RESUMO
Tempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.
Assuntos
Antioxidantes/uso terapêutico , Óxidos N-Cíclicos/uso terapêutico , Hipertensão/complicações , Isquemia/complicações , Nefropatias/prevenção & controle , Rim/irrigação sanguínea , Animais , Antioxidantes/farmacologia , Materiais Biomiméticos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Caspase 3/metabolismo , Doença Crônica , Creatinina/sangue , Óxidos N-Cíclicos/farmacologia , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/fisiopatologia , Glomérulos Renais/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Renina/metabolismo , Marcadores de Spin , Superóxido Dismutase , Ureia/sangue , Vasodilatação/efeitos dos fármacosRESUMO
To investigate the systemic and placental oxidant status as well as vascular function in experimental preeclampsia (PE) induced by nitro-L-arginine methyl ester (L-NAME). Fetal parameters and maternal blood pressure, proteinuria, mesenteric arterial bed (MAB) reactivity, and systemic and placental oxidative stress were compared between four groups: pregnant rats receiving L-NAME (60 mg/kg/day, orally) (P + L-NAME) or vehicle (P) from days 13 to 20 of pregnancy and nonpregnant rats receiving L-NAME (NP + L-NAME) or vehicle (NP) during 7 days. L-NAME administration during pregnancy induced some hallmarks of PE, such as hypertension and proteinuria. The P + L-NAME group presented lower weight gain and placental mass as well as reduced number and weight of live fetuses than P group. The vasodilator effect induced by acetylcholine (ACh) and angiotensin II (Ang II) was lower in the perfused MAB from NP + L-NAME and P + L-NAME than in control groups. Otherwise, the nitroglycerine-induced vasodilation and the phenylephrine- and Ang II-induced vasoconstriction were higher in MAB from NP + L-NAME and P + L-NAME groups than in the respective controls. Systemic and placental oxidative damage, assessed by malondialdehyde and carbonyl levels, was increased and activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced in P + L-NAME and NP + L-NAME groups compared to controls. The present data suggest that the oxidative stress and reduced bioavailability of nitric oxide may contribute to attenuation of vasodilator responses to ACh and Ang II, and hyperreactivity to Ang II in the mesentery of preeclamptic rat, which may contribute to the increased peripheral vascular resistance and BP, as well as intrauterine growth restriction in L-NAME-induced PE.
Assuntos
Estresse Oxidativo , Placenta/metabolismo , Pré-Eclâmpsia/fisiopatologia , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Arginina/análogos & derivados , Pressão Sanguínea/fisiologia , Inibidores Enzimáticos/farmacologia , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/fisiopatologia , Glutationa Peroxidase/metabolismo , Hipertensão/fisiopatologia , Malondialdeído/metabolismo , Mesentério/irrigação sanguínea , NG-Nitroarginina Metil Éster , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase , Nitroglicerina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Carbonilação Proteica/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
The aim of this study was to investigate the effect of a polyphenol-rich Açaí seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis.
Assuntos
Colesterol/metabolismo , Euterpe/química , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Polifenóis/farmacologia , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Antioxidantes/metabolismo , Peso Corporal/efeitos dos fármacos , Colesterol/biossíntese , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sementes/químicaRESUMO
BACKGROUND: Plants rich in flavonoids, such as açaí (Euterpe oleraceae Mart.), can induce antinociception in experimental animals. Here, we tested an extract obtained from the stones of açaí fruits (açaí stone extract, ASE), a native plant from the Amazon region of Brazil, in models of acute/inflammatory and chronic pain. METHODS: Antinociceptive effects of ASE were evaluated in the hot plate, formalin, acetic acid writhing, carrageenan, and neuropathic pain models, as well as in thermal hyperalgesia and mechanical allodynia models induced by spinal nerve ligation. Antinociceptive activities were modulated by the administration of cholinergic, adrenergic, opioid, and L-arginine-NO antagonists. RESULTS: Oral administration of ASE (30, 100, or 300 mg.kg(-1)) dose-dependently reduced nociceptive responses to acute/inflammatory pain in mice, including thermal hyperalgesia, acetic acid-induced writhing, and carrageenan-induced thermal hyperalgesia. Moreover, ASE reduced the neurogenic and inflammatory phases after intraplantar injection of formalin in mice. The antinociceptive effect of ASE (100 mg · kg(-1)) in a hot plate protocol, was inhibited by pre-treatment with naloxone (1 mg · kg(-1)), atropine (2 mg · kg(-1)), yohimbine (5 mg · kg(-1)), or L-NAME (30 mg · kg(-1)). Furthermore, ASE prevented chronic pain in a rat spinal nerve ligation model, including thermal hyperalgesia and mechanical allodynia. CONCLUSION: ASE showed significant antinociceptive effect via a multifactorial mechanism of action, indicating that the extract may be useful in the development of new analgesic drugs.
Assuntos
Analgésicos , Euterpe/química , Neuralgia/tratamento farmacológico , Extratos Vegetais , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , RatosRESUMO
Pre-eclampsia (PE), a syndrome of pregnancy-induced hypertension, continues to be a leading cause of maternal and fetal morbidity and mortality. The aim of this study was to investigate whether changes in oxidative status are correlated with alterations in the L-arginine-nitric oxide pathway and platelet aggregation in PE. Plasma and platelets from women with PE (n=24) or normotensive pregnancy (NP, n=27) recruited in the third trimester of gestation were used to measure oxidative damage assessed by protein carbonyl content, antioxidant activities of superoxide dismutase (SOD), catalase (CAT) and nitrite levels. Transport of L-[(3)H]-arginine, as well as the activities of the nitric oxide (NO) synthase (eNOS and inducible NO synthase (iNOS)) and platelet aggregation, were also evaluated. Plasma nitrite levels and the activities of SOD and CAT were reduced in PE (5.2±2.7, 3.4±0.8, 0.3±0.4, respectively, P<0.05) compared with NP (8.7±2.3, 6.7±3.1, 1.0±0.5, respectively), whereas protein carbonyl content and L-arginine levels were not significantly different between PE and NP groups. In platelets, L-arginine transport was reduced in PE (19.2±10.5, P<0.05) compared with NP (62.0±31.1), whereas the NOS activity, eNOS and iNOS expression, nitrite levels and platelet aggregation were unaffected. Protein carbonyl content was increased, and CAT activity was reduced in platelets from PE (0.03±0.02, 0.55±0.30, respectively, P<0.05), compared with NP (0.005±0.005, 1.01±0.36, respectively). The data suggest that a systemic impairment of antioxidant defense mechanisms is associated with decreased plasma nitrite levels, which may contribute to hypertension in PE. Oxidative stress may contribute to the reduced influx of L-arginine in platelets. Compensatory mechanisms may contribute to the maintenance of NO production and its modulatory role on platelet function.
Assuntos
Arginina/metabolismo , Plaquetas/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Pré-Eclâmpsia/metabolismo , Adolescente , Adulto , Arginina/sangue , Catalase/metabolismo , Feminino , Humanos , Óxido Nítrico/sangue , Agregação Plaquetária/fisiologia , Pré-Eclâmpsia/sangue , Gravidez , Transdução de Sinais/fisiologia , Superóxido Dismutase/metabolismoRESUMO
We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.
Assuntos
Antioxidantes/farmacologia , Fígado Gorduroso/prevenção & controle , Hipertensão/prevenção & controle , Obesidade/metabolismo , Estresse Oxidativo , Estilbenos/farmacologia , Animais , Antioxidantes/uso terapêutico , Glicemia/metabolismo , Dislipidemias/etiologia , Dislipidemias/prevenção & controle , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Hiperfagia/etiologia , Hiperfagia/metabolismo , Hiperfagia/prevenção & controle , Hipertensão/etiologia , Hipertensão/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Obesidade/complicações , Ratos , Ratos Wistar , Resveratrol , Estilbenos/uso terapêutico , Superóxido Dismutase/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , DesmameRESUMO
Postnatal early overfeeding (EO) is related to later development of overweight and other metabolic disorders. As oxidative stress is implicated in most human diseases, as obesity and diabetes, we decided to study some parameters related to oxidative stress and insulin signaling in liver from EO animals in adult life. To induce EO, litter size was reduced to three pups per litter (SL: small litter) and groups with normal litter size (NL:10 pups per litter) were used as control. After weaning, rats had free access to standard diet and water. Body weight and food intake were monitored daily and offspring were killed at 180 days-old. Significant differences had P<.05 or less. As expected, SL rats had hyperphagia, higher body weight and higher visceral fat mass at weaning and adulthood. In liver, postnatal EO programmed for lower catalase (-42%), superoxide dismutase (-45%) and glutathione peroxidase (-65%) activities. The evaluation of liver injury in adult SL group showed lower nitrite content (-10%), higher liver and plasma malondialdehyde content (+25% and 1.1-fold increase, respectively). No changes of total protein bound carbonyl or Cu/Zn superoxide dismutase protein expression in liver were detected between the groups. Regarding insulin signaling pathway in liver, SL offspring showed lower IRß (-66%), IRS1 (-50%), phospho-IRS1 (-73%), PI3-K (-30%) and Akt1 (-58%). Indeed, morphological analysis showed that SL rats presented focal areas of inflammatory cell infiltrate and lipid drops in their cytoplasm characterizing a microsteatosis. Thus, we evidenced that postnatal EO can program the oxidative stress in liver, maybe contributing for impairment of the insulin signaling.
Assuntos
Animais Recém-Nascidos/metabolismo , Resistência à Insulina , Fígado/metabolismo , Hipernutrição/metabolismo , Estresse Oxidativo , Animais , Peso Corporal , Catalase/metabolismo , Ingestão de Alimentos , Feminino , Glutationa Peroxidase/metabolismo , Insulina/metabolismo , Gordura Intra-Abdominal/crescimento & desenvolvimento , Gordura Intra-Abdominal/metabolismo , Tamanho da Ninhada de Vivíparos , Fígado/crescimento & desenvolvimento , Fígado/patologia , Nitritos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
This study investigated the endothelium-dependent vasorelaxant effects of the essential oil of Ocimum gratissimum (EOOG) in aortas and mesenteric vascular beds isolated from rats. EOOG (3-300 µg/mL) relaxed the tonic contractions induced by phenylephrine (0.1 µmol/L) in isolated aortas in a concentration-dependent manner in both endothelium-containing and endothelium-denuded preparations. This effect was partially reversed by L-NAME (100 µmol/L) but not by indomethacin (10 µmol/L) or TEA (5 mmol/L). In mesenteric vascular beds, bolus injections of EOOG (30, 50, 100, and 300 ng) decreased the perfusion pressure induced by noradrenaline (6 µmol/L) in endothelium-intact preparations but not in those treated with deoxycholate. L-NAME (300 µmol/L) but not TEA (1 mmol/L) or indomethacin (3 µmol/L) significantly reduced the vasodilatory response to EOOG at all of the doses tested. Our data showed that EOOG exerts a dose-dependent vasodilatory response in the resistance blood vessels of rat mesenteric vascular beds and in the capacitance blood vessel, the rat aorta. This action is completely dependent on endothelial nitric oxide (NO) release in the mesenteric vascular beds but only partially dependent on NO in the aorta. These novel effects of EOOG highlight interesting differences between resistance and capacitance blood vessels.
Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Ocimum/química , Óleos Voláteis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/enzimologia , Veias Mesentéricas/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Óleos Voláteis/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Wistar , Capacitância Vascular/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidoresRESUMO
Exposure to cigarette smoke (CS) is associated with lung inflammation, oxidative stress, and emphysema. The aim of this work was to study Mate tea as a possible natural antioxidant resource against emphysema development. C57BL/6 mice were distributed into 4 groups: exposed to ambient air (control), exposed to the smoke of 12 cigarettes (CS), exposed to ambient air and treated with Mate (500 mg/kg/day diluted in 100 µL) (Mate), and exposed to CS and treated with Mate (CS+Mate). All mice were treated for 60 days. On day 61 the mice were killed. Right and left lungs were removed for histology and biochemical analysis, respectively. Emphysematous lesions and inflammatory cell influxes in the CS group were evident by histological analysis. Cells showed higher 4-hydroxynonenal labeling in the CS group than in the CS+Mate group. Myeloperoxidase activity was reduced in the CS+Mate group compared to the CS group. Superoxide dismutase and catalase activities were significantly higher in the CS+Mate group compared to the CS group. The ratio of reduced to oxidized glutathione was greater in the CS+Mate group than in the CS group. CS-induced emphysema in C57BL/6 mice was prevented by Mate in association with a reduction in inflammatory and oxidative stress parameters.
Assuntos
Enfisema Pulmonar/tratamento farmacológico , Fumaça/efeitos adversos , Chá , Animais , Antioxidantes/farmacologia , Glutationa/metabolismo , Camundongos , Oxidantes , Oxirredução , Enfisema Pulmonar/induzido quimicamenteRESUMO
Heart failure (HF) is the end-stage of cardiovascular disease and is associated with a high incidence of thrombotic events. Nitric oxide (NO) mediates vasodilation and prevents platelet activation, providing an important antithrombotic effect. The aim of this study was to investigate the effects of aerobic training on survival, platelet L-arginine-NO pathway, and vasodilator properties in doxorubicin (DOX)-induced HF. Sprague Dawley rats were randomly assigned to saline/sedentary (SAL/SED), saline/exercise (SAL/EX), DOX/sedentary (DOX/SED), and DOX/exercise (DOX/EX) groups. Four weeks after intraperitoneal DOX injection (1mg/kg(-1)/d(-1); 10 days), shortening fraction in DOX/SED and DOX/EX was significantly reduced. Treadmill exercise was performed during 6 weeks, 5 days/week(-1), 30minutes/day(-1), 50% to 60% of maximum velocity. Survival was higher in DOX/EX (67%) than DOX/SED (33%). No differences were observed in intraplatelet L-arginine transport assessed by incubation with L- [(3)H]-arginine, nor in NOS activity measured by the conversion of L- [(3)H]-arginine into L- [(3)H]-citrulline among the groups. Vasodilation response to acetylcholine was impaired in DOX/SED and DOX/EX; in nitroglycerine, it was limited to DOX/SED. Aerobic training reduced mortality in DOX-induced HF animals and restored vascular smooth muscle relaxation properties. However, it did not ameliorate intraplatelet NO bioavailability and endothelial function during the period studied.
Assuntos
Arginina/metabolismo , Insuficiência Cardíaca/metabolismo , Óxido Nítrico Sintase/metabolismo , Condicionamento Físico Animal , Circulação Esplâncnica/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Plaquetas/metabolismo , Doxorrubicina/farmacologia , Ecocardiografia , Insuficiência Cardíaca/induzido quimicamente , Masculino , Nitroglicerina/farmacologia , Contagem de Plaquetas , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K-1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS: 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS: Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS: The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects.
Assuntos
Acetofenonas/uso terapêutico , Antioxidantes/uso terapêutico , Óxidos N-Cíclicos/uso terapêutico , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Catalase/metabolismo , Hipertensão Renovascular/fisiopatologia , Masculino , Ratos , Ratos Wistar , Marcadores de Spin , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To evaluate potential in vitro relaxant actions of sildenafil on human isolated bladder neck smooth muscle. METHODS: Bladder neck strips were sampled from patients (aged 55-77 years) submitted to prostatic surgery (6 adenomectomies and 1 radical prostatectomy). These were carefully dissected into 1-2 x 0.5-cm pieces and suspended in an organ bath containing 30 mL of a modified Krebs Henseleit solution, bubbled with 95% O(2)/5% CO(2). After tissue stabilization and viability test with KCl, the tissue was precontracted with phenylephrine, and a concentration-response relaxant curve to sildenafil was constructed. The effect of sildenafil was also assessed in tissues treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (inhibitors of nitric oxide synthase and guanylyl cyclase, respectively). RESULT: Sildenafil induced significant bladder neck relaxation at all concentrations tested. The maximum relaxation was 86.97% +/- 6.69%, obtained with a high concentration of sildenafil (5.1 x 10(-4) M). Both L-NAME and ODQ significantly reduced sildenafil-induced relaxation. CONCLUSIONS: Sildenafil was effective in inducing bladder neck smooth muscle relaxation in vitro. This effect was almost abolished by L-NAME and ODQ, clearly demonstrating a dependence of the nitric oxide-cyclic guanosine monophosphate pathway. Our in-vitro results suggest that sildenafil might be useful in improving lower urinary tract symptoms due to benign prostatic hyperplasia.
Assuntos
Relaxamento Muscular/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Idoso , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Purinas/farmacologia , Citrato de SildenafilaRESUMO
OBJECTIVE: To investigate the effects of sildenafil on noradrenaline- and potassium-induced contractions of isolated human seminal vesicles (SVs), as premature ejaculation is a relatively common male sexual dysfunction that currently lacks an adequate therapy, and recent in vitro tests showed that sildenafil induces relaxation of rodent isolated SVs, but it is not known whether it also inhibits isolated human SV. MATERIAL AND METHODS: Isolated strips of human SVs were suspended in an organ bath and cumulative concentration-response curves to either noradrenaline or KCl were constructed in the presence and absence of sildenafil to evaluate its inhibitory actions. RESULTS: Sildenafil (25-100 microm) induced concentration-dependent inhibitory effects on the human SV contracted by either noradrenaline or KCl. These actions of sildenafil do not therefore appear to be mediated via a competitive antagonism of alpha-adrenoceptors and are consistent with its recognized ability to inhibit phosphodiesterase-5. CONCLUSIONS: The present results show an important inhibitory action of sildenafil in the isolated human SV, supporting the therapeutic indication of this drug for treating premature ejaculation.
Assuntos
Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Glândulas Seminais/efeitos dos fármacos , Sulfonas/farmacologia , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Norepinefrina/metabolismo , Cloreto de Potássio/metabolismo , Purinas/farmacologia , Glândulas Seminais/fisiologia , Citrato de SildenafilaRESUMO
Angiotensin-converting enzyme (kininase II [ACE]) inhibitors are capable of potentiating bradykinin (BK) effects by enhancing the actions of bradykinin on B(2) receptors independent of blocking its inactivation. To investigate further the importance of ACE kininase activity on BK-induced vasodilation, we investigated the effect of inhibiting ACE, as well as other kininases, on both BK metabolism and vasodilator effect in preparations that exhibit increased ACE activity. Mesenteric arterial beds obtained from 1-kidney, 1-clip hypertensive rats presented augmented ACE and angiotensin I converting activities compared with normotensive rats. The isolated and perfused mesenteric beds were exposed to BK for 15 minutes in the absence or in the presence of kininase inhibitors; then, the perfusate was collected for analysis of the products of BK metabolism by high-performance liquid chromatography. BK was metabolized to the fragments BK(1-8), BK(1-7), and BK(1-5), and the recovery of intact BK was reduced by 47% in the hypertensive group. Recovery of BK was increased in both groups in the presence of a kininase I inhibitor and in the hypertensive group by neutral endopeptidase 24.11 inhibitor; however, ACE inhibition did not affect BK metabolism in both groups. In contrast, only the ACE inhibitor potentiated the vasodilator effect of BK in a mesenteric bed preconstricted with phenylephrine; the increase in BK effect, nevertheless, was not greater in arteries from hypertensive rats that presented an increased ACE activity when compared with those in the normotensive group. These data demonstrated that ACE inhibitor-induced potentiation of BK vasodilator effects is not related to their actions on BK degradation.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/farmacologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/enzimologia , Peptidil Dipeptidase A/metabolismo , Vasodilatadores/farmacologia , Ácido 3-Mercaptopropiônico/análogos & derivados , Ácido 3-Mercaptopropiônico/farmacologia , Animais , Pressão Sanguínea , Bradicinina/metabolismo , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Glicopeptídeos/farmacologia , Hipertensão/enzimologia , Técnicas In Vitro , Lisina Carboxipeptidase/antagonistas & inibidores , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Metaloendopeptidases/antagonistas & inibidores , Neprilisina/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/farmacologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismoRESUMO
OBJECTIVE: This study was designed to determine the protective effects of a vinifera grape skins extract (GSE, 200 mg/kg/day) on the deleterious effect observed in experimental preeclampsia, a condition where reduced nitric oxide production and increase in oxidative stress are present. METHODS: A condition similar to preeclampsia was induced by chronic inhibition of nitric oxide synthesis by L-NAME (60 mg/kg/day, orally) in pregnant rats. Blood pressure (systolic, mean and diastolic) was measured with the tail cuff method on day 20 of pregnant control rats; pregnant rats treated with L-NAME, L-NAME plus GSE or GSE from day 13 to day 20 of pregnancy. Glucose was infused in anesthetized pregnant rats at day 20 and blood glucose and insulin were estimated at time zero, 15, 30, 45 and 60 minutes after beginning of glucose infusion. The number of fetus alive was also estimated at day 20 of pregnancy. In parallel, blood pressure was measured in non-pregnant and in non-pregnant rats treated with L-NAME during 7 days. RESULTS: Increase in arterial pressure, reduction of alive fetus at the end of pregnancy and increase in insulin resistance was observed in pregnant L-NAME rats but not in pregnant L-NAME plus GSE rats or in pregnant GSE rats. Increase in arterial pressure was also observed in non-pregnant L-NAME rats. CONCLUSION: The present study demonstrated a protective effect of GSE in experimental preeclampsia since the deleterious effect induced by L-NAME that is, increased in stillbirth, hypertension and insulin resistance were significantly reduced by oral treatment with the extract. Probably an endothelium-dependent vasodilator effect and an antioxidant action play an important role on the effects of GSE in experimental preeclampsia.
Assuntos
Fitoterapia , Extratos Vegetais/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Vitis , Animais , Pressão Sanguínea , Inibidores Enzimáticos/farmacologia , Feminino , NG-Nitroarginina Metil Éster/farmacologia , Ácido Nítrico/metabolismo , Gravidez , Ratos , Ratos WistarRESUMO
The mechanisms involved in the cardioprotector effect of red wine have not yet been completely elucidated but probably an endothelium-dependent vasodilator action may play a significant role in this effect. Experiments were undertaken to determine whether a Brazilian red wine (BRW) induces vasodilation in the mesenteric vascular bed (MVB) and an antihypertensive effect was also assessed in rats with NO-deficient hypertension. In MVB precontracted with norepinephrine, BRW (alcohol-free lyophilized) induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of BRW. In vessels precontracted with norepinephrine and depolarized with KCl (25 Mm) or treated with Ca-dependent K channel blockers charybdotoxin (ChTx) plus apamin, the effect of BRW was significantly reduced. However, this effect is not affected by ATP-dependent K (KATP) channel blocker (glibenclamide). The residual vasodilator effect of BRW observed in vessels pretreated with ChTx plus apamin is completely abolished by ChTx plus apamin plus L-NAME. Concentrations of atropine, pyrilamine, yohimbine, and HOE 140 that significantly reduced the vasodilator effect of acetylcholine, histamine, clonidine, and bradykinin, respectively did not change the vasodilator effect of BRW. Chronic oral administration of BRW induced a significant reduction in systolic, mean and diastolic arterial pressure in rats with L-NAME hypertension. The present results demonstrated that vasodilator effect of BRW is dependent on endothelium-derived hyperpolarizing factor (EDHF) in combination with nitric oxide (NO). The antihypertensive effect of red wine demonstrated in the present study may play a significant role on the cardioprotective action of chronic red wine consumption.