RESUMO
Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of L-arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild-type (WT; n = 6) and endothelial cationic amino acid transporter-1 (CAT-1)-overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non-aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg/kg per day; 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11-12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively; P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg; P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT-1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.
Assuntos
Pressão Sanguínea/genética , Transportador 1 de Aminoácidos Catiônicos/genética , Células Endoteliais/metabolismo , Estresse Oxidativo/genética , Animais , Arginina/genética , Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Hipertensão/genética , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Vasoconstritores/farmacologiaRESUMO
The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter. The overall distribution correlated with that of the AT(1A)Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT(1A)R. Cre-recombinase expression in C1 neurons of AT(1A)R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT(1A)R in these neurons. Lentiviral-induced expression of wild-type AT(1A)Rs in C1 neurons of global AT(1A)R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT(1A)Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 ± 4 mmHg for AT(1A)R vs 10 ± 1 mmHg for GFP; p < 0.001), which was restored toward that of the wild-type group (28 ± 2 mmHg). This study demonstrates that AT(1A)R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.
Assuntos
Angiotensina II/fisiologia , Bulbo/metabolismo , Neurônios Motores/fisiologia , Pressorreceptores/fisiologia , Receptor Tipo 1 de Angiotensina/biossíntese , Estresse Psicológico/metabolismo , Animais , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios Motores/patologia , Receptor Tipo 1 de Angiotensina/agonistas , Estresse Psicológico/patologia , Estresse Psicológico/psicologiaRESUMO
Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin-angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1-7) [angiotensin-(1-7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1-7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Angiopatias Diabéticas/enzimologia , Peptidil Dipeptidase A/fisiologia , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apoptose , Biomarcadores/metabolismo , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Telemetria/métodosRESUMO
RATIONALE: Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7. OBJECTIVE: Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. METHODS AND RESULTS: C57Bl6, Ace2 knockout (KO), apolipoprotein E (ApoE) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic (ApoE KO) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-α. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10(-7) mol/L). CONCLUSIONS: Genetic Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Peptidil Dipeptidase A/genética , Vasculite/imunologia , Vasculite/fisiopatologia , Enzima de Conversão de Angiotensina 2 , Angiotensinas/sangue , Animais , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Pressão Sanguínea/fisiologia , Linhagem Celular Transformada , Células Endoteliais/patologia , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptidil Dipeptidase A/metabolismo , Vasculite/patologiaRESUMO
Recent evidence indicates that genetic hypertension in BPH/2J mice is sympathetically mediated, but these mice also have lower body weight (BW) and elevated locomotor activity compared with BPN/3J normotensive mice, suggestive of metabolic abnormalities. The aim of the present study was to determine whether hypertension in BPH/2J mice is associated with metabolic differences. Whole-body metabolic and cardiovascular parameters were measured over 24 h by indirect calorimetry and radiotelemetry respectively, in conscious young (10-13 weeks) and older (22-23 weeks) BPH/2J, normotensive BPN/3J and C57Bl6 mice. Blood pressure (BP) was greater in BPH/2J compared with both normotensive strains at both ages (P<0.01). Metabolic rate was greater in young BPH/2J compared with BPN/3J mice (P<0.01) but similar to C57Bl6 mice indicating that high metabolic rate is not necessarily related to the hypertension per say. The slope of the BP-metabolic rate relationship was comparable between BPH/2J and normotensive mice when adjusted for activity (P>0.1) suggesting differences in this relationship are not responsible for hypertension. EchoMRI revealed that percentage body composition was comparable in BPN/3J and BPH/2J mice (P>0.1) and both strains gained weight similarly with age (P=0.3). Taken together, the present findings indicate that hypertension in BPH/2J mice does not appear to be related to altered energy metabolism.
Assuntos
Composição Corporal/fisiologia , Metabolismo Energético/genética , Hipertensão/metabolismo , Atividade Motora/fisiologia , Animais , Metabolismo Basal/fisiologia , Pressão Sanguínea/fisiologia , Calorimetria Indireta , Hipertensão/genética , Masculino , CamundongosRESUMO
OBJECTIVE: BPH/2J hypertensive mice have an exaggerated sympathetic contribution to blood pressure (BP). Premotor sympathetic neurons within the rostroventrolateral medulla (RVLM) are a major source of sympathetic vasomotor tone and major site of action of the centrally acting sympatholytic agent, rilmenidine. The relative cardiovascular effect of rilmenidine in BPH/2J versus normotensive BPN/3J mice was used as an indicator of the involvement of the RVLM in the sympathetic contribution to hypertension in BPH/2J mice. METHODS: BPH/2J and BPN/3J mice were pre-implanted with telemetry devices to measure BP in conscious unrestrained mice. Rilmenidine was administered acutely (n=7-9/group), orally for 14 days, at a wide range of doses (n=5/group), and also infused intracerebroventricularly for 7 days (n=6/group). RESULTS: Acute intraperitoneal rilmenidine induced greater depressor and bradycardic responses in BPH/2J than BPN/3J mice (Pstrain<0.01). Both responses were reduced by atropine pre-treatment, with the remaining hypotensive effect being small and comparable between strains (Pstrain=1.0). This suggests that vagally induced reductions in cardiac output were responsible for the hypotension. Chronic intracerebroventricularly infused rilmenidine reduced BP from baseline marginally in BPH/2J mice during the dark (active) period (-6.5 ± 2 mmHg; P=0.006). Chronic orally administered rilmenidine (1-12 mg/kg per day) also had minimal effect on 24-h BP in both strains (P>0.16). CONCLUSION: The sympathetic vasomotor inhibitory effect of rilmenidine is minimal in both strains and similar in hypertensive BPH/2J and BPN/3J mice. Thus, hypertension in BPH/2J mice is not likely mediated by greater neuronal activity in the RVLM, and agents such as rilmenidine would be an ineffective treatment for this form of neurogenic hypertension.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Oxazóis/uso terapêutico , Sistema Nervoso Simpático/efeitos dos fármacos , Simpatomiméticos/uso terapêutico , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Atropina/administração & dosagem , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ritmo Circadiano , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/genética , Hipertensão/fisiopatologia , Infusões Intraventriculares , Infusões Subcutâneas , Injeções Intraperitoneais , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiopatologia , Camundongos , Atividade Motora/efeitos dos fármacos , Oxazóis/administração & dosagem , Restrição Física , Rilmenidina , Estresse Fisiológico , Sistema Nervoso Simpático/fisiopatologia , Simpatomiméticos/administração & dosagemRESUMO
OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 ± 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 ± 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20% (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and ~50% of stress-activated neurons in these regions also expressed GABAA receptors and ~45% were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.
Assuntos
Hipertensão/etiologia , Receptores de GABA-A/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Diazepam/administração & dosagem , Moduladores GABAérgicos/administração & dosagem , Bloqueadores Ganglionares/farmacologia , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos , Neuropeptídeo Y/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Tartarato de Pentolínio/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Restrição Física , Estresse FisiológicoRESUMO
BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7). Mice were preimplanted with radiotelemetry devices to measure 24-hour BP and cardiovascular responses to stress, before and 1 to 3 weeks after bilateral lesions of the MeAm. Baseline BP was 121±4 mm Hg in BPH/2J and 101±2 mm Hg in BPN/3J mice (Pstrain<0.001). MeAm lesions reduced BP by 11±2 mm Hg in BPH/2J mice (Plesion<0.001) but had no effect in BPN/3J mice. The hypotensive effect of lesions in BPH/2J mice was similar during both day and night, suggesting that the MeAm has tonic effects on BP, but the pressor response to stress was maintained in both strains. Midfrequency BP power was attenuated in both strains (Plesion<0.05) and the depressor responses to pentolinium after enalaprilat pretreatment was attenuated after lesions in BPH/2J mice (Plesion<0.001; n=3). These findings indicate that the MeAm provides a tonic contribution to hypertension in BPH/2J mice, which is independent of its role in stress reactivity or circadian BP influences.
Assuntos
Tonsila do Cerebelo/fisiologia , Modelos Animais de Doenças , Hipertensão/genética , Hipertensão/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Enalaprilato/farmacologia , Masculino , Camundongos , Camundongos Mutantes , Tartarato de Pentolínio/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , TelemetriaRESUMO
Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
Assuntos
Hipertensão/genética , MicroRNAs/genética , Sistema Renina-Angiotensina/fisiologia , Renina/sangue , Sistema Nervoso Simpático/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Enalaprilato/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Antagonistas Nicotínicos/farmacologia , Tartarato de Pentolínio/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
AIMS: The nucleus of the solitary tract (NTS) is important for cardiovascular regulation and contains angiotensin type 1A (AT1A) receptors. To assess its function, we examined the effect of expressing in AT1A receptors in the NTS of mice lacking these receptors. METHODS AND RESULTS: Bilateral microinjections of lentivirus expressing AT1A receptors (AT1Av mice, n = 6) or green fluorescent protein (GFPv, n = 8, control) under the control of the PRSx8 promotor were made into the NTS of AT1A receptors null mice (AT1A(-/-)). Telemetry devices recorded blood pressure (BP), heart rate (HR), and locomotor activity. Expression of AT1A receptors in the NTS increased BP by 11.2 ± 4 mmHg (P < 0.05) at 2 and 3 weeks, whereas GFPv mice remained at pre-injection BP. Ganglion blockade reduced BP to similar levels pre- and post-transfection in GFPv and AT1Av mice. Greater pressor responses to cage-switch stress were observed following AT1A receptors expression (+18 ± 2 mmHg pre- to +24 ± 2 mmHg post-virus, P < 0.05) with similar stress-induced pressor responses pre- and post-virus in GFPv mice. Pressor responses to restraint stress pre- and post-virus were similar in AT1Av but were 20% less post-GFPv (P < 0.001). The lack of attenuation in BP to restraint was associated with four-fold greater Fos-expression in AT1A receptors mice. AT1A receptors expression in the NTS did not alter baroreflex gain differently between groups. CONCLUSION: The results suggest that transfection of AT1A receptors on neurons in the NTS elevates BP independent of the SNS and pressor responses to aversive stimuli are associated with greater Fos-expression in forebrain regions. This study suggests a novel mechanism by which the NTS may modulate MAP in the long-term via AT1A receptors.
Assuntos
Pressão Arterial/fisiologia , Frequência Cardíaca/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Núcleo Solitário/fisiologia , Animais , Autorradiografia , Barorreflexo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Tartarato de Pentolínio/farmacologia , Proteínas Proto-Oncogênicas c-fos/análise , Estresse Psicológico/fisiopatologiaRESUMO
AIMS: The caudal ventrolateral medulla (CVLM) is important for autonomic regulation and is rich in angiotensin II type 1A receptors (AT(1A)R). To determine their function, we examined whether the expression of AT(1A)R in the CVLM of mice lacking AT(1A)R (AT(1A)(-/-)) alters baroreflex sensitivity and cardiovascular responses to stress. METHODS AND RESULTS: Bilateral microinjections into the CVLM of AT(1A)(-/-) mice of lentivirus with the phox-2 selective promoter (PRSx8) were made to express either AT(1A)R (Lv-PRSx8-AT(1A)) or green fluorescent protein (Lv-PRSx8-GFP) as a control. Radiotelemetry was used to record mean arterial pressure (MAP), heart rate (HR), and locomotor activity. Following injection of Lv-PRSx8-GFP, robust neuronal expression of GFP was observed with â¼60% of the GFP-positive cells also expressing the catecholamine-synthetic enzyme tyrosine hydroxylase. After 5 weeks, there were no differences in MAP or HR between groups, but the Lv-PRSx8-AT(1A)- injected mice showed reduced baroreflex sensitivity (-25%, P = 0.003) and attenuated pressor responses to cage-switch and restraint stress compared with the Lv-PRSx8-GFP-injected mice. Reduced MAP mid-frequency power during cage-switch stress reflected attenuated sympathetic activation (Pgroup × stress = 0.04). Fos-immunohistochemistry indicated greater activation of forebrain and hypothalamic neurons in the Lv-PRSx8-AT(1A) mice compared with the control. CONCLUSION: The expression of AT(1A)R in CVLM neurons, including A1 neurons, while having little influence on the basal blood pressure or HR, may play a tonic role in inhibiting cardiac vagal baroreflex sensitivity. However, they strongly facilitate the forebrain response to aversive stress, yet reduce the pressor response presumably through greater sympatho-inhibition. These findings outline novel and specific roles for angiotensin II in the CVLM in autonomic regulation.
Assuntos
Barorreflexo , Bulbo/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Estresse Psicológico , Animais , Autorradiografia , Pressão Sanguínea , Técnicas de Transferência de Genes , Frequência Cardíaca , Imuno-Histoquímica , Lentivirus , Masculino , Camundongos , Atividade Motora , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Restrição Física , TransgenesRESUMO
OBJECTIVE: Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin-angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice. METHODS: Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT 1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks. Pre-implanted telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity. RESULTS: MAP was reduced by losartan treatment in BPN/3J (-23 mmHg, P < 0.01) and in BPH/2J mice (-25 mmHg, P < 0.001), whereas HR was increased. Losartan had little effect on initial pressor responses to feeding or to stress, but did attenuate the sustained pressor response to cage-switch stress. During the active period, the hypotension to sympathetic blockade with pentolinium was greater in BPH/2J than BPN/3J (suggesting neurogenic hypertension), but was not affected by losartan. During the inactive period, a greater depressor response to pentolinium was observed in losartan-treated animals. CONCLUSION: The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/metabolismo , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Comportamento Animal , Pressão Sanguínea , Frequência Cardíaca , Humanos , Hipertensão/patologia , Losartan/uso terapêutico , Masculino , Camundongos , Pressão , Telemetria/métodosRESUMO
BACKGROUND: Schlager inbred hypertensive mice (BPH/2J) have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). The brain nuclei associated with the hypertension are also those involved in the integration of the cardiovascular responses to stress. Therefore, in the present study, we hypothesize that an increased contribution of the SNS in BPH/2J mice may culminate in a greater pressor response to stressful stimuli in these hypertensive mice than normotensive (BPN/3J) mice. METHODS: Male hypertensive BPH/2J and normotensive BPN/3J mice were implanted with telemetry devices and exposed to a series of behavioral "stress" tests including aversive stress (shaker, clean cage switch, and restraint) and nonaversive stress (feeding). RESULTS: Aversive stress caused a 67-88% greater pressor response in BPH/2J compared with BPN/3J mice. By contrast, the feeding-induced pressor response was not different between groups. All stressors induced tachycardia that was less in BPH/2J mice (feeding and restraint) and others were not different between groups (clean cage switch and shaker). CONCLUSIONS: These findings indicate that hypertension in BPH/2J mice is associated with greater pressor responsiveness to aversive stress but not to appetitive arousal. Thus, BPH/2J hypertensive mice may be a particularly relevant model for human hypertensive patients that overrespond to daily stressors.
Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Hipertensão/genética , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora , Restrição FísicaRESUMO
Early studies indicate that the hypertension observed in the Schlager inbred mouse strain may be attributed to a neurogenic mechanism. In this study, we examined the contribution of the sympathetic nervous system in maintaining hypertension in the BPH/2J mouse and used c-Fos immunohistochemistry to elucidate whether neuronal activation in specific brain regions was associated with waking blood pressure. Male hypertensive (BPH/2J; n=14), normotensive (BPN/3J; n=18), and C57/Bl6 (n=5) mice were implanted with telemetry devices, and after 10 days of recovery, recordings of blood pressure, heart rate, and locomotor activity were measured to determine circadian variation. Mean arterial pressure was higher in BPH/2J than in BPN/3J or C57/Bl6 mice (P<0.001), and BPH/2J animals showed exaggerated day-night differences (17+/-2 versus 6+/-1 mm Hg in BPN/3J or +8+/-2 mm Hg in C57/Bl6 mice; P<0.001). Acute sympathetic blockade with pentolinium (7.5 mg/kg IP) during the active and inactive phases reduced blood pressure to comparable levels in BPH/2J and BPN/3J mice. The number of c-Fos-labeled cells was greater in the amygdala (+180%; P<0.01), paraventricular nucleus (+110%; P<0.001), and dorsomedial hypothalamus (+48%; P<0.001) in the active (hypertensive) phase in BPH/2J compared with BPN/3J mice. The level of neuronal activation was mostly similar in these regions in the inactive phase. Of all of the regions studied, neuronal activation in the medial amygdala, as detected by c-Fos, was highly correlated to mean arterial pressure (r=0.98). These findings indicate that the hypertension is largely attributable to sympathetic nervous system activity, possibly generated through greater levels of arousal regulated by neurons located in the medial amygdala.