RESUMO
Oxidative stress is a key factor in the pathogenesis of hypertension and target organ damage, beginning in the earliest stages. Extensive evidence indicates that the pivotal role of oxidative stress in the pathogenesis of hypertension is due to its effects on the vasculature in relation to the development of atherosclerotic processes. It remains unclear, however, whether oxidative stress in the brain, particularly the autonomic nuclei (including the vasomotor center), has an important role in the occurrence and maintenance of hypertension via activation of the sympathetic nervous system. The aim of the present review is to describe the contribution of oxidative stress in the brain to the neural mechanisms that underlie hypertension, and discuss evidence that brain oxidative stress is a potential therapeutic target.
Assuntos
Encéfalo/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Estresse Oxidativo , Sistema Vasomotor/fisiopatologia , Aterosclerose/etiologia , Aterosclerose/fisiopatologia , HumanosRESUMO
Nitric oxide (NO) in the brainstem modulates blood pressure (BP). Overexpression of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM) increases BP in normotensive Wistar-Kyoto rats (WKY), but its role in BP regulation in spontaneously hypertensive rats (SHR) is unknown. We examined iNOS expression and the effect of iNOS inhibitors in the RVLM on BP and heart rate in SHR and WKY. iNOS levels in the RVLM were significantly higher in SHR than in WKY. Bilateral microinjection of aminoguanidine into the RVLM dose-dependently decreased BP and heart rate in SHR, but not in WKY. These findings suggest that iNOS expression in the RVLM of SHR contributes to increase BP.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Núcleos Ventrais do Tálamo/enzimologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Masculino , Microinjeções , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Rho-kinase is involved in the pathogenesis of hypertension and left ventricular remodelling after myocardial infarction (MI). In an earlier study, we had demonstrated that Rho-kinase in the brainstem contributes to hypertensive mechanisms via the sympathetic nervous system; however, it is not known whether Rho-kinase in the brainstem also contributes to sympathetic nerve activation after MI. Male Institute of Cancer Research mice (8-10 weeks old) were used for the study. Two days before coronary artery occlusion (MI group), the left ventricular function was estimated by echocardiography. Following this, Y-27632 (0.5 mM, 0.25 microL/h), a specific Rho-kinase inhibitor, or a vehicle was intracisternally infused in the mice using an osmotic mini-pump. Nine days after coronary artery occlusion, we evaluated the 24-hour urinary norepinephrine excretion (U-NE) as a marker of sympathetic nerve activity. Ten days after coronary artery occlusion, we measured organ weight and evaluated Rho-kinase activity in the brainstem by measuring the amount of phosphorylated ezrin/radixin/moesin proteins, one of the substrates of Rho-kinase. The control group underwent a sham operation. Rho-kinase activity, U-NE, and lungs and liver weight were significantly greater in the MI group compared with the control group. Left ventricular size increased and percent fractional shortening decreased in the MI group compared with the control group. Y-27632 significantly decreased Rho-kinase activity and attenuated the increase in U-NE after MI. These results demonstrate that Rho-kinase is activated in the brainstem after MI and that the activation of this pathway is involved in the resulting enhanced sympathetic drive.
Assuntos
Tronco Encefálico/enzimologia , Hipertensão/enzimologia , Infarto do Miocárdio/complicações , Sistema Nervoso Simpático/enzimologia , Quinases Associadas a rho/metabolismo , Amidas/farmacologia , Animais , Vias Autônomas/efeitos dos fármacos , Vias Autônomas/enzimologia , Vias Autônomas/fisiopatologia , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiopatologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiopatologia , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/urina , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/fisiologia , Piridinas/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Quinases Associadas a rho/efeitos dos fármacosRESUMO
Endothelial function is impaired in hypertensive patients. Decreased nitric oxide production and increased oxidative stress are involved in this abnormality. The aim of the present study was to evaluate whether endothelial function and oxidative stress differ following long-term antihypertensive treatment with an angiotensin type 1 receptor blocker, valsartan, or a calcium channel blocker, amlodipine, in patients with essential hypertension. Hypertensive patients were treated with valsartan (80-160 mg/day) or amlodipine (5-10 mg/day) for one year (n = 9 for each). The baseline blood pressure was similar between groups, and the magnitude of the decreases in blood pressure did not differ during treatment at three months, six months, or one year. Endothelial function and oxidative stress markers were examined before and after treatment. Endothelial function, assessed by flow-mediated vasodilation, was significantly improved in hypertensive patients treated with valsartan (5.8 +/- 1.2 to 10.7 +/- 1.4 %, p < 0.01) but not in those treated with amlodipine. The percent increase in vasodilation induced by sublingual nitroglycerin did not differ between the two groups. As markers of oxidative stress, urinary excretion of 8-isoprostane and 8-hydroxy-2'-deoxyguanosine was significantly reduced in patients treated with valsartan, but not in those treated with amlodipine. These findings suggest that the treatment of hypertensive patients with valsartan for at least one year improves endothelial function in association with reduced oxidative stress. The improved endothelial function and reduced oxidative stress might be involved in the benefits of anti-hypertensive treatment beyond simply lowering blood pressure, although the effects of treatment with valsartan or amlodipine over a much longer period are unknown.
Assuntos
Anlodipino/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Hipertensão/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valina/análogos & derivados , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Idoso , Povo Asiático , Biomarcadores/urina , Pressão Sanguínea/efeitos dos fármacos , Artéria Braquial/fisiopatologia , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Dinoprosta/análogos & derivados , Dinoprosta/urina , Endotélio Vascular/fisiopatologia , Feminino , Seguimentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Valina/uso terapêutico , Valsartana , Vasodilatação/efeitos dos fármacosRESUMO
Reactive oxygen species (ROS) in the brain are thought to contribute to the neuropathogenesis of hypertension by enhancing sympathetic nervous system activity. The nucleus tractus solitarius (NTS), which receives afferent input from baroreceptors, has an important role in cardiovascular regulation. reduced nicotinamide-adenine dinucleotide phosphate oxidase is thought to be a major source of ROS in the NTS. Rac1 is a small G protein and a key component of reduced nicotinamide-adenine dinucleotide phosphate oxidase. The role of Rac1-derived ROS in the NTS in cardiovascular regulation of hypertension is unknown. Therefore, we examined whether inhibition of Rac1 in the NTS decreases ROS generation, thereby reducing blood pressure in stroke-prone spontaneously hypertensive rats (SHRSPs). The basal Rac1 activity level in the NTS was greater in SHRSPs than in Wistar-Kyoto rats. Inhibition of Rac1, induced by transfecting adenovirus vectors encoding dominant-negative Rac1 into the NTS, decreased blood pressure, heart rate, and urinary norepinephrine excretion in SHRSPs but not in Wistar-Kyoto rats. Inhibition of Rac1 also reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and ROS generation. In addition, Cu/Zn-superoxide dismutase activity in the NTS of SHRSPs was decreased compared with that of Wistar-Kyoto rats, despite the increased ROS generation. Overexpression of Cu/Zn-superoxide dismutase in the NTS decreased blood pressure and heart rate in SHRSPs. These results indicate that the activation of Rac1 in the NTS generates ROS via reduced nicotinamide-adenine dinucleotide phosphate oxidase in SHRSPs, and this mechanism might be important for the neuropathogenesis of hypertension in SHRSPs.
Assuntos
Pressão Sanguínea , Frequência Cardíaca , Hipertensão/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Núcleo Solitário/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Adenoviridae/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Técnicas de Transferência de Genes , Predisposição Genética para Doença , Vetores Genéticos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Masculino , NADPH Oxidases/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Núcleo Solitário/enzimologia , Acidente Vascular Cerebral/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologiaRESUMO
OBJECTIVES: The brain renin-angiotensin system plays an important role in cardiovascular regulation and the pathogenesis of hypertension. Angiotensin II activates the Rho/Rho-kinase pathway in vascular smooth muscle cells and cardiomyocytes in vitro. The aim of the present study was to determine whether angiotensin II in the brainstem activates the Rho/Rho-kinase pathway, and, if so, whether this mechanism is involved in the central pressor action of angiotensin II. METHODS AND RESULTS: Angiotensin II infused intracisternally for 7 days in Wistar-Kyoto rats (WKY) increased systolic blood pressure (SBP) and urinary norepinephrine excretion. These responses were abolished by the co-infusion of Y-27632, a specific Rho-kinase inhibitor, or valsartan. The intracisternal infusion of Y-27632 or valsartan also reduced SBP and norepinephrine excretion in spontaneously hypertensive rats (SHR). Western blot analysis was performed to examine the expression levels of membranous RhoA and phosphorylated ezrin, radixin, and moesin (p-ERM), which reflects Rho/Rho-kinase activity. The expression levels of membranous RhoA and p-ERM in the brainstem were significantly greater in both angiotensin II-treated WKY and SHR than in vehicle-treated WKY. Valsartan reduced the expression levels of membranous RhoA and p-ERM in angiotensin II-treated WKY and SHR. Y-27632 reduced the expression levels of p-ERM in angiotensin II-treated WKY and SHR. CONCLUSIONS: These results suggest that the pressor response induced by intracisternally infused angiotensin II is substantially mediated by the activation of the Rho/Rho-kinase pathway via AT1 receptors of the brainstem in WKY, and that this pathway might be involved in the hypertensive mechanisms of SHR.
Assuntos
Angiotensina II/fisiologia , Encéfalo/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiologia , Amidas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Tronco Encefálico/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Norepinefrina/urina , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP/análise , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Nitric oxide (NO) in the central nervous system inhibits sympathetic nerve activity, thereby decreasing blood pressure. It is unknown, however, whether orally administered antihypertensive treatment alters NO synthase (NOS) expression, particularly in the brain, and how changes in NOS expression affects sympathetic nerve activity. Azelnidipine, a recently developed long-acting dihydropyridine calcium channel blocker, does not cause baroreflex-induced tachycardia. The aim of the present study was to determine whether antihypertensive treatment with azelnidipine alters endothelial NOS (eNOS), neuronal NOS (nNOS), or inducible NOS (iNOS) expression in the brain, and how changes in NOS affect sympathetic nerve activity. Azelnidipine (20 mg/kg/day) or hydralazine (20 mg/kg/day) was orally administered for 30 days in stroke-prone spontaneously hypertensive rats (SHRSP). Blood pressure and heart rate were measured by the tail cuff method. Urinary norepinephrine excretion was measured as a marker of sympathetic nerve activity. Western blot analysis was performed to examine eNOS, nNOS, or iNOS expression levels in the brain (cortex, cerebellum, hypothalamus, and the brain stem), heart, and aorta. The extent of blood pressure reduction was similar between the two groups. Heart rate increased in the hydralazine-treated group but did not change in the azelnidipine-treated group. Urinary norepinephrine excretion was significantly increased only in the hydralazine-treated group. Treatment with azelnidipine significantly increased eNOS expression levels in the brain, heart, and aorta, but did not alter nNOS or iNOS expression levels. Treatment with hydralazine did not change any of the NOS expression levels. These results suggest that antihypertensive treatment with azelnidipine attenuates reflex-induced sympathetic activation and enhances eNOS expression levels in the brain as well as in the heart and aorta.
Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Encéfalo/enzimologia , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Aorta/enzimologia , Ácido Azetidinocarboxílico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Norepinefrina/urina , Ratos , Ratos Endogâmicos SHR , Ratos EndogâmicosRESUMO
Estrogen protects against increases in arterial pressure (AP) by acting on blood vessels and on cardiovascular centers in the brain. The mechanisms underlying the effects of estrogen in the brain stem, however, are not clear. The aim of the present study was to determine whether ovariectomy affects AP via the Rho/Rho-kinase pathway in the brain stem. We performed bilateral ovariectomy in 12-week-old female spontaneously hypertensive rats. AP and heart rate (HR), measured using radiotelemetry in awake rats, were increased in ovariectomized rats compared with control rats (mean AP: 163+/-3 versus 144+/-4 mm Hg; HR: 455+/-4 versus 380+/-6 bpm). Continuous intracisternal infusion of Y-27632 significantly attenuated the ovariectomy-induced increase in AP and HR (mean AP: 137+/-6 versus 163+/-3 mm Hg; HR: 379+/-10 versus 455+/-4 bpm). In addition, we confirmed the increase of Rho-kinase activity in the brain stem in ovariectomized rats, and the increase was attenuated by intracisternal infusion of Y-27632 via the phosphorylated ezrin, radixin, and moesin (ERM) family, which are Rho-kinase target proteins. Furthermore, angiotensin II type 1 receptor expression in the brain stem was significantly greater in ovariectomized rats than in control rats, and the increase was partially reduced by intracisternal infusion of Y-27632. In a separate group of animals, we confirmed that the serum and cerebrospinal fluid 17beta-estradiol concentrations decreased in ovariectomized rats. These results suggest that depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension in female spontaneously hypertensive rats via activation of the renin-angiotensin system and the Rho/Rho-kinase pathway in the brain stem.
Assuntos
Tronco Encefálico/enzimologia , Hipertensão/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ovariectomia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Endogâmicos SHR , Amidas/administração & dosagem , Amidas/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Ativação Enzimática , Estradiol/sangue , Estradiol/líquido cefalorraquidiano , Feminino , Frequência Cardíaca/efeitos dos fármacos , Injeções Intraventriculares , Concentração Osmolar , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Telemetria/métodos , Quinases Associadas a rhoRESUMO
Amlodipine is a dihydropyridine calcium channel blocker that is widely used for the treatment of hypertensive patients and has an antioxidant effect on vessels in vitro. The aim of the present study was to examine whether treatment with amlodipine reduced oxidative stress in the brains of stroke-prone spontaneously hypertensive rats (SHRSP). The animals received amlodipine, nicardipine or hydralazine for 30 days in their drinking water. Levels of thiobarbituric acid-reactive substances (TBARS) in the brain (cortex, cerebellum, hypothalamus, and brainstem) were measured before and after each treatment. Systolic blood pressure decreased to similar levels in the amlodipine-, nicardipine-, and hydralazine-treated groups. Urinary norepinephrine excretion was significantly reduced in SHRSP after treatment with amlodipine, but not with nicardipine or hydralazine. Levels of TBARS in the cortex, cerebellum, hypothalamus, and brainstem were significantly higher in SHRSP than in Wistar-Kyoto rats (WKY), and were reduced in amlodipine-treated, but not in nicardipine- or hydralazine-treated, SHRSP. Electron spin resonance spectroscopy revealed increased levels of reactive oxygen species in the brains of SHRSP, which were reduced by treatment with amlodipine. Intracisternal infusion of amlodipine also reduced systolic blood pressure, urinary norepinephrine excretion, and the levels of TBARS in the brain. These results suggested that oxidative stress in the brain was enhanced in SHRSP compared with WKY rats. In addition, antihypertensive treatment with amlodipine reduced oxidative stress in all areas of the brain examined and decreased blood pressure without a reflex increase in sympathetic nerve activity in SHRSP.
Assuntos
Anlodipino/farmacologia , Química Encefálica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Anlodipino/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Cisterna Magna , Espectroscopia de Ressonância de Spin Eletrônica , Frequência Cardíaca/efeitos dos fármacos , Injeções , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Norepinefrina/urina , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The Rho/Rho-kinase pathway in the central nervous system is involved in the maintenance of dendritic spines, which form the postsynaptic contact sites of excitatory synapses. Inhibition of the Rho-kinase pathway in neuron promotes dendritic spines or branches. In contrast, activation of the Rho/Rho-kinase pathway reduces dendritic spines or branches. Recent studies suggest that morphological changes of dendritic spines occur rapidly, and spine morphology is associated with glutamate sensitivity. The aim of the present study was to determine whether Rho-kinase activity affects glutamate sensitivity in the nucleus tractus solitarii (NTS) of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). We first examined the effects of unilateral glutamate injection in the NTS. There was a significantly smaller decrease in arterial pressure in SHR than in WKY. We then examined the depressor responses evoked by unilateral glutamate injection into the NTS after preinjection of Y-27632, a specific Rho-kinase inhibitor. Preinjection of Y-27632 enhanced the glutamate response in both strains. However, the magnitude of the augmentation was significantly greater in SHR than in WKY. Furthermore, we recorded single-unit activity of NTS neurons from medulla brain slice preparations. N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was applied iontophoretically to the recorded neurons, and neuronal activity was recorded before and after Y-27632 perfusion. Y-27632 perfusion increased the response to NMDA and AMPA. These results suggest that inhibition of Rho-kinase activity in the NTS enhances glutamate sensitivity in WKY and SHR and might improve impaired glutamate sensitivity in SHR.
Assuntos
Ácido Glutâmico/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/enzimologia , Amidas/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/administração & dosagem , Técnicas In Vitro , Injeções , Peptídeos e Proteínas de Sinalização Intracelular , Iontoforese , Masculino , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Quinases Associadas a rhoRESUMO
The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or beta-galactosidase (Adbetagal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adbetagal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adbetagal-transfected rats. Microinjection of aminoguanidine or S-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-reactive substances, a marker of oxidative stress, were significantly greater in AdiNOS-transfected rats than in Adbetagal-transfected rats. Dihydroethidium fluorescence in the RVLM was increased in AdiNOS-transfected rats. In addition, nitrotyrosine-positive cells were observed in the RVLM only in AdiNOS-transfected rats. Intracisternal infusion of tempol significantly attenuated the pressor response and the increase in the levels of thiobarbituric acid-reactive substances induced by AdiNOS transfection. These results suggest that overexpression of iNOS in the RVLM increases blood pressure via activation of the sympathetic nervous system, which is mediated by an increase in oxidative stress.
Assuntos
Hipertensão/etiologia , Bulbo/enzimologia , Óxido Nítrico Sintase/fisiologia , Estresse Oxidativo , Sistema Nervoso Simpático/fisiopatologia , Tirosina/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Pressão Sanguínea , Química Encefálica , Bovinos , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacologia , Frequência Cardíaca , Hipertensão/enzimologia , Hipertensão/genética , Bombas de Infusão Implantáveis , Masculino , Bulbo/fisiopatologia , Camundongos , Microdiálise , Microinjeções , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Norepinefrina/urina , Distribuição Aleatória , Ratos , Ratos Endogâmicos WKY , Proteínas Recombinantes de Fusão/fisiologia , Marcadores de Spin , Superóxidos/análise , Transdução Genética , Tirosina/análise , Sistema Vasomotor/fisiologiaRESUMO
The Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem contributes to blood pressure regulation. Activation of this pathway might be involved in the central nervous system mechanisms of hypertension. The aim of the present study was to determine whether baroreflex control of heart rate is altered by inhibition of Rho-kinase in the NTS. Adenovirus vectors encoding dominant-negative Rho-kinase or beta-galactosidase were transfected into the nucleus tractus solitarii of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Baroreflex control of heart rate was examined by changing arterial pressure with an intravenous infusion of phenylephrine or sodium nitroprusside. The maximum gain of baroreflex control of heart rate was attenuated in SHR compared with WKY before the gene transfer. Transfection of adenovirus vectors encoding dominant-negative Rho-kinase significantly augmented the maximum gain in both WKY and SHR. The extent of this augmentation, however, was greater in SHR than in WKY. After treatment with metoprolol, the maximum gain was significantly decreased in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase, but not in nontransfected rats. In contrast, after treatment with atropine, the maximum gain was greater in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase compared with nontransfected rats, although it was decreased in both groups. These results suggest that inhibition of Rho-kinase in the NTS augments baroreflex control of heart rate, in both WKY and SHR, probably because of a cardiac sympathoinhibitory effect.