RESUMEN
OBJECTIVE: This randomized controlled clinical trial evaluated the whitening efficacy, tooth sensitivity (TS), and volunteers' satisfaction following the use of activated charcoal powder and toothpaste. METHODS: Fifty-six volunteers were randomly allocated into 4 groups (n = 14) according to a 14-day toothbrushing or whitening treatment with activated charcoal powder (ACPW), activated charcoal toothpaste (ACT), regular fluoridated toothpaste (RT), and 10 % carbamide peroxide (CP). Objective (ΔE00) and subjective (ΔSGU) color and whiteness index (ΔWID) changes were calculated. Patients self-reported the risk and intensity of TS using a visual analogue scale and the volunteer's satisfaction was determined by a questionnaire. Color assessments were analyzed by Kruskal-Wallis followed by Dwas-Steel-Crithlow-Fligner, and absolute TS risk and volunteer's satisfaction by Fisher exact test (p < 0.05). RESULTS: ACPW and ACT promoted similar effects in ΔE00, ΔSGU, and ΔWID to that observed for RT. No significant difference was found in terms of TS risk intensity. TS risk became high after 7 and 14 days, with higher TS prevalence in CP. Volunteers reported that ACPW exhibited the lowest ease-of-use, comfort, and whitening satisfaction among groups (p < 0.05). CONCLUSION: Activated charcoal-based products presented a minor and unsatisfactory whitening effect while CP resulted in optimal tooth whitening and the highest level of satisfaction among volunteers. Risk was higher from 7 days onwards and was more pronounced in the CP. CLINICAL RELEVANCE: Based on the whitening effect and patient satisfaction, this controlled-randomized clinical evidence supports that the use of activated charcoal-based products should be discouraged.
Asunto(s)
Sensibilidad de la Dentina , Blanqueamiento de Dientes , Humanos , Peróxido de Hidrógeno/uso terapéutico , Carbón Orgánico/uso terapéutico , Pastas de Dientes/uso terapéutico , Polvos , Método Simple Ciego , Blanqueamiento de Dientes/métodos , Peróxido de Carbamida , Sensibilidad de la Dentina/tratamiento farmacológicoRESUMEN
Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
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Presión Sanguínea/genética , Presión Sanguínea/fisiología , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/fisiología , Sistema Simpatoadrenal/fisiología , Simportadores/genética , Simportadores/fisiología , Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/fisiología , Animales , Restricción Calórica , Catecolaminas/biosíntesis , Línea Celular , Células Cromafines/fisiología , Transportadores de Ácidos Dicarboxílicos/deficiencia , Expresión Génica , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Longevidad/genética , Longevidad/fisiología , Malatos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Cardiovasculares , Actividad Motora/genética , Actividad Motora/fisiología , Piridinas/farmacología , Simportadores/deficienciaRESUMEN
AIMS: B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive. METHODS AND RESULTS: Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 µM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of 3H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca2+ current (n = 6) and intracellular Ca2+ transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9). CONCLUSION: C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation.
Asunto(s)
Corazón/inervación , Péptido Natriurético Tipo-C/metabolismo , Receptores del Factor Natriurético Atrial/metabolismo , Sistema Nervioso Simpático/metabolismo , Transmisión Sináptica , Animales , Presión Arterial , Señalización del Calcio , Predisposición Genética a la Enfermedad , Frecuencia Cardíaca , Hipertensión/genética , Hipertensión/metabolismo , Hipertensión/fisiopatología , Norepinefrina/metabolismo , Fenotipo , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores del Factor Natriurético Atrial/genética , Ganglio Estrellado/metabolismo , Sistema Nervioso Simpático/fisiopatología , Sístole , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
BACKGROUND AND PURPOSE: Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. METHODS: The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. RESULTS: Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung. CONCLUSIONS: Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.
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Inmunidad Innata/inmunología , Infarto de la Arteria Cerebral Media/inmunología , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Neumonía/inmunología , Animales , Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Líquido del Lavado Bronquioalveolar/microbiología , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/inmunología , Inmunidad Innata/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/microbiología , Macrófagos Alveolares/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Nervioso Parasimpático/inmunología , Parasimpaticomiméticos/farmacología , Neumonía/microbiología , Receptores Nicotínicos/genética , Receptores Nicotínicos/inmunología , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Transducción de Señal , Accidente Cerebrovascular/inmunología , VagotomíaRESUMEN
Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key functional and neuropathological features of multiple system atrophy (MSA). Whether or not these mice develop severe autonomic failure, which is a key feature of human MSA, remains unknown. We explored cardiovascular autonomic regulation using long-term blood pressure (BP) radiotelemetry and pharmacological testing. We instrumented 12 MBP1-α-syn mice and 11 wild-type mice aged 9 months for radiotelemetry. Animals were tested with atropine, metoprolol, clonidine, and trimethaphan at 9 and 12 months age. We applied spectral and cross-spectral analysis to assess heart rate (HR) and BP variability. At 9 months of age daytime BP (transgenic: 101 ± 2 vs. wild type: 99 ± 2 mmHg) and HR (497 ± 11 vs. 505 ± 16 beats/min) were similar. Circadian BP and HR rhythms were maintained. Nighttime BP (109 ± 2 vs. 108 ± 2 mmHg) and HR (575 ± 15 vs. 569 ± 14 beats/min), mean arterial BP responses to trimethaphan (-21 ± 8 vs. -10 ± 5 mmHg, P = 0.240) and to clonidine (-8 ± 3 vs. -5 ± 2 mmHg, P = 0.314) were similar. HR responses to atropine (+159 ± 24 vs. +146 ± 22 beats/min), and to clonidine (-188 ± 21 vs. -163 ± 33 beats/min) did not differ between strains. Baroreflex sensitivity (4 ± 1 vs. 4 ± 1 msec/mmHg) and HR variability (total power, 84 ± 17 vs. 65 ± 21 msec²) were similar under resting conditions and during pharmacological testing. Repeated measurements at 12 months of age provided similar results. In mice, moderate overexpression of human alpha-synuclein in oligodendrocytes is not sufficient to induce overt autonomic failure. Additional mechanisms may be required to express the autonomic failure phenotype including higher levels of expression or more advanced age.
RESUMEN
Natural disturbances in tropical forests modify the availability and quality of resources and alter the patterns of bird distribution. These environmental changes increase the metabolic rate and disrupt the redox balance promoting oxidative stress. This study aimed to compare the abundance of Willisornis poecilinotus between gaps and the understory of a forest with undisturbed canopy at Caxiuanã National Forest. The abundance was correlated with vegetation heights. The oxidative stress and the stress promoting factors were determined in both sites of sampling. We captured 81 specimens of W. poecilinotus. The number of captures was high in gaps. The specimens sampled at gaps showed high levels of oxidative stress. The biomarkers of oxidative stress were significantly correlated in gaps. The variability of oxidative stress and oxidative damage were explained only by site of sampling. These results suggest that gaps are stressors sites to W. poecilinotus, which probably can be due to an increase of metabolic rate to deal with new flight strategies of foraging and avoid predation.
Os distúrbios naturais nas florestas tropicais contribuem para heterogeneidade do habitat, alterando os padrões de distribuição das aves. Estas alterações no ambiente elevam o metabolismo, promovendo distúrbios no balanço redox, e em consequência o estresse oxidativo. O objetivo deste estudo foi comparar a abundância de Willisornis poecilinotus entre clareiras e sub-bosque de dossel intacto associando-a a altura da vegetação na Floresta Nacional de Caxiuanã. A seguir, foi avaliado o estresse oxidativo e os fatores promotores de estresse foram determinados nos ambientes selecionados. Foram capturados 81 espécimes de W. poecilinotus. O número de capturas foi superior nas clareiras, quando comparado ao sub-bosque de dossel contínuo. Os espécimes capturados nas clareiras apresentaram índices de estresse oxidativo significativamente elevados. Foi observada correlação significativa entre os marcadores de estresse oxidativo nas clareiras. As variações do biomarcador de dano oxidativo e do estresse oxidativo foram explicadas somente pelo sítio de amostragem. Estes resultados sugerem que as clareiras são sítios de estímulos estressores para W. poecilinotus o que provavelmente resulta da maior demanda metabólica para novas estratégias de forrageio e para evitar a predação.
RESUMEN
The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.
Asunto(s)
Imidazoles/farmacología , Erección Peniana/efectos de los fármacos , Proteínas Proto-Oncogénicas/agonistas , Receptores Acoplados a Proteínas G/agonistas , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Animales , Imidazoles/antagonistas & inhibidores , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/farmacología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/fisiología , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
The present study describes aspects of feeding ecology of Dash-dot Tetra Hemigrammus belottii (Characiformes: Characidae) collected in the Urucu River basin in Coari, Amazonas (Brazil), aims to respond the following question: What is the influence of hydrological periods (dry and wet) and spatial distribution in the diet of H. belottii? The specimens were collected between 2006 and 2009 in seven streams in the Urucu basin using standard capture methods. Their stomachs were removed for diet composition analyses. The alimentary items were weighed and identified for subsequent analyzes related to feeding intensity by repletion index (RI%) and importance by alimentary index (AIi%). A total of 227 specimens were analyzed, with a mean standard length of 16.5±5.6 mm. The RI% values indicated that H. belottii fed more intensively during the dry season. The principal items in the diet were Formicidae (IAi% = 69.6), fragments of allochthonous exoskeleton (IAi% = 17.7), and Coleoptera (IAi% = 6.0). The composition of the diet did not vary significantly between seasons or among habitats, which may be related to the abundance of the items exploited by the species throughout the year. Hemigrammus belottii showed a generalist insectivore feeding habits which was mainly composed by allochthonous item.
O presente estudo descreve a dieta da espécie Hemigrammus belottii (Characiformes: Characidae) coletados na bacia do Rio Urucu no município de Coari, Amazonas, (Brasil), buscando responder o seguinte questionamento: Qual a influência dos períodos hidrológicos (seco e chuvoso) e da distribuição espacial na dieta de H. belottii? Os espécimes tiveram seus estômagos retirados e os itens alimentares pesados e identificados para posteriores análises relacionadas à intensidade alimentar, pelo Índice de Repleção (IR%) e pelo índice de importância alimentar (IAi%). Foi analisado um total de 227 espécimes, com comprimento padrão médio de 16,54 mm ± 5,6 mm. Baseado no IR% verificou-se para H. belottii uma maior intensidade alimentar durante o período da seca. A dieta da espécie foi composta predominantemente pelos itens Formicidae (IAi% = 69,6), fragmento de exoesqueleto alóctone (IAi% = 17,7) e Coleoptera (IAi% = 6,0), com sua composição se mostrando independente de períodos hidrológicos e de sua distribuição espacial, que pode ser atribuído à alta disponibilidade de itens alimentares utilizados pela espécie durante o ano todo. De um modo geral H. belottii evidenciou um hábito alimentar insetívoro generalista, com predomínio de itens de origem alóctone.
RESUMEN
Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL(-/-) and SPL(+/+) mice with telemetric devices and applied AngII (1.0 mg kg(-1) day(-1), minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50 mg kg(-1) day(-1), gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL(-/-) and in SPL(+/+) mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL(+/+) mice. Compared with SPL(+/+) mice, SPL(-/-) mice showed a greater increase in daytime BP with AngII (19.2 ± 0.8 vs. 13.5 ± 1.6 mmHg, p < 0.05). SPL(-/-) showed a greater depressor response to valsartan. BP and heart rate decreased more with trimethaphan and metoprolol in AngII-treated SPL(-/-) than in AngII-treated SPL(+/+) mice. SPL(-/-) mice responded more to icv AngII. Furthermore, brainstem AT1-R and AngII type 2 receptor (AT2-R) expression was reduced in SPL(-/-) mice. AngII treatment normalized AT1-R and AT2-R expression levels. In summary, our findings suggest that SPL restrains AngII-mediated sympathetic nervous system activation. SPL is a hitherto unrecognized molecule with regard to central blood pressure control and may pave the way to novel strategies for the treatment of hypertension.
Asunto(s)
Angiotensina II/fisiología , Presión Sanguínea/fisiología , Proteínas de Microfilamentos/fisiología , Proteínas del Tejido Nervioso/fisiología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Encéfalo/metabolismo , Regulación de la Expresión Génica , Frecuencia Cardíaca , Masculino , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismo , Vasopresinas/genética , Vasopresinas/metabolismoRESUMEN
We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure-independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-ß (ERß) protects the females from left ventricular hypertrophy, we treated male and female ERß-deficient (ERß(-/-)) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (+16%) heart weight/tibia length ratios compared with WT females (+7%) at 6 weeks. In ERß(-/-) mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (+23%), even greater than ERß(-/-) males (+10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ERß(-/-) females developed dilative left ventricular hypertrophy. The hypertrophic response in female ERß(-/-) mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ERß(+/+) females showed robust protective p38 and extracellular signal-regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin Aß expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ERß(-/-) mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ERß agonist. We conclude that a functional ERß is essential for inducing adaptive p38 and extracellular signal-regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies.
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Desoxicorticosterona/farmacología , Receptor beta de Estrógeno/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Mineralocorticoides/farmacología , Caracteres Sexuales , Análisis de Varianza , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Western Blotting , Ecocardiografía , Femenino , Citometría de Flujo , Hidralazina/farmacología , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Inmunohistoquímica , Masculino , Ratones , Miocardio/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacosRESUMEN
A-kinase anchoring proteins (AKAPs) tether protein kinase A (PKA) and other signaling proteins to defined intracellular sites, thereby establishing compartmentalized cAMP signaling. AKAP-PKA interactions play key roles in various cellular processes, including the regulation of cardiac myocyte contractility. We discovered small molecules, 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives, which inhibit AKAP-PKA interactions in vitro and in cultured cardiac myocytes. The molecules bind to an allosteric site of regulatory subunits of PKA identifying a hitherto unrecognized region that controls AKAP-PKA interactions. FMP-API-1 also activates PKA. The net effect of FMP-API-1 is a selective interference with compartmentalized cAMP signaling. In cardiac myocytes, FMP-API-1 reveals a novel mechanism involved in terminating ß-adrenoreceptor-induced cAMP synthesis. In addition, FMP-API-1 leads to an increase in contractility of cultured rat cardiac myocytes and intact hearts. Thus, FMP-API-1 represents not only a novel means to study compartmentalized cAMP/PKA signaling but, due to its effects on cardiac myocytes and intact hearts, provides the basis for a new concept in the treatment of chronic heart failure.
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Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Miocitos Cardíacos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Sistemas de Mensajero Secundario/fisiología , Proteínas de Anclaje a la Quinasa A/genética , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/genética , Animales , Enfermedad Crónica , AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Masculino , Contracción Miocárdica/efectos de los fármacos , Ratas , Ratas Endogámicas WKY , Sistemas de Mensajero Secundario/efectos de los fármacosRESUMEN
Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.
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Leptina/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Presión Sanguínea/fisiología , Enalapril/farmacología , Masculino , Ratones , Ratones Obesos , Ratones Transgénicos , Obesidad/metabolismo , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/genética , ARN Mensajero/metabolismo , Sistema Renina-Angiotensina/fisiologíaRESUMEN
The leptin-deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and of the renin-angiotensin system in the cardiovascular abnormalities observed in obesity using a model lacking leptin. To this purpose, we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice, while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of angiotensin-converting enzyme by enalapril treatment had similar effects, prior to the loss of weight. These findings suggest that the renin-angiotensin system is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice and support a role of this interplay in the pathogenesis of obesity, hypertension, and metabolic syndrome.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Obesidad/genética , Angiotensina II/metabolismo , Animales , Barorreflejo , Modelos Animales de Enfermedad , Análisis de Fourier , Hipertensión/sangre , Hipertensión/metabolismo , Leptina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-AngiotensinaRESUMEN
OBJECTIVE: Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) -/- and +/+ mice. METHODS AND RESULTS: EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion. However, the EDHF responses were abolished by catalase and by apamin/charybdotoxin (ChTx), but not by iberiotoxin, nor by the cytochrome P450 inhibitor PPOH. All four EETs (order of potency: 8,9-EET >14,15-EET approximately 5,6-EET >11,12-EET) and all 4 dihydroxy derivatives (14,15-DHET approximately 8,9-DHET approximately 11,12-DHET >5,6-DHET) produced dose-dependent vasodilation. Endothelial removal or L-NAME blocked 8,9-EET and 14,15-DHET-dependent dilations. The effects of apamin/ChTx were minimal. 8,9-EET and 14,15-DHET induced NO production in endothelial cells. ADU (100 microg/mL in drinking water) lowered blood pressure in angiotensin II-infused hypertension, but not in L-NAME-induced hypertension. Blood pressure and EDHF responses were similar in L-NAME-treated sEH +/+ and -/- mice. CONCLUSIONS: Our data indicate that the EDHF response in mice is caused by hydrogen peroxide, but not by P450 eicosanoids. Moreover, P450 eicosanoids are vasodilatory, largely through their ability to activate endothelial NO synthase (eNOS) and NO release.
Asunto(s)
Arterias/fisiología , Sistema Enzimático del Citocromo P-450/metabolismo , Eicosanoides/fisiología , Tono Muscular/fisiología , Óxido Nítrico/fisiología , Vasodilatación/fisiología , Animales , Arterias/efectos de los fármacos , Factores Biológicos/fisiología , Presión Sanguínea/efectos de los fármacos , Catalasa/metabolismo , Caribdotoxina/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Eicosanoides/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Epóxido Hidrolasas/deficiencia , Epóxido Hidrolasas/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos , Ratones Noqueados , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , NG-Nitroarginina Metil Éster/farmacología , Péptidos/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Leptin receptor-deficient db/db mice develop human type 2 diabetes mellitus, hypertension, and obesity with disrupted circadian blood pressure (BP) rhythm. Whether leptin is the sole mechanism mediating autonomic imbalance and hypertension is unclear. To explore this notion further, we measured BP by radiotelemetry combined with fast Fourier transformation and assessed autonomic function pharmacologically before and after renin-angiotensin system blockade with enalapril. The resting period BP (117+/-3 versus 108+/-1.0 mm Hg) and heart rate (HR; 488+/-12 versus 436+/-8 bpm) were higher in db/db mice compared with db/+ mice. BP and HR amplitudes were lower in db/db mice compared with db/+ mice. BP response to trimetaphan (-43+/-5 versus -27+/-3 mm Hg) and HR response to metoprolol (-59+/-12 versus -5+/-4 bpm) were greater in db/db mice than in db/+ mice. The HR response to atropine was blunted in db/db mice (59+/-17 versus 144+/-24 bpm), as were baroreflex sensitivity and HR variability. Enalapril improved autonomic regulation in db/db mice. Stimulation of central alpha-2 adrenoreceptors enhanced both parasympathetic HR control and baroreflex sensitivity in db/db mice. We suggest that functional, rather than structural, alpha-2 adrenoceptor changes and the renin-angiotensin system are involved in the increased sympathetic and decreased parasympathetic tones in db/db mice. Our data suggest that db/db mice exhibit features found in humans with type 2 diabetic autonomic neuropathy and could serve as a model for this complication.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/etiología , Corazón/fisiopatología , Hipertensión/complicaciones , Receptores de Leptina/genética , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Enalapril/farmacología , Corazón/inervación , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MutaciónRESUMEN
Spinophilin controls intensity/duration of G protein-coupled receptor signaling and thereby influences synaptic activity. We hypothesize that spinophilin affects blood pressure through central mechanisms. We measured blood pressure and heart rate in SPL-deficient (SPL(-/-)), heterozygous SPL-deficient (SPL(+/-)), and wild-type (SPL(+/+)) mice by telemetry combined with fast Fourier transformation. We also assessed peripheral vascular reactivity and performed echocardiography. SPL(-/-) had higher mean arterial pressure than SPL(+/-) and SPL(+/+) (121+/-2, 112+/-1, and 113+/-1 mm Hg). Heart rate was inversely related to spinophilin expression (SPL(-/-) 565+/-0.4, SPL(+/-) 541+/-5, SPL(+/+) 525+/-8 bpm). The blood pressure response to prazosin, trimethapane, and the heart rate response to metoprolol were stronger in SPL(-/-) than SPL(+/+) mice, whereas heart rate response to atropine was attenuated in SPL(-/-). Mesenteric artery vasoreactivity after angiotensin II, phenylephrine, and the thromboxane mimetic (U46619) as well as change in heart rate, stroke volume, and cardiac output after dobutamine were similar in SPL(-/-) and SPL(+/+). Baroreflex sensitivity was attenuated in SPL(-/-) compared with SPL(+/-) and SPL(+/+), which was confirmed by pharmacological testing. Heart rate variability parameters were attenuated in SPL(-/-) mice. We suggest that an increase in central sympathetic outflow participates in blood pressure and heart rate increases in SPL(-/-) mice. The elevated blood pressure in SPL(-/-) mice was associated with attenuated baroreflex sensitivity and decreased parasympathetic activity. Our study is the first to show a role for the spinophilin gene in blood pressure regulation.
Asunto(s)
Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiología , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Ecocardiografía de Estrés , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/inervación , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilefrina/farmacología , Prazosina/farmacología , Transducción de Señal , Vasoconstricción/efectos de los fármacos , Función VentricularRESUMEN
We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy and 1% saline in drinking water) and focused on calcineurin signaling. We excluded confounding effects of blood pressure elevation or sex-related blood pressure differences by treating DOCA-salt mice with hydralazine (250 mg/L in drinking water). We found that directly measured mean arterial blood pressure was lowered to control values with hydralazine and corroborated this finding in separate mouse groups with radiotelemetry. Male mice were more responsive to DOCA-salt-related effects. They developed more left ventricular hypertrophy and more renal hypertrophy after 6 weeks of DOCA-salt+hydralazine compared with female mice. In hearts, transcripts for calcineurin Abeta and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Abeta, as indicated by diminished phosphorylation of NFATc2 in male mice, accounted for this sex-specific difference. Stretch-related, inflammatory, and profibrotic responses were also accentuated in male mice, as shown by higher transcript levels of atrial natriuretic peptide, monocyte chemoattractant protein-1, and transforming growth factor-beta. Our results support sex-specific regulation of the calcineurin pathway in response to largely blood pressure-independent mineralocorticoid action. We suggest that sex-specific calcineurin activation determines the maladaptive cardiac and renal hypertrophic responses and accompanying organ injury in male mice.
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Presión Sanguínea/efectos de los fármacos , Desoxicorticosterona/farmacología , Hipertensión/fisiopatología , Mineralocorticoides/farmacología , Caracteres Sexuales , Animales , Antihipertensivos/farmacología , Calcineurina/metabolismo , Ecocardiografía , Femenino , Hidralazina/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/metabolismo , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Cloruro de Sodio Dietético/farmacologíaRESUMEN
Non-Obese Diabetic (NOD) mice show profound pathomorphological changes in sympathetic ganglia during the development of type 1 diabetes mellitus. We tested the hypothesis that NOD mice represent an experimental model to investigate cardiovascular changes seen in humans with diabetic autonomic neuropathy. Blood glucose (BG) levels were measured once a week. Diabetes mellitus was diagnosed as BG levels exceeded 250 mg/dl twice. NOD mice that did not become diabetic served as control group. Blood pressure (BP) and heart rate (HR) were monitored by telemetry and baroreflex sensitivity (BRS) was calculated with the sequence method or with cross spectral analysis. The measurements were obtained before onset of diabetes and during the 4th week of diabetes. The onset of diabetes was accompanied by a continuous decline in HR (615+/-14 vs. 498+/-23 bpm), whereas BP values remained stable (108+/-2 vs. 111+/-2 mm Hg). The circadian HR rhythm increased in diabetic NOD mice. BRS was higher in diabetic NOD mice than in controls. Atropine reduced BRS more profoundly in diabetic mice compared to non-diabetic mice. Despite pathomorphological similarities of the diabetic autonomic neuropathy between patients with diabetes and diabetic NOD mice, the changes in blood pressure regulation are different. In conclusion the use of diabetic NOD mice as a functional model for human diabetes may be questioned.
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Arritmias Cardíacas/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Neuropatías Diabéticas/fisiopatología , Corazón/inervación , Corazón/fisiopatología , Antagonistas Adrenérgicos beta/farmacología , Animales , Arritmias Cardíacas/etiología , Enfermedades del Sistema Nervioso Autónomo/etiología , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Glucemia/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Bradicardia/etiología , Bradicardia/fisiopatología , Trastornos Cronobiológicos/etiología , Trastornos Cronobiológicos/fisiopatología , Modelos Animales de Enfermedad , Femenino , Ganglios Simpáticos/fisiopatología , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Ratones , Ratones Endogámicos NOD , Antagonistas Muscarínicos/farmacología , Reproducibilidad de los Resultados , TelemetríaRESUMEN
Mas codes for a G protein-coupled receptor that is implicated in angiotensin-(1-7) signaling. We studied the cardiovascular phenotype of Mas-deficient mice backcrossed onto the FVB/N genetic background using telemetry and found that they exhibit higher blood pressures compared with controls. These Mas(-/-) mice also had impaired endothelial function, decreased NO production, and lower endothelial NO synthase expression. Reduced nicotinamide-adenine dinucleotide phosphate oxidase catalytic subunit gp91(phox) protein content determined by Western blotting was higher in Mas(-/-) mice than in controls, whereas superoxide dismutase and catalase activities were reduced. The superoxide dismutase mimetic, Tempol, decreased blood pressure in Mas(-/-) mice but had a minimal effect in control mice. Our results show a major cardiovascular phenotype in Mas(-/-) mice. Mas-deletion results in increased blood pressure, endothelial dysfunction, and an imbalance between NO and reactive oxygen species. Our animals represent a promising model to study angiotensin-(1-7)-mediated cardiovascular effects and to evaluate Mas agonistic compounds as novel cardioprotective and antihypertensive agents based on their beneficial effects on endothelial function.
Asunto(s)
Presión Sanguínea , Endotelio Vascular/fisiopatología , Proteínas Proto-Oncogénicas/deficiencia , Receptores Acoplados a Proteínas G/deficiencia , Vasodilatación , Animales , Antioxidantes/farmacología , Aorta/metabolismo , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Western Blotting , Óxidos N-Cíclicos/farmacología , Masculino , Glicoproteínas de Membrana , Ratones , Ratones Endogámicos , Ratones Noqueados , NADPH Oxidasa 2 , NADPH Oxidasas , Óxido Nítrico/metabolismo , Estrés Oxidativo , Fenotipo , Proto-Oncogenes Mas , Especies Reactivas de Oxígeno/metabolismo , Marcadores de SpinRESUMEN
The antithrombotic effect of angiotensin(Ang)-(1-7) has been reported, but the mechanism of this effect is not known. We investigated the participation of platelets and receptor Mas-related mechanisms in this action. We used Western blotting to test for the presence of Mas protein in rat platelets and used fluorescent-labeled FAM-Ang-(1-7) to determine the specific binding for Ang-(1-7) and its displacement by the receptor Mas antagonist A-779 in rat platelets and in Mas(-/ -) and Mas(+/+) mice platelets. To test whether Ang-(1-7) induces NO release from platelets, we used the NO indicator DAF-FM. In addition we examined the role of Mas in the Ang-(1-7) antithrombotic effect on induced thrombi in the vena cava of male Mas(-/ -) and Mas(+/+) mice. The functional relevance of Mas in hemostasis was evaluated by determining bleeding time in Mas(+/+) and Mas(-/ -) mice. We observed the presence of Mas protein in platelets, as indicated by Western Blot, and displacement of the binding of fluorescent Ang-(1-7) to rat platelets by A-779. Furthermore, in Mas(+/+) mouse platelets we found specific binding for Ang-(1-7), which was absent in Mas(-/ -) mouse platelets. Ang-(1-7) released NO from rat and Mas(+/+) mouse platelets, and A-779 blocked this effect. The NO release stimulated by Ang-(1-7) was abolished in Mas(-/ -) mouse platelets. Ang-(1-7) inhibited thrombus formation in Mas(+/+) mice. Strikingly, this effect was abolished in Mas(-) (/) (-)mice. Moreover, Mas deficiency resulted in a significant decrease in bleeding time (8.50 +/- 1.47 vs. 4.28 +/- 0.66 min). This study is the first to show the presence of Mas protein and specific binding for Ang-(1-7) in rat and mouse platelets. Our data also suggest that the Ang-(1-7) antithrombotic effect involves Mas-mediated NO release from platelets. More importantly, we showed that the antithrombotic effect of Ang-(1-7) in vivo is Mas dependent and that Mas is functionally important in hemostasis.