RESUMO
Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.
RESUMO
Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.
RESUMO
The present study examined the role of the sympathetic system and pulmonary afferent feedback in the baroreflex inhibition by chemical stimulation of the dorsal periaqueductal gray matter (DPAG) of the anesthetized rat. The baroreflex bradycardia was induced by phenylephrine infusions (PHE, 50 µg/ml/min, i.v.) given either alone or combined with glutamate microinjections (GLU, 10 nmol/100 nl) into the DPAG. GLU microinjections alone produced marked increases in respiratory amplitude (67±19%), but barely changed the respiratory frequency (15±3 cpm) and blood pressure (14±2 mm Hg), and did not affect the heart rate. In contrast, the same injections produced a 92% inhibition of PHE-induced bradycardia (from -62 to -5 bpm). Because GLU microinjections per se had little effects on blood pressure, the baroreflex inhibition should be credited to the deactivation of both the vagal and sympathetic reflex pathways at the medulla. Indeed, the baroreflex was inhibited in only 47% following the DPAG stimulation of atenolol-treated rats. The GLU-evoked inhibition of baroreflex was also correlated with concomitant increases in respiratory amplitude. The role of pulmonary feedback in baroreflex inhibition was thus examined before and after the neuromuscular blockade of atenolol-treated rats. In spontaneously breathing rats, GLU microinjections reversed PHE-induced bradycardia to tachycardia, thereby producing a 153% inhibition of reflex bradycardia (from -38 bpm to +20 bpm). In contrast, the baroreflex inhibition was attenuated in only 53% after neuromuscular blockade (from -34 to -16 bpm). Data are the first evidence of the contribution of pulmonary stretch receptor feedback in DPAG-evoked inhibition of reflex bradycardia.
Assuntos
Barorreflexo/fisiologia , Bradicardia/fisiopatologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores Pulmonares de Alongamento/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Aminoácidos Excitatórios/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Ácido Glutâmico/farmacologia , Masculino , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores Pulmonares de Alongamento/efeitos dos fármacos , Ratos , Ratos Wistar , Estimulação Química , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Stimulation of the periaqueductal gray matter (PAG) and the deeper layers of superior colliculus (SC) produces both freezing (tense immobility) and flight (trotting, galloping and jumping) behaviors along with exophthalmus (fully opened bulging eyes) and, less often, micturition and defecation. The topography of these behaviors within the distinct layers of SC remains unclear. Therefore, this study compared the defensive repertoire of intermediate (ILSC) and deep (DLSC) layers of SC to those of dorsolateral periaqueductal gray matter (DLPAG) and lateral periaqueductal gray matter (LPAG) [Neuroscience 125 (2004) 71]. Electrical stimulation was carried out through intensity- (0-70 microA) and frequency-varying (0-130 Hz) pulses. Chemical stimulation employed a slow microinfusion of N-methyl-d-aspartic acid (NMDA, 0-2.3 nmol, 0.5 nmol/min). Probability curves of intensity-, frequency- and NMDA-evoked behaviors, as well as the unbiased estimates of median stimuli, were obtained by threshold logistic analysis. Compared with the PAG, the most important differences were the lack of frequency-evoked jumping in both layers of SC and the lack of NMDA-evoked galloping in the ILSC. Moreover, although galloping and jumping were also elicited by NMDA stimulation of DLSC, effective doses were about three times higher than those of DLPAG, suggesting the spreading of the injectate to the latter structure. In contrast, exophthalmus, immobility and trotting were evoked throughout the tectum structures. However, whatever the response and kind of stimulus, the lowest thresholds were always found in the DLPAG and the highest ones in the ILSC. Besides, neither the appetitive, nor the offensive, muricide or male reproductive behaviors were produced by any kind of stimulus in the presence of appropriate targets. Accordingly, the present data suggest that the deeper layers of SC are most likely involved in the increased attentiveness (exophthalmus, immobility) or restlessness (trotting) behaviors that herald a full-blown flight reaction (galloping, jumping) mediated in the PAG.
Assuntos
Agressão/fisiologia , Reação de Fuga/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Colículos Superiores/fisiologia , Agressão/efeitos dos fármacos , Animais , Comportamento Animal , Mapeamento Encefálico , Distribuição de Qui-Quadrado , Limiar Diferencial/efeitos dos fármacos , Limiar Diferencial/fisiologia , Limiar Diferencial/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Reação de Fuga/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , N-Metilaspartato/farmacologia , Probabilidade , Ratos , Ratos Wistar , Estimulação QuímicaRESUMO
The cardiovascular effects induced by the aqueous fraction of the ethanol extract of the stem (AFS) of Solanum stipulaceum Roem. & Schult were studied in rats. In non-anesthetized rats, AFS injections produced significant and dosedependent hypotension associated with increase in heart rate. In isolated rat superior mesenteric rings, AFS was able to antagonize the contractions induced by phenylephrine and KCl. The vasorelaxant activity of AFS was not inhibited by either removal of vascular endothelium, L-NAME, atropine or indomethacine. In isolated rat atrial preparations, AFS produced concentration-related negative inotropic and chronotropic responses. These results suggest that the hypotensive effect of AFS is due to a peripheral vasodilation, which can not be attributed to the participation of vascular endothelium. Finally, AFS acts directly on the heart decreasing contractility and heart rate.
RESUMO
The importance of the integrity of the ipsilateral rostral ventrolateral medulla (RVLM) in the pressor response to activation of unilateral arterial chemoreceptors was evaluated. To achieve this goal, the left carotid body artery was ligated prior to the experiment and a guide cannula was implanted in the direction of the right RLVM, i.e. the side where the carotid body artery was kept intact. On the day of the experiment, the chemoreflex was activated with potassium cyanide (KCN, i.v.) before and after unilateral microinjection of kynurenic acid into the rostral or caudal aspect of the RVLM. The data indicated that microinjection of kynurenic into the rostral or caudal aspect of the RVLM produced no effect on the pressor response of chemoreflex activation. These data suggest that chemoreflex activation excites a neuronal network in which the processing of the sympatho-excitatory component of the chemoreflex is not restricted to an excitatory projection from the nucleus tractus solitarii to the ipsilateral RVLM.
Assuntos
Pressão Sanguínea/fisiologia , Corpo Carotídeo/fisiologia , Células Quimiorreceptoras/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Cinurênico/farmacologia , Núcleo Solitário/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/fisiopatologia , Artérias Carótidas/fisiologia , Ligadura , Masculino , Microinjeções , Ratos , Ratos Wistar , Receptores de Glutamato/fisiologia , Núcleo Solitário/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , VigíliaRESUMO
This study was carried out to investigate the effects of chemical lesions of dorsal periaqueductal gray (DPAG) on resting arterial pressure (AP) and heart rate (HR) as well as on cardiac baroreflex of conscious normotensive rats. Lesions were performed by bilateral microinjections of 150 mM NMDA into the DPAG (DPAG-lesion group). Controls were similarly injected with 165 mM NaCl (DPAG-sham group). Animals with chronic lesions confined only to the superior colliculus (SC-lesion group) were also used as controls of DPAG-lesion. Cardiovascular parameters were recorded 1 or 7 days after the microinjections of NMDA in acute and chronic groups, respectively. Cardiac baroreflex was assessed by measuring the HR responses to the intravenous injection of phenylephrine or sodium nitroprusside. Baroreflex was estimated by sigmoidal curve fitting of HR responses. An increased baroreflex gain was observed in chronic DPAG-lesion rats compared to both DPAG-sham (p < 0.01) and SC-lesion (p < 0.05) chronic groups. The chronic DPAG-lesion group showed also an elevation of both the tachycardia (p < 0.05) and bradycardia (p < 0.01) plateaus compared to chronic DPAG-sham rats, while the SC-lesion group showed an elevation of the bradycardia plateau only (p < 0.01). Similar results on baroreflex function were observed following acute lesion of the DPAG, i.e. an increase in baroreflex gain (p < 0.01) and the elevation of both tachycardia (p < 0.05) and bradycardia plateaus (p < 0.01) compared to the acute DPAG-sham group. Resting AP and HR did not differ among the chronic groups. In contrast, the acute lesion of the DPAG produced a reduction in AP (p < 0.01) accompanied by an increase in HR (p < 0.01). The present data suggest that the DPAG is involved in the tonic and reflex control of AP and HR in conscious rats. In addition, the SC seems to contribute to the baroreflex cardioinhibition.
Assuntos
Hemodinâmica/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Algoritmos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Denervação , Agonistas de Aminoácidos Excitatórios/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hemodinâmica/efeitos dos fármacos , Masculino , Microinjeções , N-Metilaspartato/farmacologia , Nitroprussiato/farmacologia , Substância Cinzenta Periaquedutal/anatomia & histologia , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Vasodilatadores/farmacologiaRESUMO
Microinjection of L-glutamate into the lateral commissural nucleus tractus solitarii (NTS) of unanesthetized rats evokes increases in mean arterial pressure (MAP) and a bradycardia. In a previous study we verified that this increase in MAP is mediated sympathetically because prazosin (i.v.) blocks this response. The aim of the present study was to evaluate the role of the rostral ventrolateral medulla (RVLM) in the pressor response produced by L-glutamate microinjected into the NTS of unanesthetized rats. L-Glutamate was microinjected into the NTS before and 15 and 90 min after microinjection of kynurenic acid into the ipsilateral RVLM. Pressor (+24+/-3 vs. +6+/-3 mm Hg) and bradycardic (-101+/-10 vs. -3+/-12 bpm) responses to L-glutamate microinjected into the NTS (n = 8) were almost abolished 15 min after microinjection of kynurenic acid into the RVLM when compared with control responses. Both pressor (+23+/-6 mm Hg) and bradycardic (-93+/-16 bpm) responses to L-glutamate into the NTS returned to control values 90 min after microinjection of kynurenic acid into the RVLM. These data indicate that the pressor response to L-glutamate into the NTS is essentially dependent on the ipsilateral RVLM and also that this sympatho-excitatory response is mediated by excitatory amino acid receptors in RVLM neurons.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Bulbo/fisiologia , Núcleo Solitário/fisiologia , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Ácido Cinurênico/administração & dosagem , Ácido Cinurênico/farmacologia , Masculino , Bulbo/anatomia & histologia , Microinjeções , Ratos , Ratos Wistar , Núcleo Solitário/anatomia & histologiaRESUMO
There are clinical and experimental evidences that the cardiopulmonary reflex function is impaired in chronic hypertension, but it could be due to myocardial hypertrophy rather than to hypertension itself. To test this hypothesis we evaluated the Bezold-Jarisch reflex in experimental conditions of myocardial hypertrophy and arterial normotension. Adult male Wistar rats were subjected to myocardial hypertrophy (MHR) treating them with the beta-adrenoceptor agonist isoproterenol (0.3 mg/kg/day, s.c.) for 15 days and compared with vehicle injected control rats (CR). No significant changes in body weight (283+/-14 vs. 299+/-9 g), resting mean arterial pressure (104+/-4 vs. 110+3 mm Hg) or heart rate (330+/-11 vs. 358+/-18 bpm) were observed in MHR compared to CR. As expected, MHR showed left and right ventricular and left atrial hypertrophy when compared to CR. The bradycardia and hypotension that characterizes the Bezold-Jarisch reflex, induced by the 5-HT3, agonist phenyldiguanide (1.5-24.0 microg/kg, i.v.), were significantly decreased in MHR compared to CR. Cardiac muscarinic responsiveness, which was assessed by electrical stimulation of the efferent vagus in anesthetized animals or by stimulation of muscarinic receptors in isolated hearts, was unchanged or increased, respectively, in MHR compared to CR. Additional studies showed that the baroreflex and chemoreflex were also attenuated in MHR compared to CR. These data indicate that cardiac hypertrophy impairs the Bezold-Jarisch reflex probably due to changes at central integrative areas of the reflex.
Assuntos
Barorreflexo/fisiologia , Cardiomegalia/fisiopatologia , Hipertensão/fisiopatologia , Sistema Nervoso Parassimpático/fisiologia , Acetilcolina/farmacologia , Anestesia , Animais , Pressão Sanguínea/fisiologia , Peso Corporal , Células Quimiorreceptoras/fisiologia , Estado de Consciência , Estimulação Elétrica , Frequência Cardíaca/fisiologia , Masculino , Sistema Nervoso Parassimpático/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologiaRESUMO
Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factors and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, s.c.) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1% NaCl and 0.03% KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighted. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 +/- 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 +/- 0.01 mg/g) compared to control (1.92 +/- 0.04 and 0.48 +/- 0.01 mg/g, respectively) rats. MAP was significantly higher (39%) in DOCA-salt rats. Renal denervation prevented (P > 0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 +/- 0.03 mg/g) and RVW/BW (0.52 +/- 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity.