenos/farmacologia , Coração/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/farmacologia , RNA Mensageiro/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Arginina/análogos & derivados , Arginina/efeitos dos fármacos , Arginina/genética , Arginina/metabolismo , Caveolina 1/efeitos dos fármacos , Caveolina 1/genética , Caveolina 1/metabolismo , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Inflamação/genética , Inflamação/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , NADPH Oxidases/efeitos dos fármacos , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosuvastatina Cálcica , Quinases Associadas a rho/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
Reduction in the synthesis or bioavailability of nitric oxide plays a significant role in the development of hypertension. Propolis is a resinous product collected by honeybees from various plant sources. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamines. The aim of this study was to examine the effect of propolis on blood pressure (BP), TH, and total RNA levels in the adrenal medulla, heart, and hypothalamus tissues in chronic nitric oxide synthase (NOS)-inhibited rats by N(w)-nitro-l-arginine methyl ester (L-NAME). Rats received NOS inhibitor (L-NAME) for 15 days to produce hypertension and propolis for the last 5 days. TH activity and total RNA levels significantly increased in adrenal medulla, heart, and hypothalamus tissues in L-NAME-treated groups (P < .05). TH activity and total RNA levels of L-NAME+propolis-treated rats reduced (P < .05) compared with L-NAME-treated groups. TH activity in propolis-treated rats was reduced to the control values. L-NAME led to a significant increase in BP compared with the control group. Propolis administration to L-NAME-treated rats reduced BP but this was not statistically significant compared to L-NAME-treated groups. These results suggest that propolis decreases TH activity in NOS-inhibited hypertensive rats and thereby may modulate the synthesis of catecholamine and BP.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Óxido Nítrico Sintase/antagonistas & inibidores , Própole/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Hipertensão/enzimologia , Hipertensão/genética , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos WistarRESUMO
Renal prostacycline (PGI(2)) and oxidative stress are known to be important factors that effect the natriurezis and diuresis. 8-iso prostaglandin F(2)α± (8-isoprostane), a member of F(2)-isoprostanes, is formed from the nonenzymatic reaction of arachidonic acid and oxygen radicals in vivo and in vitro, and also it is a marker of oxidative stress in vivo. The aim of this study is to determine the role of renal PGI(2) and 8-isoprostane in a salt and nitric oxide (NO) inhibition-induced hypertension model. Rats were distributed equally among four groups (n = 6 per group). Control rats were given normal salt diet (0.32%); high-salt (HS) rats were given high salt diet (3.2%); NG-nitro-L-arginine (L-NNA) rats were given normal salt diet and 25 mg/kg L-NNA; HS+L-NNA rats were given high salt diet and 25 mg/kg L-NNA. Rats were placed in individual metabolic cages for 17 days. Systolic blood pressure (SBP) was measured at days initial, 7th and 14th .Urinary 8-isoprostane and PGI(2) levels were analyzed. Salt- loading alone did not change SBP values. The average SBP in L-NNA and HS+L-NNA groups were shown to significantly enhance compared to initial and day 7th in the same groups, respectively. The levels of 8-isoprostane in the HS+L-NNA group was significantly enhanced compared to the other groups. L-NNA or HS diet alone did not change the levels of 8-isoprostane compared to the control group. L-NNA alone did not change PGI(2) levels in urine compared to the control. PGI(2) levels in the HS, and the HS+L-NNA group was significantly higher compared to the control group. This study concluded that NOS inhibition plus salt-loading induced oxidative stress and increased renal PGI(2). Also, it is suggested that augmented oxidative stress may aggravate the hypertension. But the renal synthesis of PGI(2) is increased in order to augment the diuresis and natriuresis without the effect of blood pressure (BP).
Assuntos
Dinoprosta/análogos & derivados , Epoprostenol/urina , Hipertensão/etiologia , Óxido Nítrico/antagonistas & inibidores , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Dinoprosta/urina , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Hipertensão/fisiopatologia , Hipertensão/urina , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio na Dieta/administração & dosagemRESUMO
The aim of this study was to investigate the possible protective effects of lycopene (LC) and ellagic acid (EA) on cisplatin (CP)-induced testicular apoptosis in male rats. The control group was treated with placebo; LC, EA and CP groups were given alone LC, EA and CP, respectively; the CP+LC group was treated with a combination of CP and LC; and the CP+EA group was treated with a combination of CP and EA. Although CP significantly increased the number of Bax-positive (apoptotic) cells it had no effect on the number of Bcl-2-positive (antiapoptotic) cells compared with the control group. Administration of CP caused significant increase in lipid peroxidation and nonsignificant decrease in superoxide dismutase (SOD) activity along with some histopathological lesions in testicular tissue. However, combined treatments of LC or EA in addition to CP tended to prevent the CP-induced testicular apoptosis, histopathological lesions and lipid peroxidation.
Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Carotenoides/farmacologia , Cisplatino/farmacologia , Ácido Elágico/farmacologia , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Peroxidação de Lipídeos/efeitos dos fármacos , Licopeno , Masculino , Malondialdeído/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/antagonistas & inibidores , Testículo/patologia , Testículo/fisiologia , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
Lycopene is one of the major carotenoids and is found almost exclusively in tomatoes and tomato products. This study was performed to evaluate the effect of lycopene on methanol-induced liver injury and to compare the results with those after fomepizole, which is used in treatment of methanol intoxication. Experiments were carried out with 30 female Wistar rats weighting 180-200 g. Rats were injected with a intraperitoneally dose of 3 g/kg methanol as a 50% solution in isotonic saline once for intoxication. Rats were pretreated with fomepizole (50 mg/kg) and/or lycopene (10 mg/kg) before methanol. After 24 hours all the drug-treated and intoxicated rats were sacrificed under anesthesia. Malondialdehyde (MDA) levels were determined in order to assess lipid peroxidation, and caspase-3 activity was determined by immunostaining of liver tissues to evaluate apoptosis. Methanol administration significantly increased the MDA level and caspase-3 activity in liver. Pretreatment with lycopene and/or fomepizole decreased the MDA levels significantly. Similarly, lycopene and fomepizole decreased methanol-induced caspase-3 activity. The findings of the present study demonstrate that methanol intoxication causes hepatic toxicity in rats and that this is likely a result of reactive oxygen species and apoptosis induction. Lycopene has protective effects against methanol-induced hepatic injury similar to fomepizole. It was demonstrated for the first time that both lycopene and fomepizole prevent methanol-induced hepatic injury by reducing the increase of lipid oxidation and caspase-3 activation.
Assuntos
Carotenoides/uso terapêutico , Caspase 3/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Fígado/enzimologia , Metanol/toxicidade , Pirazóis/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Fomepizol , Humanos , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/enzimologia , Hepatopatias Alcoólicas/metabolismo , Licopeno , Malondialdeído/metabolismo , Metanol/metabolismo , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
OBJECTIVE: To determine the effect of melatonin, a pineal secretory product that prevents testicular ischemia/reperfusion (IR) injury through its antioxidative properties, on epididymal sperm quality in a rat testicular IR injury model. DESIGN: Experimental study. SETTING: University pharmacology laboratory. ANIMAL(S): Fifty-six 8-week-old male Wistar albino rats. INTERVENTION(S): Left testicular artery and vein occluded for 1 hour; before the bilateral orchiectomy, the organ was allowed to reperfuse 30 days. Melatonin (10 mg/kg IP) or vehicle (1% ethanol in saline) was administrated for 10 minutes before reperfusion and for 1 hour after reperfusion. MAIN OUTCOME MEASURE(S): After 24 hours of reperfusion, the rats were decapitated, and the testicular tissue samples were obtained for histologic examination. In addition, after 30 days of reperfusion, the epididymal sperm concentration, motility, and abnormal sperm rates were determined in the sperm collected from the epididymis. RESULT(S): A statistically significant decrease in sperm concentration resulted from IR as well as an increase in sperm abnormalities, but the sperm motility did not change. Melatonin treatment did not prevent the IR-induced reduction in sperm concentration. However, melatonin treatment statistically significantly decreased the sperm abnormalities when compared with the IR injured samples. CONCLUSION(S): Melatonin may improve sperm morphology for a protective effect in IR-induced testicular injury.
Assuntos
Epididimo/efeitos dos fármacos , Melatonina/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Epididimo/patologia , Injeções Intraperitoneais , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/irrigação sanguínea , Testículo/patologia , Fatores de TempoRESUMO
Testicular torsion is a common syndrome that could lead to infertility. We investigated the therapeutic effects of lycopene, an antioxidant caretenoid, on testicular ischemia/reperfusion (IR) injury that resembles testicular torsion. Male Wistar albino rats were divided into three groups: sham (n = 6), IR (n = 18), and ischemia/reperfusion with lycopene (IRL, n = 18). Left testicular artery and vein was occluded for 1 h, followed by reperfusion of 3 h, 24 h or 30 days in IR and IRL animals. Either corn oil (vehicle) or lycopene (4 mg/kg) was administrated once daily by gavage to IR or IRL animals, respectively, 5 min after ischemia. Sham-operated animals were treated with vehicle by gavage 5 min after the operation. IR decreased sperm motility and concentration in both ipsilateral and contralateral testes and increased abnormal sperm rate in ipsilateral testis after 30 days of reperfusion. Treatment with lycopene increased the motility in bilateral testes and decreased the rate of abnormal sperm in ipsilateral testis to the sham level, but did not increase sperm concentration in bilateral testes. IR increased the activities of catalase and glutathione peroxidase and the level of reduced glutathione by 24 h of reperfusion, but malondialdehyde remained unchanged. Lycopene treatment restored the enzyme activities but not the reduced glutathione level. Lycopene treatment also ameliorated the IR-induced tissue damage in bilateral testes. In conclusion, the therapeutic antioxidant effect of lycopene on germ cells could serve as a promising intervention to oxidative stress-associated infertility problems, such as testicular torsion.
Assuntos
Antioxidantes/farmacologia , Carotenoides/farmacologia , Traumatismo por Reperfusão/complicações , Doenças Testiculares/etiologia , Doenças Testiculares/prevenção & controle , Testículo/efeitos dos fármacos , Testículo/patologia , Animais , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Licopeno , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/induzido quimicamente , Espermatozoides/metabolismoRESUMO
Increased levels of reactive oxygen species, alterations in nitric oxide synthesis, and increased migration of neutrophils to the ischemic tissue play an important role in the pathophysiology of myocardial ischemia-reperfusion (IR) injury. In this study, we have evaluated the effects of melatonin on myeloperoxidase (MPO) activity, tissue glutathione (GSH), lipid peroxidation levels, and blood pressure in L-NAME-induced hypertensive rats with or without IR. NOS inhibitor L-NAME was administrated before inducing cardiac ischemia for 15 days intraperitoneally. For the cardiac ischemia, the left coronary artery was ligated for 30 min, and reperfusion was performed for 120 min after the ischemia. L-NAME treatment in non-ischemic animals increased blood pressure and lipid peroxidation, and decreased glutathione level in myocardial tissue significantly as compared with non-L-NAME-treated animals. Melatonin reversed L-NAME-induced blood pressure elevation and oxidative changes. Cardiac IR increased MDA levels and MPO activity and decreased GSH levels as compared with non-ischemic animals. L-NAME treatment did not change in IR-induced MDA and GSH levels as compared with ischemic control animals. However, MPO activity was significantly higher than control ischemic animals. MDA levels and MPO activity resulting from ischemic injury in melatonin-treated animals were significantly less than L-NAME-treated animals. Taken together-the ischemic and non-ischemic control and melatonin-treated animals-this study shows that neutrophil migration plays an important role on the development of ischemic injury in hypertensive rats.