RESUMEN
Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 µM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 µM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.
Asunto(s)
Vasodilatación , Animales , Masculino , Vasodilatación/efectos de los fármacos , Porcinos , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Arteria Femoral/fisiología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Vasos Coronarios/metabolismo , Arteria Renal/efectos de los fármacos , Arteria Renal/metabolismo , Arteria Renal/fisiología , Dopamina/metabolismo , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: The aim of the present study was to evaluate different signaling pathways by which exercise training would interfere in endothelial function in obesity. Therefore, we examined adipocytokine levels and their receptors in the corpus cavernosum and femoral artery from trained rats on a high-fat diet. METHODS: Functional experiments were performed in control sedentary and trained rats, and sedentary (h-SD) and trained male Wistar rats on a high-fat diet (h-TR). Nitric oxide (NO) and reactive oxygen species (ROS) were evaluated in vascular tissue. Circulating adipocytokines and their receptors were analyzed. RESULTS: In the h-SD group, the maximal responses to acetylcholine (ACh) were reduced in the femoral artery and corpus cavernosum as well as the electrical field stimulation, accompanied by an increase in circulating insulin, leptin, TNF-α, MCP-1, and PAI-1. Downregulation of ObR protein expression in the femoral artery was observed without alterations in AdipoR1 and TNFR1 in both preparations. A positive effect was observed in the h-TR group regarding the relaxation response to ACh and circulating adipocytokines, resulting in increased NO production and reduced ROS generation. Exercise restored the ObR protein expression only in the femoral artery. CONCLUSION: Aerobic exercise training ameliorated the inflammatory adipocytokines and restored the relaxation responses in the corpus cavernosum and femoral artery in rats on a high-fat diet.
Asunto(s)
Adipoquinas/sangre , Dieta Alta en Grasa , Arteria Femoral/metabolismo , Pene/irrigación sanguínea , Condicionamiento Físico Animal , Receptores de Adipoquina/metabolismo , Vasoconstricción , Vasodilatación , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Arteria Femoral/efectos de los fármacos , Mediadores de Inflamación/sangre , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptores de Adiponectina/metabolismo , Receptores de Leptina/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Conducta Sedentaria , Transducción de Señal , Superóxido Dismutasa/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
This study aimed to analyzing the effect of chronic sodium overload upon carotid and femoral injury, and its relation to vascular angiotensin modulation. Male C57Bl6 mice were divided in: control (cont), receiving 1% NaCl solution for 2 weeks (salt-2) or 12 weeks (salt-12). Two-weeks before the end of the study, a 2mm catheter was implanted around the left femoral and carotid arteries to induce injury. Blood pressure (BP) and heart rate (HR) were measured at the end of the study by tail plethysmography. Arteries were collected and prepared for histological analysis to determine arterial thickening and perivascular collagen deposition. Angiotensin II and Ang(1-7) were quantified in fresh arteries using the HPLC method. There were no differences in body weight, BP and HR. Intima/media ratio had a similar increase in both injured arteries of cont and salt-2 mice, but a more pronounced increase was observed in salt-12 mice (31.1±6%). On the other hand, sodium overload modified perivascular collagen deposition, increasing thick fibers (cont: 0.5%; salt-2: 3.4%; salt-12: 0.6%) and decreasing thin fibers (cont: 7.4%; salt-2: 0.5%; salt-12: 6.8%) in non-injured arteries. Injured arteries presented similar collagen fiber distribution. Angiotensin quantification showed increased Ang(1-7) in salt treated mice (salt-2: +72%; salt-12: +45%) with a concomitant decrease in Ang II (salt-2: -54%; salt-12: -60%). Vascular injury increased significantly Ang(1-7) in salt-12 mice (+80%), maintaining Ang II reduction similar to that of a non-injured artery. The lack of changes in BP and HR suggests that the structural changes observed may be due to non-hemodynamic mechanisms such as local renin-angiotensin system. Collagen evaluation suggests that sodium overload induces time-related changes in vascular remodeling. The increase of artery injury with concomitant increase in Ang(1-7) in 12-week treated mice shows a direct association between the duration of salt treatment and the magnitude of vascular injury.
Asunto(s)
Angiotensinas/metabolismo , Arterias Carótidas/efectos de los fármacos , Traumatismos de las Arterias Carótidas/inducido químicamente , Arteria Femoral/efectos de los fármacos , Arteria Femoral/lesiones , Cloruro de Sodio/efectos adversos , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Arterias Carótidas/fisiología , Colágeno/metabolismo , Relación Dosis-Respuesta a Droga , Elasticidad , Arteria Femoral/patología , Arteria Femoral/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neointima/inducido químicamente , Peptidil-Dipeptidasa A/metabolismo , Remodelación Vascular/efectos de los fármacosRESUMEN
Neurological diseases are common in inflammatory bowel disease (IBD) patients, but their exact prevalence is unknown. Method We prospectively evaluated the presence of neurological disorders in 121 patients with IBD [51 with Crohn's disease (CD) and 70 with ulcerative colitis (UC)] and 50 controls (gastritis and dyspepsia) over 3 years. Results Our standard neurological evaluation (that included electrodiagnostic testing) revealed that CD patients were 7.4 times more likely to develop large-fiber neuropathy than controls (p = 0.045), 7.1 times more likely to develop any type of neuromuscular condition (p = 0.001) and 5.1 times more likely to develop autonomic complaints (p = 0.027). UC patients were 5 times more likely to develop large-fiber neuropathy (p = 0.027) and 3.1 times more likely to develop any type of neuromuscular condition (p = 0.015). Conclusion In summary, this is the first study to prospectively establish that both CD and UC patients are more prone to neuromuscular diseases than patients with gastritis and dyspepsia. .
Doenças neurológicas são comuns em pacientes com doença inflamatória intestinal (DII), mas sua prevalência exata é desconhecida. Métodos Nós estudamos prospectivamente a presença de distúrbios neurológicos em 121 pacientes com DII [51 com doença de Crohn (DC) e 70 com colite ulcerativa (RCU)] e 50 controles (gastrite e dispepsia) ao longo de 3 anos. Resultados A avaliação neurológica padronizada (que incluiu testes eletrodiagnósticos) demonstrou que pacientes com DC foram 7,4 vezes mais propensos a desenvolver neuropatias de fibras grossas do que os controles (p = 0,045), 7,1 vezes mais propensos a desenvolver qualquer tipo de condição neuromuscular (p = 0,001) e 5,1 vezes mais propensos a desenvolver queixas autonômicas (p = 0,027). Pacientes com RCU foram 5 vezes mais propensos de desenvolver neuropatia de fibras grossas (p = 0,027) e 3,1 vezes mais propensos a desenvolver qualquer tipo de condição neuromuscular (p = 0,015). Conclusão Em resumo, este é o primeiro estudo prospectivo a estabelecer que os pacientes tanto com DC quanto de RCU são mais propensos a doenças neuromusculares do que os pacientes com gastrite e dispepsia. .
Asunto(s)
Animales , Femenino , Embarazo , Antiinflamatorios/farmacología , Dexametasona/farmacología , Microcirculación/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Efectos Tardíos de la Exposición Prenatal , Acetilcolina/farmacología , Peso Corporal/efectos de los fármacos , Bradiquinina/farmacología , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/embriología , Microcirculación/embriología , NG-Nitroarginina Metil Éster/farmacología , Nitroprusiato/farmacología , Ovinos , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
OBJECTIVES: The clinical significance of ischemia/reperfusion of the lower extremities demands further investigation to enable the development of more effective therapeutic alternatives. This study investigated the changes in the vascular reactivity of the rabbit femoral artery and nitric oxide metabolites under partial ischemia/ reperfusion conditions following cilostazol administration. METHODS: Ischemia was induced using infrarenal aortic clamping. The animals were randomly divided into seven groups: Control 90 minutes, Ischemia/Reperfusion 90/60 minutes, Control 120 minutes, Ischemia/Reperfusion 120/90 minutes, Cilostazol, Cilostazol before Ischemia/Reperfusion 120/90 minutes, and Ischemia 120 minutes/Cilostazol/ Reperfusion 90 minutes. Dose-response curves for sodium nitroprusside, acetylcholine, and the calcium ionophore A23187 were obtained in isolated femoral arteries. The levels of nitrites and nitrates in the plasma and skeletal muscle were determined using chemiluminescence. RESULTS: Acetylcholine-and A23187-induced relaxation was reduced in the Ischemia/Reperfusion 120/90 group, and treatment with cilostazol partially prevented this ischemia/reperfusion-induced endothelium impairment. Only cilostazol treatment increased plasma levels of nitrites and nitrates. An elevation in the levels of nitrites and nitrates was observed in muscle tissues in the Ischemia/Reperfusion 120/90, Cilostazol/Ischemia/Reperfusion, and Ischemia/ Cilostazol/Reperfusion groups. CONCLUSION: Hind limb ischemia/reperfusion yielded an impaired endothelium-dependent relaxation of the femoral artery. Furthermore, cilostazol administration prior to ischemia exerted a protective effect on endothelium-dependent vascular reactivity under ischemia/reperfusion conditions.
Asunto(s)
Arteria Femoral/efectos de los fármacos , Isquemia/prevención & control , Óxido Nítrico/sangre , Daño por Reperfusión/prevención & control , Tetrazoles/administración & dosificación , Vasodilatadores/administración & dosificación , Animales , Cilostazol , Modelos Animales de Enfermedad , Miembro Posterior/irrigación sanguínea , Isquemia/inducido químicamente , Isquemia/metabolismo , Masculino , Conejos , Distribución Aleatoria , Daño por Reperfusión/inducido químicamente , Daño por Reperfusión/metabolismoRESUMEN
Although the vasorelaxing effects of testosterone (T) and various androgen metabolites have been observed in a variety of blood vessels and species, previous studies have not systematically compared the vasorelaxing effects of androgen metabolites in different vascular beds within the same species. Therefore, we studied the vasorelaxing effects of T and its 5-reduced metabolites (5α- and 5ß-DHT) on KCl-induced contractions of the canine left coronary artery, femoral artery and saphenous vein, using standard isometric recordings. KCl contractions were inhibited by each androgen in a concentration-dependent manner from 1.8 to 310µM. Vascular sensitivity and efficacy were expressed as inhibitory concentration 50 (IC50) and maximal relaxation (R(max)), respectively. The coronary artery was significantly more sensitive to androgen-induced vasorelaxation than the saphenous vein or femoral artery. These vasorelaxing responses were unaffected by an antiandrogen (Flutamide) or the sulfhydryl reagent, N-ethylmaleimide, suggesting a nongenomic mechanism independent of signaling mediated by the androgen receptor or G proteins. Concentration-response curves were unchanged in endothelium-denuded preparations; thus, the endothelium appears to have no role in androgen-induced vasorelaxation. 5ß-DHT was the most potent androgen in both coronary and femoral artery, but all three androgens were equipotent in the saphenous vein. It is concluded that: 1) significant regional differences exist in vasorelaxing effects of androgen metabolites in the canine vasculature; 2) structural differences in these androgens determine their vasorelaxing efficacy; and 3) regional differences in androgen-induced vasorelaxation may account for some of the conflicting findings reported on the vasorelaxing effects of the androgens.
Asunto(s)
Andrógenos/metabolismo , Vasos Sanguíneos/metabolismo , Dihidrotestosterona/metabolismo , Testosterona/metabolismo , Vasodilatación , Vasodilatadores/metabolismo , Antagonistas de Andrógenos/farmacología , Andrógenos/química , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Dihidrotestosterona/antagonistas & inhibidores , Dihidrotestosterona/química , Perros , Etilmaleimida/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Flutamida/farmacología , Técnicas In Vitro , Masculino , Concentración Osmolar , Reproducibilidad de los Resultados , Vena Safena/efectos de los fármacos , Vena Safena/metabolismo , Estereoisomerismo , Reactivos de Sulfhidrilo/farmacología , Testosterona/antagonistas & inhibidores , Vasodilatación/efectos de los fármacos , Vasodilatadores/antagonistas & inhibidores , Vasodilatadores/químicaRESUMEN
FUNDAMENTO: A doença coronária tem sido amplamente estudada em pesquisas cardiovasculares. No entanto, pacientes com doença arterial periférica (DAP) têm piores resultados em comparação àqueles com doença arterial coronariana. Portanto, os estudos farmacológicos com artéria femoral são altamente relevantes para a melhor compreensão das respostas clínicas e fisiopatológicas da DAP. OBJETIVO: Avaliar as propriedades farmacológicas dos agentes contráteis e relaxantes na artéria femoral de ratos. MÉTODOS: As curvas de resposta de concentração à fenilefrina contrátil (FC) e à serotonina (5-HT) e os agentes relaxantes isoproterenol (ISO) e forskolina foram obtidos na artéria femoral de ratos isolada. Para as respostas ao relaxamento, os tecidos foram contraídos com FC ou 5-HT. RESULTADOS: A potência de classificação na artéria femoral foi de 5-HT > FC para as respostas contráteis. Em tecidos contraídos com 5-HT, as respostas de relaxamento ao isoproterenol foram praticamente abolidas em comparação aos tecidos contraídos com FC. A forskolina, um estimulante da adenilil ciclase, restaurou parcialmente a resposta de relaxamento ao ISO em tecidos contraídos com 5-HT. CONCLUSÃO: Ocorre uma interação entre as vias de sinalização dos receptores β-adrenérgicos e serotoninérgicos na artéria femoral. Além disso, esta pesquisa fornece um novo modelo para estudar as vias de sinalização serotoninérgicas em condições normais e patológicas que podem ajudar a compreender os resultados clínicos na DAP.
BACKGROUND: Coronary heart disease has been widely studied in cardiovascular research. However, patients with peripheral artery disease (PAD) have worst outcomes compared to those with coronary artery disease. Therefore, pharmacological studies using femoral artery are highly relevant for a better understanding of the pathophysiologic responses of the PAD. OBJECTIVE: The aim of this study was to evaluate the pharmacologic properties of the contractile and relaxing agents in rat femoral artery. METHODS: Concentration response curves to the contractile phenylephrine (PE) and serotonin (5-HT) and the relaxing agents isoproterenol (ISO) and forskolin were obtained in isolated rat femoral artery. For relaxing responses, tissues were precontracted with PE or 5-HT. RESULTS: The order rank potency in femoral artery was 5-HT > PE for contractile responses. In tissues precontracted with 5-HT, relaxing responses to isoproterenol was virtually abolished as compared to PE-contracted tissues. Forskolin, a stimulant of adenylyl cyclase, partially restored the relaxing response to ISO in 5-HT-precontracted tissues. CONCLUSION: An interaction between β-adrenergic- and serotoninergic- receptors signaling pathway occurs in femoral artery. Moreover, this study provides a new model to study serotoninergic signaling pathway under normal and pathological conditions which can help understanding clinical outcomes in the PAD.
FUNDAMENTO: La enfermedad coronaria ha sido ampliamente estudiada en las investigaciones cardiovasculares. Sin embargo, los pacientes con enfermedad arterial periférica (EAP), tienen los peores resultados en comparación con aquellos con la enfermedad arterial coronaria. Por tanto, los estudios farmacológicos con la arteria femoral son extremadamente importantes para obtener una mejor comprensión de las respuestas clínicas y fisiopatológicas de la EAP. OBJETIVO: Evaluar las propiedades farmacológicas de los agentes contráctiles y relajantes en la arteria femoral de los ratones. MÉTODOS: Las curvas de concentración-respuesta a los agentes conctráctiles fenilefrina (FE) y a la serotonina (5-HT) y los agentes relajantes isoproterenol (ISO) y forskolina, se obtuvieron en la arteria femoral de ratones ya aislada. Para las respuestas a la relajación, los tejidos fueron contraídos con FE o 5-HT. RESULTADOS: La potencia de clasificación en la arteria femoral fue de 5-HT > FE para las respuestas contráctiles. En los tejidos contraídos con 5-HT, las respuestas de relajación al isoproterenol fueron prácticamente eliminadas en comparación con los tejidos contraídos con FE. La forskolina, un estimulante de la adenilil ciclasa, restauró parcialmente la respuesta de relajación al ISO en los tejidos contraídos con 5-HT. CONCLUSIÓN: Ocurre una interacción entre las vías de señalización de los receptores β-adrenérgicos y serotoninérgicos en la arteria femoral. Además, esa investigación suministra un nuevo modelo para estudiar las vías de señalización serotoninérgicas en condiciones normales y patológicas que puedan ayudar a comprender los resultados clínicos en la EAP.
Asunto(s)
Animales , Masculino , Ratas , Arteria Femoral/efectos de los fármacos , Enfermedad Arterial Periférica/fisiopatología , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Colforsina/farmacología , Isoproterenol/farmacología , Modelos Animales , Fenilefrina/farmacología , Ratas Wistar , Serotonina/farmacologíaRESUMEN
BACKGROUND: Coronary heart disease has been widely studied in cardiovascular research. However, patients with peripheral artery disease (PAD) have worst outcomes compared to those with coronary artery disease. Therefore, pharmacological studies using femoral artery are highly relevant for a better understanding of the pathophysiologic responses of the PAD. OBJECTIVE: The aim of this study was to evaluate the pharmacologic properties of the contractile and relaxing agents in rat femoral artery. METHODS: Concentration response curves to the contractile phenylephrine (PE) and serotonin (5-HT) and the relaxing agents isoproterenol (ISO) and forskolin were obtained in isolated rat femoral artery. For relaxing responses, tissues were precontracted with PE or 5-HT. RESULTS: The order rank potency in femoral artery was 5-HT > PE for contractile responses. In tissues precontracted with 5-HT, relaxing responses to isoproterenol was virtually abolished as compared to PE-contracted tissues. Forskolin, a stimulant of adenylyl cyclase, partially restored the relaxing response to ISO in 5-HT-precontracted tissues. CONCLUSION: An interaction between ß-adrenergic- and serotoninergic- receptors signaling pathway occurs in femoral artery. Moreover, this study provides a new model to study serotoninergic signaling pathway under normal and pathological conditions which can help understanding clinical outcomes in the PAD.
Asunto(s)
Arteria Femoral/efectos de los fármacos , Enfermedad Arterial Periférica/fisiopatología , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Animales , Colforsina/farmacología , Isoproterenol/farmacología , Masculino , Modelos Animales , Fenilefrina/farmacología , Ratas , Ratas Wistar , Serotonina/farmacologíaRESUMEN
The purpose of this study was to qualify and quantify the femoral artery blood flow by duplex Doppler ultrasonography (DDU) in healthy dogs, before and after the administration of a combination of acepromazine maleate and buprenorphine hydrochloride (ACP-BPN). Seven healthy adult mongrel dogs and three adult beagles were used. Heart rate, arterial blood pressure and measurement of femoral artery blood flow by DDU were also recorded. The DDU measurements were: femoral artery diameter (FAD), peak systolic velocity (PSV), early retrograde (EDV) and end diastolic velocities (EnDV), mean velocity (BMV), pulsatility index (PI), flow velocity integral (FVI) and femoral blood flow (FBF). After 30 min, combination ACP-BPN was administered intramuscularly, and all the measurements were recorded again. The ACP-BPN protocol induced a significant decrease in systolic, mean, and diastolic arterial blood pressure, and heart rate. A significant increase in peak systolic velocity and integral flow velocity integral of the femoral blood were obtained. The Doppler spectra of the blood flow in the femoral artery revealed a spectral dispersion pattern after ACP-BPN administration in all the dogs. These results demonstrate that despite quantitative and qualitative changes, the overall femoral blood flow (FBF) is not significantly modified.
Asunto(s)
Acepromazina/farmacología , Velocidad del Flujo Sanguíneo/veterinaria , Buprenorfina/farmacología , Perros/fisiología , Arteria Femoral/efectos de los fármacos , Acepromazina/administración & dosificación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Buprenorfina/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacología , Quimioterapia Combinada , Arteria Femoral/fisiología , Ultrasonografía Doppler Dúplex/veterinariaRESUMEN
BACKGROUND: The majority of studies have investigated the effect of exercise training (TR) on vascular responses in diabetic animals (DB), but none evaluated nitric oxide (NO) and advanced glycation end products (AGEs) formation associated with oxidant and antioxidant activities in femoral and coronary arteries from trained diabetic rats. Our hypothesis was that 8-week TR would alter AGEs levels in type 1 diabetic rats ameliorating vascular responsiveness. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats were divided into control sedentary (C/SD), sedentary diabetic (SD/DB), and trained diabetic (TR/DB). DB was induced by streptozotocin (i.p.: 60 mg/kg). TR was performed for 60 min per day, 5 days/week, during 8 weeks. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (PHE) and tromboxane analog (U46619) were obtained. The protein expressions of eNOS, receptor for AGEs (RAGE), Cu/Zn-SOD and Mn-SOD were analyzed. Tissues NO production and reactive oxygen species (ROS) generation were evaluated. Plasma nitrate/nitrite (NO(x)â»), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS) and N(ε)-(carboxymethyl) lysine (CML, AGE biomarker). A rightward shift in the concentration-response curves to ACh was observed in femoral and coronary arteries from SD/DB that was accompanied by an increase in TBARS and CML levels. Decreased in the eNOS expression, tissues NO production and NO(x)â» levels were associated with increased ROS generation. A positive interaction between the beneficial effect of TR on the relaxing responses to ACh and the reduction in TBARS and CML levels were observed without changing in antioxidant activities. The eNOS protein expression, tissues NO production and ROS generation were fully re-established in TR/DB, but plasma NO(x)â» levels were partially restored. CONCLUSION: Shear stress induced by TR fully restores the eNOS/NO pathway in both preparations from non-treated diabetic rats, however, a massive production of AGEs still affecting relaxing responses possibly involving other endothelium-dependent vasodilator agents, mainly in coronary artery.
Asunto(s)
Vasos Coronarios , Diabetes Mellitus Experimental , Endotelio Vascular/fisiopatología , Arteria Femoral , Productos Finales de Glicación Avanzada/metabolismo , Condicionamiento Físico Animal , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Experimental/terapia , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Factores Relajantes Endotelio-Dependientes/metabolismo , Factores Relajantes Endotelio-Dependientes/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Arteria Femoral/fisiopatología , Productos Finales de Glicación Avanzada/farmacología , Masculino , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , EstreptozocinaRESUMEN
OBJECTIVES: The clinical significance of ischemia/reperfusion of the lower extremities demands further investigation to enable the development of more effective therapeutic alternatives. This study investigated the changes in the vascular reactivity of the rabbit femoral artery and nitric oxide metabolites under partial ischemia/ reperfusion conditions following cilostazol administration. METHODS: Ischemia was induced using infrarenal aortic clamping. The animals were randomly divided into seven groups: Control 90 minutes, Ischemia/Reperfusion 90/60 minutes, Control 120 minutes, Ischemia/Reperfusion 120/90 minutes, Cilostazol, Cilostazol before Ischemia/Reperfusion 120/90 minutes, and Ischemia 120 minutes/Cilostazol/ Reperfusion 90 minutes. Dose-response curves for sodium nitroprusside, acetylcholine, and the calcium ionophore A23187 were obtained in isolated femoral arteries. The levels of nitrites and nitrates in the plasma and skeletal muscle were determined using chemiluminescence. RESULTS: Acetylcholine-and A23187-induced relaxation was reduced in the Ischemia/Reperfusion 120/90 group, and treatment with cilostazol partially prevented this ischemia/reperfusion-induced endothelium impairment. Only cilostazol treatment increased plasma levels of nitrites and nitrates. An elevation in the levels of nitrites and nitrates was observed in muscle tissues in the Ischemia/Reperfusion 120/90, Cilostazol/Ischemia/Reperfusion, and Ischemia/ Cilostazol/Reperfusion groups. CONCLUSION: Hind limb ischemia/reperfusion yielded an impaired endothelium-dependent relaxation of the femoral artery. Furthermore, cilostazol administration prior to ischemia exerted a protective effect on endotheliumdependent vascular reactivity under ischemia/reperfusion conditions.
Asunto(s)
Animales , Masculino , Conejos , Arteria Femoral/efectos de los fármacos , Isquemia/prevención & control , Óxido Nítrico/sangre , Daño por Reperfusión/prevención & control , Tetrazoles/administración & dosificación , Vasodilatadores/administración & dosificación , Modelos Animales de Enfermedad , Miembro Posterior/irrigación sanguínea , Isquemia/inducido químicamente , Isquemia/metabolismo , Distribución Aleatoria , Daño por Reperfusión/inducido químicamente , Daño por Reperfusión/metabolismoRESUMEN
We tested the hypothesis that small changes in angiotensin I-converting enzyme (ACE) expression can alter the vascular response to injury. Male mice containing one, two, three, and four copies of the Ace gene with no detectable vascular abnormality or changes in blood pressure were submitted to cuff-induced femoral artery injury. Femoral thickening was higher in 3- and 4-copy mice (42.4 +/- 4.3% and 45.7 +/- 6.5%, respectively) compared with 1- and 2-copy mice (8.3 +/- 1.3% and 8.5 +/- 0.9%, respectively). Femoral ACE levels from control and injured vessels were assessed in 1- and 3-copy Ace mice, which represent the extremes of the observed response. ACE vascular activity was higher in 3- vs. 1-copy Ace mice (2.4-fold, P < 0.05) in the control uninjured vessel. Upon injury, ACE activity significantly increased in both groups [2.41-fold and 2.14-fold (P < 0.05) for 1- and 3-copy groups, respectively] but reached higher levels in 3- vs. 1-copy Ace mice (P < 0.05). Pharmacological interventions were then used as a counterproof and to indirectly assess the role of angiotensin II (ANG II) on this response. Interestingly, ACE inhibition (enalapril) and ANG II AT(1) receptor blocker (losartan) reduced intima thickening in 3-copy mice to 1-copy mouse values (P < 0.05) while ANG II treatment significantly increased intima thickening in 1-copy mice to 3-copy mouse levels (P < 0.05). Together, these data indicate that small physiologically relevant changes in ACE, not associated with basal vascular abnormalities or blood pressure levels, do influence the magnitude of cuff-induced neointima thickening in mice.
Asunto(s)
Dosificación de Gen , Peptidil-Dipeptidasa A/genética , Túnica Íntima/patología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/enzimología , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/fisiopatología , Constricción , Enalapril/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/enzimología , Arteria Femoral/lesiones , Losartán/farmacología , Ratones , Ratones Transgénicos , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Espectrometría de Fluorescencia , Túnica Íntima/efectos de los fármacos , Túnica Íntima/fisiopatologíaRESUMEN
The aim of the investigation was to study the possible effects of in vivo infusion of nitric oxide (NO) blockers upon the in vitro endothelium-dependent femoral reactivity. The experimental model tested herein was the inferior canine hindlimb global ischemia induced by infrarenal abdominal aortic cross-clamping followed by reperfusion. The NO blockers employed in the tests were N(G)-nitro-l-arginine methyl ester (L-NAME), aminoguanidine (AMG), and methylene blue (MB), which were infused immediately after the anesthesia induction. The research protocol was standardized in two main experimental groups, control and ischemia/reperfusion (I/R) injury, randomized in eight subgroups including controls and NO blockers. The femoral artery vascular reactivity was studied in vitro with the aid of a setup consisting of eight organ chambers, where segments of 4-5 mm were suspended and connected to force transducers in the presence of indomethacin to block the cyclooxygenase pathway. The NO-release pathway was evaluated by using specific pharmacological agonists in the in vitro experiments. The L-NAME in vivo infusion led to in vitro endothelium dysfunction in both groups and was associated with high mortality in the animals submitted to I/R. AMG and MB, two clinically used drugs, did not cause in vitro endothelium dysfunction in either of the two groups, which gives evidence that these drugs are not deleterious in the milieu of I/R injury. Nitrite/nitrate plasma levels were not significant except for the L-NAME groups, which presented significant NO decrease.
Asunto(s)
Factores Relajantes Endotelio-Dependientes/antagonistas & inhibidores , Arteria Femoral/efectos de los fármacos , Miembro Posterior/irrigación sanguínea , Isquemia/fisiopatología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Reperfusión , Animales , Inhibidores de la Ciclooxigenasa/farmacología , Perros , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Arteria Femoral/fisiopatología , Guanidinas/farmacología , Indometacina/farmacología , Masculino , Azul de Metileno/farmacología , Músculo Liso Vascular/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Nitratos/sangre , Óxido Nítrico/agonistas , Nitritos/sangre , Distribución Aleatoria , Daño por Reperfusión/fisiopatología , Vasodilatadores/farmacologíaRESUMEN
Breast reconstruction after cancer treatment is based on the circulation of pedicle and microvascular flaps. This article aimed to verify the effect of tamoxifen (TMX) pretreatment in arterial anastomosis in rats. Twenty female Wistar rats were equally divided into two groups. TMX (0.3 mg/kg) was administered to the experimental group for 2 weeks orally. After this period, the right femoral artery was sectioned and a terminoterminal anastomosis performed. The same procedure was done in the control group, except that the animals received the vehicle without TMX. One week later, the femoral arteries were inspected for flow through the anastomosis, and the vessel near it was sent to light microscopic examination. It was observed mild vasculite in both groups. The intimal thickness and total vessel wall in the TMX-treated group was significantly higher. A real thrombotic effect upon the arterial vascular anastomosis was not observed, eventhough, TMX induced intimal hyperplasia.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Arteria Femoral/efectos de los fármacos , Microcirugia , Tamoxifeno/uso terapéutico , Grado de Desobstrucción Vascular/efectos de los fármacos , Anastomosis Quirúrgica , Animales , Femenino , Arteria Femoral/patología , Arteria Femoral/cirugía , Ratas , Ratas Wistar , Trombosis/etiología , Trombosis/prevención & controlRESUMEN
Despite the extensive research on the pharmacology of L-arginine, there are only few data on its antithrombotic properties. We studied the effect of oral L-arginine administration in a model of arterial thrombosis in rabbits divided into three groups: group 1, group without intervention; group 2, control group, treated with normal diet and submitted to the thrombosis-triggering protocol; group 3, treated for 2 weeks with L-arginine (2.25%) prior the protocol. L-Arginine did not alter platelet aggregation nor coagulation parameters but reduced vascular activities of both ADPase (49.1 +/- 8.5 versus 28.9 +/- 8.3 versus 18.8 +/- 10.3 nmoles inorganic phosphate/min per mg protein; mean +/- SD; group 1 versus group 2 versus group 3, respectively; ANOVA F = 19.21; P < 0.0001) and ATPase (97.8 +/- 15.8 versus 52.1 +/- 11.6 versus 31.9 +/- 16.3 nmoles inorganic phosphate/min per mg protein; mean +/- SD; group 1 versus group 2 versus group 3, respectively; ANOVA, F = 34.65; P < 0.0001). L-Arginine did not reduce the thrombi area (17.1 mm, 9.02 and 48.07, versus 27.04 mm, 25.4 and 70.39, median, percentile 25 and 75 respectively, P = 0.079; group 2 versus group 3, respectively). In conclusion, oral L-arginine administration did not inhibit thrombosis, and, conversely, it significantly reduced the arterial wall ADPase and ATPase activities. This effect may limit its antithrombotic properties.
Asunto(s)
Adenosina Trifosfatasas/efectos de los fármacos , Apirasa/efectos de los fármacos , Arginina/farmacología , Agregación Plaquetaria/efectos de los fármacos , Trombosis/prevención & control , Adenosina Trifosfatasas/metabolismo , Administración Oral , Análisis de Varianza , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/enzimología , Apirasa/metabolismo , Arginina/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Distribución de Chi-Cuadrado , Arteria Femoral/efectos de los fármacos , Arteria Femoral/enzimología , Masculino , Modelos Animales , Conejos , Estadísticas no Paramétricas , Trombosis/etiología , Trombosis/patologíaRESUMEN
O autor comparou, experimentalmente, a eficácia da droga abciximab, um antagonista do receptor da glicoproteína IIb/IIIa das plaquetas, na prevençäo da trombose nas microanastamoses arteriais em ratos Wistar.Utilizou 20 animais, dos quais 10, do grupo controle, receberam soluçäo salina e 10 receberam abciximab, na concentraçäo de 0, 8mg/Kg, injetados na veia femoral.Trinta minutos após a administraçäo da soluçäo salina ou abciximab, todos os animais foram submetidos ao mecanismo provocador de trombose vascular da artéria femoral do lado oposto ao utilizado para administraçäo da droga, por meio de um trauma externo promovido por aparelho IMPACTOR, desenvolvido pela New York University para padronizaçäo de lesäo da medula nervosa, o que padronizou a lesäo arterial. Todos os animais foram submetidos à microanastomose vascular com mononáilon 10-0, em pontos separados, no local do trauma externo.Foram realizados testes para analisar a perviabilidade vascular da artéria femoral no peíodo de 10, 20 e 30 minutos após o término da anastomose. Após este período, todas as artérias femorais submetidas à microanastomoses foram ressecadas e analisadas em microscopia óptica para avaliar a presença de formaçäo de trombos.Após a análise estatística dos dados, o autor conclui que o uso do antagonista do receptor da glicoproteína IIb/IIIa das plaquetas diminui a incidência de tromboses nas microanastomoses vasculares.
Asunto(s)
Animales , Ratas , Anastomosis Quirúrgica/efectos adversos , Arteria Femoral/efectos de los fármacos , Arteria Femoral/patología , Arteria Femoral/cirugía , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/administración & dosificación , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/efectos adversos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/efectos de los fármacos , Trombastenia , Trombosis/prevención & controlRESUMEN
To analyze the effect of hyperthermia on the vascular response, the isometric response of isolated rabbit femoral artery segments was recorded at 37 degreesC and hyperthermia (41 and 44 degreesC). Contraction to potassium (5 x 10(-3)-5 x 10(-2) M) was significantly greater at 41 and 44 than at 37 degreesC and increased by inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine (L-NNA; 10(-4) M) or endothelium removal at 37 degreesC but not at 41 or 44 degreesC. Norepinephrine (10(-9)-10(-4) M) produced a concentration-dependent contraction greater at 41 or 44 than at 37 degreesC and not modified by endothelium removal or L-NNA at either temperature. Phenylephrine (10(-9)-10(-4) M) produced a contraction increased by warming to 44 degreesC but not to 41 degreesC. The specific alpha2-adrenoceptor agonist BHT-920 produced a weak contraction, reduced by the alpha1-adrenoceptor antagonist prazosin (10(-6) M) and increased at 44 degreesC but not at 41 degreesC. The concentration-dependent contraction to endothelin-1 (ET-1; 10(-11)-10(-7) M) was increased by warming to 41 and 44 degreesC and by endothelium removal or L-NNA at 37 degreesC but not at 41 or 44 degreesC. Response to ET-1 was reduced by endothelin ETA-receptor antagonist BQ-123 (10(-5) M) and ETB-receptor antagonist BQ-788 (10(-5) M). In arteries precontracted with ET-1 (10(-8)-3 x 10(-8) M), relaxation to sodium nitroprusside (10(-8)-10(-4) M) was increased at 41 and 44 degreesC vs. at 37 degreesC, but that of ACh (10(-8)-10(-4) M) or adenosine (10(-8)-10(-4) M) was not different at all temperatures studied. Relaxation to ACh, but not adenosine, was reduced similarly by L-NNA at all temperatures studied. These results suggest hyperthermia in muscular arteries may inhibit production of, and increase dilatation to, NO, resulting in unchanged relaxation to ACh and increased constriction to KCl and ET-1, and may increase constriction to stimulation of alpha1-adrenoceptors by NO-independent mechanisms.
Asunto(s)
Arteria Femoral/fisiopatología , Fiebre/fisiopatología , Vasoconstricción/fisiología , Vasodilatación/fisiología , Acetilcolina/farmacología , Adenosina/farmacología , Animales , Azepinas/farmacología , Antagonistas de los Receptores de Endotelina , Endotelina-1/farmacología , Arteria Femoral/efectos de los fármacos , Técnicas In Vitro , Óxido Nítrico/biosíntesis , Nitroarginina/farmacología , Nitroprusiato/farmacología , Norepinefrina/farmacología , Cloruro de Potasio/farmacología , Conejos , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Independently of it's effects on the coagulation cascade, thrombin can interact with the endothelium and release vasodilatory mediators as prostacyclin, endothelium dependent relaxing factor and potentiate the vascular changes induced by vasoconstrictors like endothelin or cathecolamines. Therefore, in the present study we tested the effect of thrombin in the pulmonary and femoral canine arteries and compared it with the effects on human umbilical artery; we also explore the possible mechanism of action of thrombin-induced changes in vascular tone by using specific inhibitors. Thrombin induced a concentration-dependent and endothelium-dependent relaxation on canine arteries (pulmonary or femoral) and endothelium-independent contraction of human umbilical arteries, neither the relaxation nor the contraction were significantly affected by incubation of the vessels with: a cyclooxygenase inhibitor (indomethacin), lypooxygenase inhibitor (BW 755C) or a soup of antagonists (atropine, metysergyde, propanolol, meperamine or phenoribenzamine) to block muscarinic, histaminic, serotoninergic or adrenergic receptors. However, incubation of the vessels with heparin or a calcium channel blocker did prevented the vasoconstrictor effect of thrombin in human umbilical veins. This results suggests that thrombin can elicit changes in vascular tone and the effect is dependent of the vessel stimulated, and the presence of the endothelium. Thus, thrombin-dependent change in vascular tone is not mediated by arachidonic acid metabolites, sympathetic or parasympathetic neurotransmitters, histamine or serotonine receptors. Thrombin effects may be mediated by interaction with an specific receptor coupled with a calcium signal.