RESUMO
1. Cardiovascular reactivity, an abrupt rise in blood pressure (BP) and heart rate in response to psychoemotional stress, is a risk factor for heart disease. Pharmacological and molecular genetic studies suggest that brain angiotensin (Ang) II and AT(1) receptors are required for the normal expression of sympathetic cardiovascular responses to various psychological stressors. Moreover, overactivity of the brain AngII system may contribute to enhanced cardiovascular reactivity in hypertension. 2. Conversely, brain AT(1) receptors appear to be less important for the regulation of sympathetic cardiovascular responses to a range of stressors involving an immediate physiological threat (physical stressors) in animal models. 3. Apart from threatening events, appetitive stimuli can induce a distinct, central nervous system-mediated rise in BP. However, evidence indicates that brain AT(1) receptors are not essential for the regulation of cardiovascular arousal associated with positively motivated behaviour, such as anticipation and the consumption of palatable food. The role of central AT(1) receptors in regulating cardiovascular activation elicited by other types of appetitive stimuli remains to be determined. 4. Emerging evidence also indicates that brain AT(1) receptors play a limited role in the regulation of cardiovascular responses to non-emotional natural daily activities, sleep and exercise. 5. Collectively, these findings suggest that, with respect to cardiovascular arousal, central AT(1) receptors may be involved primarily in the regulation of the defence response. Therefore, these receptors could be a potential therapeutic target for selective attenuation of BP hyperreactivity to aversive stressors, without altering physiologically important cardiovascular adjustments to normal daily activities, sleep and exercise.
Assuntos
Angiotensina II/fisiologia , Comportamento Apetitivo/fisiologia , Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Sistema Cardiovascular/fisiopatologia , Receptor Tipo 1 de Angiotensina/metabolismo , Estresse Psicológico/fisiopatologia , Angiotensina II/metabolismo , Animais , Sistema Cardiovascular/metabolismo , Hipertensão/metabolismo , Hipertensão/psicologia , Camundongos , RatosRESUMO
Angiotensin AT1 receptors are implicated in behavioral and physiological processes associated with fear and stress. However, the precise role of AT1 receptors in modulating fear-related behavior and its relation to their physiological effects remains unclear. Here, we examined innate and learned fear responses and their relationship to cardiovascular arousal in AT1A receptor knockout (AT1A-/-) mice. Using synchronized video and blood pressure telemetry, we found that, in a novel test environment, AT1A-/- mice showed reduced neophobia but a similar rise in blood pressure, as compared to AT1A+/+ mice. In response to a discrete threat, footshock, both flight behavior and cardiovascular arousal were decreased in AT1A-/- mice. Reduced flight behavior was also observed in AT1A-/- mice in the elevated T-maze test. During fear conditioning, the immediate freezing response to the first shock, but not the rate of freezing acquisition was decreased in AT1A-/- mice. Likewise, AT1A-/- mice showed reduced freezing and pressor responses to the first re-exposure, but normal rate of freezing extinction over subsequent trials. Similarly, in the elevated T-maze, the rates of avoidance acquisition and escape learning remained unchanged in AT1A-/- mice. Finally, after re-exposure, AT1A-/- mice displayed altered c-Fos expression, compared to AT1A+/+ mice, in the hypothalamus and periaqueductal gray but not in fear-related limbic-cortical areas, nor in medullary nuclei that convey visceral afferent information. We conclude that AT1A receptor knockout reduces innate fear responses, without affecting learning efficiency in mice. These effects are dissociable from cardiovascular effects and likely reflect altered neurotransmission in hypothalamic-midbrain defense regions.
Assuntos
Pressão Sanguínea/fisiologia , Medo/fisiologia , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensinas/metabolismo , Animais , Ansiedade/fisiopatologia , Sistema Cardiovascular/metabolismo , Condicionamento Operante/fisiologia , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/fisiologiaRESUMO
BACKGROUND: We have recently shown that the renin enhancer, a regulatory element of renin gene transcription, is important in the long-term control of basal blood pressure (BP). In this study, we examined whether the renin enhancer deficit alters the acute pressor response to emotional stress in mice. METHODS: Under fluothane anesthesia, wild-type (C57BL6, n=7) and the Ren-1c enhancer knockout (REKO, n=8) mice were implanted with telemetry devices to measure BP and locomotor activity. RESULTS: Resting BP in REKO mice (94+/-3 mm Hg) was lower than in wild-type mice (102+/-2 mm Hg). Shaker stress elicited prompt pressor (+25+/-2 mm Hg), tachycardic (+145+/-25 beats/min), and locomotor responses in wild-type mice. The BP and locomotor responses were decreased in REKO mice by 39%+/-12% (P=.03) and 64%+/-11% (P=.02), respectively, whereas the tachycardic response remained unchanged. Restraint stress increased BP by 27+/-1 mm Hg in wild-type mice. The BP response was attenuated in REKO mice by 21%+/-8% (P=.05), and this attenuation could not be ascribed to reduced locomotor activity during stress. Cardiovascular arousal associated with presentation and eating palatable food was similar in wild-type (+19+/-2 mm Hg and +174+/-21 beats/min) and REKO (+19+/-2 mm Hg and +147+/-17 beats/min) mice. The contractile response to the alpha-adrenoceptor agonist phenylephrine was reduced in aortas from REKO mice, whereas that to angiotensin II was not different between strains. CONCLUSIONS: The disrupted regulation of renin synthesis caused by the renin enhancer deficit in mice is associated with a selective reduction in BP reactivity to aversive stress, which may be mediated by multiple central and peripheral mechanisms.
Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Locomoção/fisiologia , Renina/sangue , Estresse Psicológico/fisiopatologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Ração Animal , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilefrina/farmacologia , Restrição Física , Fatores de Risco , Estresse Psicológico/sangue , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
Nitric oxide (NO) has been critically implicated in the central regulation of autonomic function. We recently found, however, that acute (up to 30min) blockade of NO synthase (NOS) in the rostral ventrolateral medulla (RVLM) inhibited sympathetic baroreflex transmission, without altering the cardiovascular response to psychological (air-jet) stress in rabbits. In the present study, we examined the effect of the later phase (1-3h) of NOS inhibition in the RVLM on the pressor and sympathetic responses to air-jet stress in conscious rabbits. Air-jet evoked a sustained increase in blood pressure (+14+/-2mmHg), heart rate (+37+/-9beats/min) and renal sympathetic nerve activity (+52+/-8%). Bilateral microinjection of a NOS inhibitor l-NAME (10nmol) into RVLM did not affect resting parameters or stress responses during the first 30min after injection. Conversely, in the later phase of NOS inhibition, the pressor, tachycardic and renal sympathetic responses to air-jet stress were reversibly attenuated by 48-72%. Microinjection of l-NAME outside the RVLM did not change stress responses. Microinjection of glutamate (3nmol) into the RVLM induced similar pressor effects before and after l-NAME (+30+/-6mmHg and +26+/-6mmHg, respectively). Microinjection of d-NAME altered neither stress responses nor pressor response to glutamate. These results suggest that NOS inhibition in the RVLM has a dual effect on the autonomic response to psychological stress. In the early phase, NOS inhibition has little impact on this response. However, in the later phase, NOS inhibition attenuates the stress response, perhaps via indirect mechanisms such as altering the local redox state.
Assuntos
Pressão Sanguínea/fisiologia , Bulbo/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Bulbo/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , CoelhosRESUMO
BACKGROUND: We have recently shown that microinjection of the superoxide dismutase mimetic tempol into the pressor region of the rostral ventrolateral medulla attenuates the cardiovascular response to mental (air-jet) stress in rabbits. In the present study, we examined the influence of tempol on the blood pressure (BP) and heart rate (HR) responses to stress in the key region of the hypothalamic defense area, the dorsomedial hypothalamus (DMH). METHODS: New Zealand White rabbits were implanted with guide cannulae for microinjection into the DMH. After 2 weeks of recovery, the cardiovascular response to air-jet stress was evaluated before and after bilateral injections of equimolar doses (20 nmol) of the superoxide scavengers tempol, tiron, or 3-carbamoyl proxyl (3-CP). RESULTS: Microinjection of superoxide scavengers into the DMH did not alter resting BP or HR. Air-jet stress evoked a sustained increase in BP (+16 +/- 2 mm Hg) and HR (+48 +/- 5 beats/min). Tempol attenuated the pressor and tachycardic responses to air-jet stress by 39% +/- 10% and 37% +/- 8%, respectively (P < .05), without altering stress-induced tachypnea. Similarly, tiron selectively decreased the BP and HR responses to stress by 33% +/- 8% and 53% +/- 13%, respectively (P < .05). Conversely, 3-CP, which is structurally close to tempol but has a lower superoxide scavenging activity, did not alter the cardiovascular stress response, and neither did vehicle. Microinjection of tempol or tiron just outside the DMH had little effect on stress responses. CONCLUSIONS: This study provides first published evidence that superoxide in the DMH is important in the regulation of acute hypertensive and tachycardic responses to mental stress.
Assuntos
Antioxidantes/farmacologia , Óxidos N-Cíclicos/farmacologia , Hipertensão/fisiopatologia , Hipotálamo Médio/efeitos dos fármacos , Hipotálamo Médio/fisiologia , Estresse Psicológico/fisiopatologia , Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/administração & dosagem , Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Animais , Antioxidantes/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Óxidos N-Cíclicos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Injeções Intraventriculares , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacologia , Coelhos , Marcadores de Spin , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/farmacologia , Taquicardia/fisiopatologiaRESUMO
OBJECTIVE: To determine the suitability of a new logistic curve fitting procedure to measure the diurnal rates of transition from the active to the asleep periods separately. METHOD: We applied this method to 24-h telemetry recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively), heart rate (HR) and locomotor activity of normotensive Sprague-Dawley rats (SDR) and spontaneously hypertensive rats (SHR). RESULTS: There was a similar pattern of higher awake and lower sleep values (16 +/- 1 mmHg SAP, 77 +/- 2 bpm HR and 40 +/- 2 units activity) in SHR. In SDR, awake-asleep differences were less for SAP (9 +/- 1 mmHg) but similar for HR (83 +/- 2 bpm). In SHR, while the blood pressure patterns were symmetrical, the rate of rise in activity and HR during arousal was more rapid than the rate of decline during the dark to light transition. By contrast in SDR, the arousal rate of increase in blood pressure and HR was much less than the rate of decline. Thus SHR have an exaggerated arousal surge in DAP compared with SDR. Double logistic provides a better fit than Cosinor or square wave and better estimates of day-night differences than partial Fourier. CONCLUSIONS: Analysis of 24-h recordings by a new logistic curve method reveals distinct asymmetric circadian patterns of cardiovascular and activity changes in rats. The greater surge in arousal blood pressure in SHR is not associated with differences in HR or activity changes and may be inherent to the underlying mechanisms contributing to the hypertension in SHR.
Assuntos
Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Hipertensão/fisiopatologia , Modelos Cardiovasculares , Animais , Determinação da Pressão Arterial , Feminino , Modelos Logísticos , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , TelemetriaRESUMO
In conscious, chronically instrumented rabbits (n = 7), airjet stress evoked increases in arterial pressure (AP) and renal sympathetic nerve activity (RSNA), which were greatest in the first 2 min (+ 10 mm Hg and + 127%, respectively), but then rapidly reached a stable level (+ 7 mm Hg and + 37%, respectively). Bilateral microinjection into the rostral ventrolateral medulla (RVLM) of an ionotropic excitatory amino acid (EAA) receptor antagonist kynurenate (10 nmol/200 nl) did not affect resting AP and RSNA, but reduced their initial peak responses to airjet by 80% and 52%, respectively, without altering the stable levels of these responses. By contrast, bilateral microinfusion of glutamate (2 nmol/20 nl/min) into the RVLM increased resting AP by 13 mm Hg, but did not alter the RSNA and AP responses to airjet stress. These results suggest that the RVLM is an essential site for conveying excitatory environmental influences to the sympathetic nervous system in conscious rabbits. The EAA receptors are critically important in initiating the pressor and sympathoexcitatory responses to acute emotional stress, but play relatively little role in the maintenance of these responses.
Assuntos
Bulbo/fisiopatologia , Receptores de Glutamato/metabolismo , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Doença Aguda , Animais , Feminino , Ácido Glutâmico/farmacologia , Ácido Cinurênico/farmacologia , Masculino , Bulbo/efeitos dos fármacos , Microinjeções , Estimulação Física , CoelhosRESUMO
RATIONALE: Vigilant scanning of the environment is a major risk assessment activity in many species. However, due to difficulties in its manual scoring, scanning has rarely been quantified in laboratory rodent studies. OBJECTIVES AND METHODS: We developed a novel method for automated measurement of vigilant scanning in mice, based on simultaneous tracking of an animal's nose- and center-points. The studied scanning parameters included the frequency and duration of scans and scanning (nose-point) speed. The sensitivity of these parameters to anxiolytic diazepam (1-2 mg/kg) and anxiogenic FG-7142 (5 mg/kg) was evaluated upon exposure to the context (conditioning chamber) before and 24 h after footshock. RESULTS: Scanning behavior was observed in all C57BL/6, 129xC57BL/6, and DBA/2 mice, as recurrent stationary episodes accompanied by observatory head movements. These episodes respectively comprised 28 ± 1%, 29 ± 1%, and 24 ± 2% of preexposure time. Diazepam dose-dependently decreased the scanning frequency and duration, without affecting the scanning speed. Fear conditioning increased freezing and inhibited other behaviors upon reexposure, with scanning being only marginally affected and still comprising 17 ± 2%, 16 ± 2%, and 19 ± 1% of reexposure time, respectively. Consequently, scanning accounted for most (DBA/2) or virtually all (C57BL/6 and 129xC57BL/6) gross motor activities upon reexposure. FG-7142 mirrored the effects of conditioning, inducing behavioral inhibition with scanning being least affected. CONCLUSIONS: Two-point tracking is effective for studying vigilant scanning in mice. Using this approach, we show that scanning is a key risk assessment activity in both unconditioned and conditioned mice; scanning is resistant to threat-induced behavioral inhibition and is highly sensitive to anxiolytic treatment.
Assuntos
Ansiedade/fisiopatologia , Atenção/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacologia , Atenção/efeitos dos fármacos , Comportamento Animal , Carbolinas/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Diazepam/administração & dosagem , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nariz , Fatores de Tempo , Gravação em VídeoRESUMO
BACKGROUND: Abnormal circadian variation of blood pressure (BP) increases cardiovascular risk. In this study, we examined the influence of angiotensin AT(1A) receptors on circadian BP variation, and specifically on its behavioral activity-related and -unrelated components. METHODS: BP and locomotor activity were recorded by radiotelemetry in AT(1A)-receptor knockout mice (AT(1A)(-/-)) and their wild-type controls (AT(1A)(+/+)) placed on a normal-salt diet (NSD) or high-salt diet (HSD, 3.1% Na). RESULTS: The 24-h BP was lower in AT(1A)(-/-) than AT(1A)(+/+) mice on a NSD (92 +/- 2 and 118 +/- 2 mm Hg, respectively), whereas the day-night BP difference (DeltaDNBP) was similar between groups (11 +/- 2 and 12 +/- 1 mm Hg, respectively). HSD increased BP by 20 +/- 2 mm Hg and DeltaDNBP by 7 +/- 1 mm Hg in AT(1A)(-/-) mice, without affecting these parameters much in AT(1A)(+/+) mice. The DeltaDNBP increase in AT(1A)(-/-) mice was caused by nondipping BP during the inactive late-dark period. Conversely, BP rise associated with circadian behavioral activation during the early dark period was not altered by HSD in AT(1A)(-/-) mice. The BP change associated with spontaneous ultradian activity-inactivity bouts was also similar between strains on HSD as was the BP rise associated with induced (cage-switch) behavioral activity. Ganglionic or alpha(1)-adrenergic blockade decreased BP in both strains; HSD did not affect this response in AT(1A)(-/-), but abolished it in AT(1A)(+/+) mice. CONCLUSIONS: AT(1A)-receptor deficiency, when combined with HSD, can increase circadian BP difference in mice. This increase is mediated principally by activity-unrelated factors, such as the nonsuppressibility of basal resting sympathetic tone by HSD, thus suggesting a form of salt-/volume-dependent hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/deficiência , Sódio na Dieta/farmacologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologiaRESUMO
We determined whether genetic deficiency of angiotensin II Type 1A (AT(1A)) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT(1A)(-/-) (85+/-2 mm Hg) than in AT(1A)(+/+) (112+/-2 mm Hg) mice; heart rate was not different between groups. Cage-switch stress for 90 minutes elevated blood pressure by +24+/-2 mm Hg in AT(1A)(+/+) and +17+/-2 mm Hg in AT(1A)(-/-) mice (P<0.01), and heart rate increased by +203+/-9 bpm in AT(1A)(+/+) and +121+/-9 bpm in AT(1A)(-/-) mice (P<0.001). Locomotor activation was less in AT(1A)(-/-) (3.0+/-0.4 U) than in AT(1A)(+/+) animals (6.0+/-0.4 U), but differences in blood pressure and heart rate persisted during nonactive periods. In contrast to wild-type mice, spontaneous baroreflex sensitivity was not inhibited by stress in AT(1A)(-/-) mice. After cage-switch stress, c-Fos immunoreactivity was less in the paraventricular (P<0.001) and dorsomedial (P=0.001) nuclei of the hypothalamus and rostral ventrolateral medulla (P<0.001) in AT(1A)(-/-) compared with AT(1A)(+/+) mice. Conversely, greater c-Fos immunoreactivity was observed in the medial nucleus of the amygdala, caudal ventrolateral medulla, and nucleus of the solitary tract (P<0.001) of AT(1A)(-/-) compared with AT(1A)(+/+) mice. Greater activation of the amygdala suggests that AT(1A) receptors normally inhibit the degree of stress-induced anxiety, whereas the lesser activation of the hypothalamus and rostral ventrolateral medulla suggests that AT(1A) receptors play a key role in autonomic cardiovascular reactions to acute aversive stress, as well as for stress-induced inhibition of the baroreflex.
Assuntos
Barorreflexo/fisiologia , Hipertensão/fisiopatologia , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Estresse Fisiológico/fisiologia , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Atividade Motora/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Taquicardia/metabolismo , Taquicardia/fisiopatologia , TelemetriaRESUMO
Pharmacological evidence suggests that angiotensin II type 1 (AT(1)) receptors are involved in the regulation of cardiovascular response to emotional stress and reinforcing effect of dietary salt on this response. In this study, we examined the effect of genetic deletion of AT(1A) receptors on the cardiovascular effects of stress and salt in mice. AT(1A) receptor knockout (AT(1A)(-/-)) and wild-type (AT(1A)(+/+)) mice were implanted with telemetry devices and placed on a normal (0.4%) or high (3.1%) salt diet (HSD). Resting blood pressure (BP) in AT(1A)(-/-) mice (84+/-3 mm Hg) was lower than in AT(1A)(+/+) mice (107+/-2 mm Hg). Negative emotional (restraint) stress increased BP by 33+/-3 mm Hg in AT(1A)(+/+) mice. This response was attenuated by 40% in AT(1A)(-/-) mice (18+/-3 mm Hg). Conversely, the BP increase caused by food presentation and feeding was similar in AT(1A)(-/-) (25+/-3 mm Hg) and AT(1A)(+/+) mice (26+/-3 mm Hg). HSD increased resting BP by 14+/-4 mm Hg in AT(1A)(-/-) mice without affecting it significantly in AT(1A)(+/+) mice. Under these conditions, the pressor response to restraint stress in AT(1A)(-/-) mice (30+/-3 mm Hg) was no longer different from that in wild-type animals (28+/-3 mm Hg). The BP response to feeding was not altered by HSD in either AT(1A)(-/-) or AT(1A)(+/+) mice (25+/-2 and 27+/-3 mm Hg, respectively). These results indicate that AT(1A) receptor deficiency leads to a reduction in BP reactivity to negative emotional stress, but not feeding. HSD can selectively reinforce the cardiovascular response to negative stress in AT(1A)(-/-) mice. However, there is little interaction between AT(1A) receptors, excess dietary sodium and feeding-induced cardiovascular arousal.
Assuntos
Pressão Sanguínea/fisiologia , Emoções/fisiologia , Receptor Tipo 1 de Angiotensina/genética , Sódio na Dieta/farmacologia , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Animais , Apetite , Área Sob a Curva , Comportamento Alimentar/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Restrição Física , TelemetriaRESUMO
Arginase upregulation is associated with aging and cardiovascular diseases. In this study we report on the cardiovascular phenotype of the arginase II knockout (KO) mouse. We demonstrate that vascular sensitivity and reactivity altered over time in these animals such that no influence on responses to vasoconstrictor activity was observed in 7-week-old KO mice, but dampened responses to norepinephrine and phenylephrine were observed by 10 and 15 weeks with Rho kinase influencing these effects in the 15-week-old animals. Despite these dampened vasoconstrictory responses, KO mice demonstrated increased mean arterial pressure from 8 weeks old. This hypertensive phenotype was associated with an increase in left ventricular weight, left ventricular systolic pressure, and diminished diastolic function. KO mice also show enhanced plasma norepinephrine turnover, suggesting an increased sympathetic outflow. In conclusion, our data suggest that global loss of arginase II activity results in hypertension. We suggest that this strain of mouse warrants further investigation as a potentially novel model of hypertension.
Assuntos
Arginase/metabolismo , Arginina/farmacologia , Hipertensão/genética , Hipertensão/fisiopatologia , Óxido Nítrico/metabolismo , Análise de Variância , Animais , Arginase/farmacologia , Barorreflexo , Velocidade do Fluxo Sanguíneo , Determinação da Pressão Arterial , Catecolaminas/sangue , Catecolaminas/metabolismo , Modelos Animais de Doenças , Feminino , Testes de Função Cardíaca , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Probabilidade , Distribuição Aleatória , Sensibilidade e Especificidade , Ureia/metabolismo , Resistência Vascular/genética , Resistência Vascular/fisiologia , Vasoconstrição/genética , Vasoconstrição/fisiologiaRESUMO
Cardiovascular reactivity, an abrupt increase in blood pressure and heart rate in response to emotional stress, is a risk factor for hypertension and heart disease. Brain angiotensin II (Ang II) type 1 (AT(1)) receptor is increasingly recognized as an important regulator of cardiovascular reactivity. Given that a wide variety of AT(1) receptor signalling pathways exists in neurones, the precise molecular mechanisms that underlie central cardiovascular actions of Ang II during emotional stress are yet to be determined. Growing evidence, however, indicates that reactive oxygen species, and in particular superoxide (.O(2)(-)), are important intracellular messengers of many actions of brain Ang II. In particular, studies employing microinjection of .O(2)(-) scavengers directly into the rostral ventrolateral medulla (RVLM) and dorsomedial hypothalamus of rabbits have shown that the activation of AT(1) receptor-.O(2)(-) signalling is required for full manifestation of the cardiovascular response to emotional stress. This role of .O(2)(-) appears to be highly specific, because .O(2)(-) scavengers in the RVLM do not alter the sympathoexcitatory response to baroreceptor unloading or sciatic nerve stimulation. The subcellular mechanisms for the stress-induced .O(2)(-) production are likely to include the activation of NADPH oxidase and are essentially independent of nitric oxide. This review summarizes current knowledge of redox-sensitive signalling mechanisms in the brain that regulate cardiovascular effects of stress. Additionally, it presents initial evidence that .O(2)(-) may be less important in the activation of central pressor pathways mediating cardiovascular arousal associated with appetitive events, such as food anticipation and feeding.
Assuntos
Encéfalo/metabolismo , Sistema Cardiovascular/fisiopatologia , Estresse Psicológico/fisiopatologia , Superóxidos/metabolismo , Animais , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Coelhos , Receptor Tipo 1 de Angiotensina/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA(A) agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56-63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT(1)-receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.
Assuntos
Angiotensina II/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Núcleo Hipotalâmico Dorsomedial/metabolismo , Ingestão de Alimentos/fisiologia , Estresse Psicológico/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/farmacologia , Ácido Caínico/farmacologia , Muscimol/farmacologia , Coelhos , Tetrazóis/farmacologiaRESUMO
The important cardiovascular regulator renin contains a strong in vitro enhancer 2.7 kb upstream of its gene. Here we tested the in vivo role of the mouse Ren-1c enhancer. In renin-expressing As4.1 cells stably transfected with Ren-1c promoter with or without enhancer, expression of linked beta-geo reporter, stable expression, and colony formation were dependent on the presence of the enhancer. We then generated mice carrying a targeted deletion of the enhancer (REKO mice) and found marked depletion of renin in renal juxtaglomerular and submandibular ductal cells, as well as hyperplasia of macula densa cells. Plasma creatinine was increased, but electrolytes were normal. Male REKO mice implanted with telemetry devices had 9 +/- 1 mm Hg lower mean arterial pressure (p < 0.001), which was partly normalized by a high NaCl diet. Locomotor activity was lower, and baroreflex sensitivity was normal. Markedly reduced mean arterial pressure variability in the midfrequency band indicated a contribution of reduced sympathetic vasomotor tone to the hypotension. In conclusion, the renin enhancer is critical for renin gene expression and physiological sequelae, including response to alteration in salt intake. The REKO mouse may be useful as a low renin expression model.
Assuntos
Regulação da Expressão Gênica , Renina/genética , Animais , Sistema Cardiovascular , Elementos Facilitadores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Genéticos , Regiões Promotoras Genéticas , Renina/química , Renina/metabolismo , Sais/farmacologia , Telemetria , TransfecçãoRESUMO
Nitric oxide (NO) deficiency in the rostral ventrolateral medulla (RVLM) has been implicated in impaired baroreflex control in hypertensive and heart failure animals. However, the role of local NO in normal baroreflex regulation remains unclear. This study aimed to examine the role of NO in tonic and baroreflex control of blood pressure (BP) in the RVLM of conscious rabbits. Microinjections of NO donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside (5 to 20 nmol), or NO itself (20 to 200 pmol) into the RVLM dose-dependently increased BP. Bilateral microinjections of an NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol), its inactive enantiomer D-NAME, or soluble guanylate cyclase (sGC) inhibitors, 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (ODQ, 250 pmol) and methylene blue (10 nmol), into the RVLM did not affect resting BP, heart rate, or renal sympathetic nerve activity (RSNA). However, L-NAME, methylene blue, and ODQ decreased RSNA baroreflex gain by 42% to 55%, whereas D-NAME did not affect this reflex. Co-microinjections of L-NAME and superoxide scavenger tempol (20 nmol) decreased RSNA baroreflex gain by 37+/-8%. Microinjections of a neuronal NOS (nNOS) inhibitor, 7-nitroindazole (500 pmol), into the RVLM decreased RSNA baroreflex gain by 42+/-12%, without altering resting BP, heart rate, or RSNA. Local administration of inducible NOS (iNOS) inhibitors, S-methylisothiourea (0.25 nmol) and aminoguanidine (0.25 and 2.5 nmol), affected neither resting nor baroreflex parameters. These results suggest that nNOS-derived NO facilitates sympathetic baroreflex transmission in the RVLM at least in part via a sGC-dependent, superoxide-independent mechanism. However, local nNOS and iNOS play little role in the tonic support of BP in conscious rabbits.
Assuntos
Barorreflexo/efeitos dos fármacos , Bulbo/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Barorreflexo/fisiologia , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/química , Microinjeções , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Coelhos , Solubilidade , Marcadores de SpinRESUMO
In this study, we examined the effect of excitatory amino acid (EAA) receptor blockade in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex in conscious rabbits. Rabbits were implanted with guide cannulas for bilateral microinjections into the RVLM (+2 to +3 mm from the obex, n = 8) or into the intermediate ventrolateral medulla (IVLM; 0 to +1 mm from the obex, n = 5) and with an electrode for measuring renal sympathetic nerve activity (RSNA). After 7 days of recovery, microinjection of the EAA receptor antagonist kynurenate (10 nmol) into the RVLM did not affect resting RSNA or arterial pressure. Kynurenate decreased the gain of the RSNA baroreflex by 53% but did not change the reflex range. By contrast, injection of kynurenate into the IVLM increased resting arterial pressure and RSNA by 27 mmHg and 88%, respectively, but did not alter the RSNA baroreflex gain or range. Pentobarbital sodium anesthesia attenuated the gain and range of the RSNA baroreflex by 78 and 40%, respectively. Under these conditions, microinjection of kynurenate into the RVLM did not cause any further change in the gain of this reflex. These results suggest that endogenous EAA neurotransmitters in the RVLM are important in modulating the sympathetic baroreflex in conscious rabbits. Anesthesia can mask the functional significance of EAAs in the RVLM in modulating the baroreflexes, which may explain why previous studies in anesthetized animals found no effect of blocking EAA receptors in the RVLM on sympathetic baroreflexes.
Assuntos
Barorreflexo/fisiologia , Rim/inervação , Bulbo/fisiologia , Receptores de Glutamato/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estado de Consciência , Feminino , Rim/efeitos dos fármacos , Ácido Cinurênico/farmacologia , Masculino , Bulbo/efeitos dos fármacos , Pentobarbital/farmacologia , Coelhos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
In this study, we examined the role of angiotensin type 1 (AT1) receptors in the rostral ventrolateral medulla (RVLM) in mediating the pressor action of emotional stress in conscious rabbits. Rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the RVLM and an electrode for measuring renal sympathetic nerve activity (RSNA). Airjet stress evoked increases in arterial pressure, heart rate, and RSNA, which reached a maximum (+9+/-1 mm Hg, +20+/-5 beats/min, and +93+/-17%, respectively) in the first 2 minutes of stress exposure. Then RSNA rapidly returned to prestress values, while arterial pressure and heart rate remained close to the maximal level until the conclusion of the 7-minute airjet exposure. Microinjections of the nonselective angiotensin receptor antagonist sarile (0.5 nmol, n=8) or AT1 receptor antagonists losartan (2 nmol, n=6) or candesartan (0.2 nmol, n=6) into the RVLM did not alter resting cardiovascular parameters. By contrast, the antagonists attenuated the sustained phase (4 to 7 minutes) of the pressor stress response by 55% to 89%. However, only sarile decreased the onset of this response. The antagonists affected neither the stress-induced tachycardia nor the pressor response to glutamate microinjections. Microinfusion of angiotensin II (4 pmol/min, n=8) into the RVLM did not change the pressor response to airjet stress but attenuated tachycardic response by 47%. Microinjections of vehicle did not alter the cardiovascular stress response. Sarile, losartan, and angiotensin II did not affect the sympathoexcitatory response to baroreceptor unloading. These results suggest that AT1 receptors in the RVLM are important in mediating the pressor effects of emotional stress in conscious rabbits.