RESUMO
Myocardial ischemia initiates a chain of pathological conditions leading to cardiomyocyte death. Therefore, pharmacological treatment to stop ischemia-induced damage is necessary. Fibrates, have been reported to decrease inflammatory markers and to modulate the renin-angiotensin system (RAS). Our aim was to explore if clofibrate treatment, administered one week after myocardial event, decreases MI-induced cardiac damage. Wistar rats were assigned to: 1. Sham or 2. Coronary artery ligation (MI). Seven days after, rats were subdivided to receive vehicle (V) or clofibrate [100 mg/kg (C)] daily for 7 days. Blood samples and left ventricle were analyzed. RAS components [angiotensin II, angiotensin converting enzyme (ACE), and AT1-receptor] decreased in MI-C compared to MI-V, while [Ang-(1-7), bradykinin, ACE-2, and AT2-receptor] raised in response to clofibrate treatment. Oxidative stress markers increased in MI-V rats, a profile reverted in MI-C rats. Nitric oxide (NO) pathway (Akt, eNOS, and NO) exhibits a lower participation in MI-V, but clofibrate raised NO-pathway components and its production. MI-induced fibrosis and structural damage was also improved by clofibrate-treatment. In conclusion, clofibrate administration to 7 days MI-rats exerts an antioxidant, pro-vasodilator expression profile, and anti-fibrotic effect suggesting that PPARα activation can be considered a therapeutic target to improve cardiac condition posterior to ischemia.
Assuntos
Clofibrato/administração & dosagem , Clofibrato/farmacologia , Ventrículos do Coração/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Fibrose , Ventrículos do Coração/patologia , Masculino , Isquemia Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Fatores de TempoRESUMO
Under pathological conditions, nitric oxide can become a mediator of oxidative cellular damage, generating an unbalance between oxidant and antioxidant systems. The participation of neuronal nitric oxide synthase (nNOS) in the neurodegeneration mechanism has been reported; the activation of N-methyl-D-aspartate (NMDA) receptors by agonist quinolinic acid (QUIN) triggers an increase in nNOS function and promotes oxidative stress. The aim of the present work was to elucidate the participation of nNOS in QUIN-induced oxidative stress in knock-out mice (nNOS-/-). To do so, we microinjected saline solution or QUIN in the striatum of wild-type (nNOS +/+), heterozygote (nNOS+/-), and knock-out (nNOS-/-) mice, and measured circling behavior, GABA content levels, oxidative stress, and NOS expression and activity. We found that the absence of nNOS provides a protection against striatal oxidative damage induced by QUIN, resulting in decreased circling behavior, oxidative stress, and a partial protection reflected in GABA depletion. We have shown that nNOS-derived NO is involved in neurological damage induced by oxidative stress in a QUIN-excitotoxic model.
Assuntos
Corpo Estriado/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Quinolínico/farmacologia , Animais , Antioxidantes/farmacologia , Corpo Estriado/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Ácido Quinolínico/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
We studied hydroxyeicosatetraenoic acid (HETE) release in response to ANG II from preglomerular microvessels (PGMVs), the vascular segment governing changes in renal vascular resistance. PGMVs were isolated from Sprague-Dawley rats and incubated with NADPH and hormones at 37 degrees C. Eicosanoids were extracted, and cytochrome P-450 (CYP)-derived HETEs were purified and quantitated by negative chemical ionization gas chromatography-mass spectroscopy. PGMVs produced primarily 20- and 19-HETEs, namely, 7.9 +/- 1.7 and 2.2 +/- 0.5 ng/mg protein, respectively. ANG II (5 nM) increased CYP-HETE release by two- to threefold; bradykinin, phenylephrine, and Ca(2+) ionophore were without effect. [Sar(1)]ANG II (0.1-100 microM) dose dependently stimulated 19- and 20-HETEs, an effect blocked by the AT(2)-receptor antagonist PD-123319 as well as by U-73122, a phospholipase C inhibitor. Microvascular 20-HETE release was increased more than twofold by the third day in response to ANG II (120 ng. kg(-1). min(-1)) infused subcutaneously for 2 wk; it was not further enhanced after 14 days, although blood pressure continued to rise. Thus an AT(2)-phospholipse C effector unit is associated with synthesis of a vasoconstrictor product, 20-HETE, in a key renovascular segment.
Assuntos
Angiotensina II/análogos & derivados , Ácidos Hidroxieicosatetraenoicos/metabolismo , Rim/irrigação sanguínea , Rim/enzimologia , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Ácidos Araquidônicos/metabolismo , Arteríolas/metabolismo , Capilares/efeitos dos fármacos , Capilares/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Estrenos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Ácidos Hidroxieicosatetraenoicos/análise , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , NADP/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/metabolismo , Fosfolipases Tipo C/metabolismoRESUMO
To assess the effect of angiotensin II on ion transport in rat isolated proximal tubules and establish the arachidonic acid cytochrome P450 metabolites' role mediating angiotensin II effect and to analyze whether corticosteroids play a role modulating this effect, we studied the effect of low (10 and 100 pM) and high (0.1-1 microM) angiotensin II concentrations on proximal tubule ion transport, measured as (86)Rb uptake. Low angiotensin II produced a stimulation on the (86)Rb uptake (195.79 +/- 35, 377.9 +/- 81, and 300 +/- 49 pg (86)Rb/microg protein/2 min, for control and 10 and 100 pM angiotensin II, respectively). High angiotensin II concentration inhibited ion transport (0.1 microM, 57.9 +/- 5 and 1 microM, 47.3 +/- 4 pg (86)Rb/microg protein/2 min), this effect was prevented by 17-ODYA and by losartan, while indomethacin had no effect. Dexamethasone treatment increased angiotensin II-induced (86)Rb uptake inhibition and arachidonic acid metabolism (19-, 20-HETE and 12-HETE), while adrenalectomy partly prevented angiotensin II-induced inhibition and decreased cytochrome P450-dependent arachidonic acid metabolism. In conclusion, high doses of angiotensin II produce inhibition of ion transport in rat isolated proximal tubules; this effect is mediated by AT(1) receptors, involves cytochrome P450-dependent arachidonic acid metabolites, and is upregulated by corticosteroids.
Assuntos
Angiotensina II/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Transporte de Íons/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Adrenalectomia , Angiotensina II/antagonistas & inibidores , Animais , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Ácidos Graxos Insaturados/farmacologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ácidos Hidroxieicosatetraenoicos/farmacologia , Indometacina/farmacologia , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/metabolismo , Losartan/farmacologia , Masculino , Ouabaína/farmacologia , Ratos , Ratos Sprague-Dawley , Radioisótopos de Rubídio/metabolismoRESUMO
Nitric oxide is an important regulator of vascular tone. Deficiencies in nitric oxide release have been implicated in hypertension. In the present study we evaluated vascular reactivity to phenylephrine and acetylcholine in isolated aorta ring preparations from sham and aortic coarctation-induced hypertensive rats and nitric oxide release under resting conditions and after stimulation with acetylcholine. Aortic vessels were divided in upper segment and lower segment in relation to the coarctation; both segments were tested for vascular reactivity and nitric oxide release. Phenylephrine produced higher vasoconstriction in upper segments from hypertensive rats compared to sham operated animals. Lower segments in both experimental groups were not significantly different. Relaxation produced by acetylcholine showed a higher EC50 in the upper segments from hypertensive rats; lower segments in both experimental groups were not significantly different. Aortic rings from hypertensive rats had a higher level of nitric oxide release compared to sham operated rats. Lower segments from hypertensive rats released significantly more nitric oxide. These results suggest that shear stress induced nitric oxide release in lower aortic segments from aortic coarctation-induced hypertensive rats.
Assuntos
Aorta/metabolismo , Coartação Aórtica/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/biossíntese , Acetilcolina/farmacologia , Análise de Variância , Animais , Aorta/química , Aorta/efeitos dos fármacos , Coartação Aórtica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/química , Endotélio Vascular/efeitos dos fármacos , Masculino , Óxido Nítrico/análise , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: To evaluate the contribution of nitric oxide to the regulation of angiotensin II-induced renal vasoconstriction in normotensive rats and in rats with aortic coarctation-induced hypertension. METHODS: We evaluated the renal vascular reactivity of nonischemic kidney to angiotensin II with and without nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester) in the isolated perfused kidney. The nitrite concentration in renal perfusate of nonischemic kidney was measured as an index of nitric oxide released and the activity of nitric oxide synthase in renal tissue was determined by production of [3H]-L-citrulline. RESULTS: The perfusion of NG-nitro-L-arginine methyl ester potentiated angiotensin II-induced renal vasoconstriction in normotensive rats but had no effect on hypertensive rats. The release of nitrites in kidneys from hypertensive rats was lower than that in kidneys from normotensive rats. The activity of renal nitric oxide synthase was less in the hypertensive rats than it was in the normotensive rats. CONCLUSIONS: Nitric oxide counteracts the vasoconstrictor effect of angiotensin II in normotensive rats, whereas this protective mechanism is impaired in hypertensive rats. This impairment potentiates effect of angiotensin II on vascular resistance, thereby contributing to the development of high blood pressure.
Assuntos
Angiotensina II/farmacologia , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Rim/irrigação sanguínea , Óxido Nítrico/fisiologia , Circulação Renal/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Rim/fisiopatologia , Masculino , Perfusão , Ratos , Ratos WistarRESUMO
Vasorelaxant activity induced by nitric oxide has been associated with a regulator activity on the blood pressure. In the present study we evaluated the nitric oxide contribution of the regulation of angiotensin II-induced vasoconstriction in normotensive rats and aortic coarctation-induced hypertensive rats. Renal vascular reactivity to angiotensin II was evaluated in the presence and absence of nitric oxide synthesis inhibitor; NG-nitro-L-arginine methyl ester. Nitrite concentration in perfusate was measured as an index of nitric oxide released and nitric oxide synthase activity was determined by production of 3H-L-citrulline. Renal NG-nitro-L-arginine methyl ester perfusion potentiated angiotensin II-induced vasoconstriction in normotensive rats but did not affect angiotensin II effect on hypertensive rats. The release of nitrites was lower in the kidneys from hypertensive rats than normotensive rats. Renal nitric oxide synthase activity was decreased in the hypertensive rats compared to the normotensive rats. We suggest that in normotensive rats, nitric oxide counteracts angiotensin II vasoconstrictor action, whereas, in hypertensive rats this mechanism is impaired, therefore, potentiating angiotensin II increase in vascular resistance thereby contributing to the developing of high blood pressure.
Assuntos
Angiotensina II/farmacologia , Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Coartação Aórtica , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática , Hipertensão/etiologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Nitritos/metabolismo , Ratos , Ratos WistarRESUMO
Los docentes en ciencias de la salud, en virtud de su formacion academica, carecen de metodologia y entrenamiento para realizar el proceso de ensenanza-aprendizaje como profesores de carrera y al realizar los examenes a los alumnos solo llevan el proposito de asignar calificaciones por lo que se han convertido en sucesos angustiantes para el alumno. Los examenes llamados tambien mediciones, tienen ventajes y desventajas, asi como indicaciones precisas. En el presente trabajo se revisa el examen de opcion multiple, con sus caracteristicas e indicaciones, haciendo hincapie en como mejorarlo, proporniendo por parte de los autores un ordenamiento para realizar preguntas en un examen de opcion multiple, asi como sugerencias para mejorar los reactivos, el analisis minimo estadistico que debe llevarse hasta la formacion de un banco de preguntas, sencillo y economico y al alcance de cualquier docente