RESUMEN
BACKGROUND: Ethical social media use underpins effective online engagement for dementia prevention research. Existing social media guidelines are broad and lack empirical justification reflecting the values and priorities of the dementia community and the challenges specific to prevention research. OBJECTIVES: By engaging professional and community experts, we sought to identify the ethical issues, motivators, and barriers pertaining to social media engagement for dementia prevention research. DESIGN: Semi-structured, qualitative interviews conducted online. SETTING: We recruited participants using a combination of accessible online databases, advertisements/posters through organizational newsletters and websites, social media, registries, and from our network of colleagues. PARTICIPANTS: Professional experts working in dementia research (n=15; e.g., researchers, coordinators) and experts with lived experience (n=14). Experts were from Canada, the USA, the UK, and Chile. MEASUREMENTS: Discussions were analyzed using thematic qualitative analysis methods. RESULTS: Professional experts revealed a dearth of social media guidelines for prevention research, relying on informal sources to supplement ethics board approval. They sought methods of strategic communication for public dialogue (e.g., misinformation, criticism). Experts by experience appreciated the educational benefits of social media but raised risks such as diminished online privacy, dementia-related stigma, being targeted for predatory practices, and misinformation. Various digital inequities (e.g., age, socioeconomic status) dampen social media's reach to diverse publics. Participants acknowledged that younger aging populations have more digital fluency and may benefit more from social media research engagement. CONCLUSIONS: Research professionals and community members identified ethical and contextual factors surrounding the use of social media for dementia prevention, and a need for more guidance. The next project phase will use these data to inform the co-creation of ethical guidelines for brain health research.
Asunto(s)
Demencia , Medios de Comunicación Sociales , Humanos , Proyectos de Investigación , Comunicación , Demencia/prevención & control , CanadáRESUMEN
A phononic crystal (PC) consisting of a square array of cylindrical polyvinylchloride inclusions in air is used to construct a variety of acoustic logic gates. In a certain range of operating frequencies, the PC band structure shows square-like equi-frequency contours centered off the gamma point. This attribute allows for the realization of non-collinear wave and group velocity vectors in the PC wave vector space. This feature can be utilized to control with great precision, the relative phase between propagating acoustic waves in the PC. By altering the incidence angle of the impinging acoustic beams or varying the PC thickness, interferences occur between acoustic wave pairs. It is recognized that information can be encoded with this mechanism (e.g., wave amplitudes/interference patterns) and accordingly to construct a series of logic gates emulating Boolean functions. The NAND, XOR, and NOT gates are demonstrated with finite-difference time-domain simulations of acoustic waves impinging upon the PC.
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Acústica/instrumentación , Modelos Teóricos , Cloruro de Polivinilo/química , Procesamiento de Señales Asistido por Computador , Sonido , Simulación por Computador , Cristalización , Movimiento (Física) , Análisis Numérico Asistido por Computador , Factores de TiempoRESUMEN
We report on picosecond ultrasonic measurements obtained on aluminum and platinum nanostructures with variable dot size and lateral periodicity which realized a 2D phononic crystal. Performing investigations at different resolution scales, we have identified individual modes of vibration depending on the dot size, and mode of vibration strongly correlated with the bi-dimensional organization. The platinum dots sputtered on an aluminum layer have shown a behavior of isolated oscillators without any coupling between neighbor elements in this phononic crystal. The frequency of such normal modes, extracted from time resolved measurements are in good agreement with 3D finite element simulations. In contrast, with aluminum dot systems where the coupling is more efficient we observe a complex spectrum of vibrational modes related to the band structure induced by the bi-dimensional patterning.
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Algoritmos , Rayos Láser , Ensayo de Materiales/métodos , Modelos Químicos , Nanoestructuras/química , Nanoestructuras/ultraestructura , Ultrasonido , Simulación por Computador , Elasticidad , Dosis de Radiación , Radiometría/métodos , VibraciónRESUMEN
To determine if the defective interactions among D(1)-like receptors, G proteins, and Na(+)/H(+) exchanger 3 (NHE3) are consequences of hypertension, we studied these interactions in rats, before (2--3 wk) and after (12 wk) the establishment of hypertension. To eliminate the confounding influence of second messenger action on D(1) receptor-NHE3 interaction, studies were performed in renal brush-border membranes (BBM) devoid of cytoplasmic second messengers. NHE3 activity increased with age in Wistar-Kyoto (WKY) rats (3 wk = 1.48 +/- 0.39, n = 13; 12 wk = 2.83 +/- 0.15, n = 16, P < 0.05) but not in spontaneously hypertensive rats (SHRs; 3 wk = 2.52 +/- 0.37, n = 11; 12 wk = 2.81 +/- 0.20, n = 16). D(1) receptor protein tended to decrease, whereas NHE3 protein tended to increase with age in both WKY and SHRs. However, the inhibitory effect of a D(1)-like agonist, SKF-81297, on NHE3 activity increased with age in WKY rats (3 wk = -40.7 +/- 5.3%, n = 10, 12 wk = -58.7 +/- 4.6%, n = 12, P < 0.05) but not in SHRs (3 wk = -27.6 +/- 5.9%, n = 11, 12 wk = -25.1 +/- 3.2%, n = 11). The decreased inhibitory effect of another D(1)-like agonist, fenoldopam, on NHE3 activity in SHRs was not caused by increased activity and binding of G beta gamma to NHE3 as has been reported in young WKY rats. G(s)alpha mediates, in part, the inhibitory effect of D(1)-like agonists on NHE3 activity. In WKY rats, fenoldopam increased G(s)alpha/NHE3 binding to the same extent in 2-wk-old (1.5-fold, n = 4) and adult (1.5-fold, n = 4) rats. In contrast, in SHRs, fenoldopam decreased the amount of G(s)alpha bound to NHE3 in 2-wk-old SHRs and had no effect in 4-wk-old and adult SHRs. These studies indicate that the decreased inhibitory effect of D(1)-like agonists on NHE3 activity in SHRs (compared with WKY rats) precedes the development of hypertension. This may be caused, in part, by a decreased interaction between G(s)alpha and NHE3 in BBM secondary to impaired D(1)-like receptor function.
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Envejecimiento/fisiología , Fenoldopam , Hipertensión/fisiopatología , Receptores de Dopamina D1/fisiología , Animales , Presión Sanguínea , Agonistas de Dopamina/farmacología , Fenoldopam/farmacología , Proteínas de Unión al GTP/metabolismo , Riñón/metabolismo , Masculino , Microvellosidades/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Dopamina D1/agonistas , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismoRESUMEN
In fetal sheep, severe hypotension causes heart rate (HR) slowing. Studies during development have also shown that a reflex bradycardia and hypotension can be elicited after chemostimulation with veratridine and is dependent on the age of the animal. In adults, a vagally mediated depressor reflex characterized by bradycardia, hypotension, and withdrawal of efferent sympathetic activity can be observed after stimulation of chemosensitive or mechanosensitive cardiac receptors with veratridine or in circumstances of reduced cardiac filling. This reflex, known as the Bezold-Jarisch reflex, plays a role in disease states such as myocardial ischemia and hemorrhage. The objectives of our study were to determine whether a sympathoinhibitor depressor reflex, along with the bradycardia, is observed during pharmacologically induced hypotension in fetal and newborn lambs. In both fetal and newborn lambs, HR and renal sympathetic nerve activity (RSNA) initially increased (p < 0.05) in response to nitroprusside infusion to reach a maximum value. The range (or "plateau") of mean arterial blood pressure over which maximum RSNA was maintained constant before withdrawal of sympathetic tone started to be observed was significantly (p < 0.05) smaller in fetuses (0.3 +/- 0.3 mm Hg) than newborn (6 +/- 1 mm Hg) lambs. Similarly, the plateau over which maximum HR was maintained before onset of bradycardia was significantly smaller in fetuses (4 +/- 1 versus 11 +/- 2 mm Hg). The mean arterial blood pressure level ("threshold") at which a depressor reflex was triggered was significantly (p < 0.05) lower in fetal than newborn sheep (35 +/- 2 versus 53 +/- 3 mm Hg for HR and 35 +/- 2 versus 57 +/- 2 mm Hg for RSNA). The rates of fall (slopes) for both HR and RSNA were also significantly (p < 0.05) more pronounced in fetuses (1.85 +/- 0.27 and 6.08 +/- 2.45%/mm Hg) than in newborns (1.21 +/- 0.16 and 1.97 +/- 0.32%/mm Hg). Bilateral vagotomy significantly increased the plateau of mean arterial blood pressure over which maximum RSNA and HR were maintained constant. Vagotomy also decreased the threshold for both RSNA and HR and the slope of the RSNA response to the nitroprusside infusion in newborn lambs. Results from this study show that activation of the arterial baroreflex during nitroprusside-induced hypotension is followed by withdrawal of sympathetic tone and bradycardia and that this depressor reflex is more pronounced in late-gestation fetuses than newborn lambs and is significantly attenuated after bilateral vagotomy in newborn lambs.
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Sistema Nervioso Autónomo/fisiopatología , Feto/fisiopatología , Hipotensión/fisiopatología , Animales , Animales Recién Nacidos , Análisis de los Gases de la Sangre , Femenino , Enfermedades Fetales/fisiopatología , Hematócrito , Hemodinámica , Embarazo , Ovinos , VagotomíaRESUMEN
OBJECTIVE: To determine if spontaneous hypertension is secondary to defective interaction among dopamine receptor, G protein, and Na(+)/H(+) exchanger 3 (NHE3). METHODS: The inhibitory effect of a D(1) dopamine agonist upon NHE3 activity and its impact upon G(s)alpha/NHE3 binding in renal brush border membrane (BBM) of spontaneously hypertensive rats (SHRs) 2 - 3 weeks before and 12 weeks after the establishment of hypertension were examined. In order to avoid the confounding influence of second messenger on D(1) receptor/NHE3 interaction, study was made in BBM devoid of cytoplasmic component. RESULTS: NHE3 activity increased with age in Wister-Kyoto (WKY) rats but not in SHRS. D1 receptor expression did change with age in both WKY rats and SHRs. The inhibitory effect of a D(1)-like agonist on NHE3 activity increased with age in WKY rats but not in SHRs. In WKY rats, another D(1)-like agonist, fedoldopam, increased G(s)alpha/NHE3 binding to the same extent in 2 week old and adult rats, but decreased the amount of G(s)(alpha)bound to NHE3 in 2 week old SHRs. CONCLUSION: The decrease of inhibitory effect of D(1)-like agonist upon NHE3 activity in SHRs precedes the development of hypertension. Spontaneous hypertension may be caused, in part, by a decreased interaction between G(s)alpha and NHE3 in BBM secondary to D(1)-like receptor function.
Asunto(s)
Agonistas de Dopamina/farmacología , Fenoldopam/farmacología , Hipertensión/fisiopatología , Receptores de Dopamina D1/fisiología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Envejecimiento/fisiología , Animales , Presión Sanguínea , Proteínas de Unión al GTP/metabolismo , Riñón/metabolismo , Masculino , Microvellosidades/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Dopamina D1/agonistas , Intercambiador 3 de Sodio-HidrógenoRESUMEN
Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.
Asunto(s)
Trasplante de Médula Ósea , Osteocondrodisplasias/genética , Osteocondrodisplasias/terapia , Antígenos CD/sangre , Niño , Preescolar , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Recién Nacido , Trasplante de Riñón , Linfopenia/complicaciones , Linfopenia/diagnóstico , Masculino , Osteocondrodisplasias/complicaciones , Linaje , Insuficiencia Renal/complicaciones , Insuficiencia Renal/cirugía , Tacrolimus/uso terapéuticoRESUMEN
The decreased natriuretic action of dopamine in the young has been attributed to decreased generation of cAMP by the activated renal D(1)-like receptor. However, sodium/hydrogen exchanger (NHE) 3 activity in renal brush-border membrane vesicles (BBMV) can be modulated independent of cytoplasmic second messengers. We therefore studied D(1)-like receptor regulation of NHE activity in BBMVs in 2-, 4-, and 12-wk-old (adult) rats. Basal NHE activity was least in 2-wk-old compared with 4- and 12-wk-old rats. D(1)-like agonist (SKF-81297) inhibition of NHE activity was also least in 2-wk-old (-1 +/- 9%, n = 3) compared with 4 (-15 +/- 5%, n = 6)- and 12 (-65 +/- 4%, n = 6)-wk-old rats. The decreased response to the D(1)-like agonist in BBMV was not caused by decreased D(1) receptors or NHE3 expression in the young. G(s)alpha, which inhibits NHE3 activity by itself, coimmunoprecipitated with NHE3 to the same extent in 2-wk-old and adult rats. G(s)alpha function was also not impaired in the young because guanosine 5'-O-(3-thiotriphosphate) decreased NHE activity to a similar extent in 4-wk-old and adult rats. Galpha(i-3) protein expression in BBMV also did not change with age. In contrast, Gbeta expression and the amount of Gbeta that coimmunoprecipitated with NHE3 in BBMV was greatest in 2-wk-old rats and decreased with age. Gbeta common antibodies did not affect D(1)-like agonist inhibition of NHE activity in adult rats (8%) but markedly increased it (48%)in 4-wk-old rats. We conclude that the decreased inhibitory effect of D(1)-like receptors on NHE activity in BBMV in young rats is caused, in part, by the increased expression and activity of the G protein subunit Gbeta/gamma. The direct regulation of NHE activity by G protein subunits may be an important step in the maturation of renal tubular ion transport.
Asunto(s)
Subunidades beta de la Proteína de Unión al GTP , Subunidades gamma de la Proteína de Unión al GTP , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP Heterotriméricas , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/crecimiento & desarrollo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Benzazepinas/farmacología , Agonistas de Dopamina/farmacología , Fenoldopam/farmacología , Túbulos Renales Proximales/química , Masculino , Proteínas de la Membrana/metabolismo , Microvellosidades/química , Microvellosidades/enzimología , Tamaño de los Órganos , Ratas , Ratas Endogámicas WKY , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5 , Sistemas de Mensajero Secundario/efectos de los fármacos , Intercambiador 3 de Sodio-HidrógenoRESUMEN
Previous work in our laboratory has demonstrated impairment of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) during the newborn period. The present study was designed to test the hypothesis that this delayed maturation is secondary to incomplete central integration of vagal afferent input. Term fetal (135-140 days; n = 6), newborn (3-7 days of age; n = 8), and young adult (6-8 wk old; n = 8) sheep anesthetized with alpha-chloralose underwent vagal afferent nerve stimulation. All animals had undergone prior sinoaortic denervation to eliminate influences from the arterial baroreceptors. After determination of optimal stimulation parameters, RSNA responses to gradual increases in stimulation frequency (1.0-16 Hz) were recorded and compared by one-way ANOVA. RSNA decreased progressively with increased frequency of stimulation in all three groups of animals. When comparing the three groups at any given frequency of stimulation, reflex withdrawal of RSNA tended to be more pronounced in newborn lambs (P < 0.05 for 1 and 4 Hz). Heart rate (HR) was also noted to decrease significantly with vagal afferent stimulation in each of the groups, but no significant differences in the reflex decreases in HR were noted among the three groups of animals. These results demonstrate that central integration of vagal afferent input is intact in fetal and newborn sheep. These results suggest that the delayed maturation of cardiopulmonary reflex-mediated changes in RSNA seen early in development appears to depend on intrinsic alterations in baroreceptor function rather than incomplete central integration.
Asunto(s)
Envejecimiento/fisiología , Feto/fisiología , Corazón/inervación , Pulmón/inervación , Sistema Nervioso Simpático/fisiología , Nervio Vago/fisiología , Vías Aferentes/embriología , Vías Aferentes/fisiología , Animales , Animales Recién Nacidos/fisiología , Estimulación Eléctrica , Corazón/embriología , Pulmón/embriología , Ovinos , Sistema Nervioso Simpático/embriología , Nervio Vago/embriologíaRESUMEN
Renal sympathetic nerve activity (RSNA) increases rapidly after delivery of term fetal sheep and parallels the rise in heart rate (HR) and arterial pressure. To examine the RSNA response at birth in immature lambs, experiments were performed in chronically instrumented preterm fetal sheep (118- to 125-day gestation, term 145 days) before and after delivery by cesarean section. HR remained unchanged from fetal values at 1 and 4 h after birth, whereas mean arterial blood pressure (MABP) decreased significantly (P < 0.05) by 4 h after delivery. RSNA significantly decreased after premature birth in all animals studied (n = 6), achieving only 39 +/- 17% of fetal RSNA (P < 0.05; all results are mean +/- SE). Because cardiovascular function after premature birth is improved by the use of antenatal corticosteroids, we also tested the hypothesis that corticosteroid administration would evoke a more pronounced sympathetic response in prematurely delivered lambs (n = 7, 118- to 125-day gestation). After maternal administration of dexamethasone (5 mg i.m., 48 and 24 h before delivery), RSNA increased after birth in six of seven fetuses to 166 +/- 32% of the fetal RSNA value. Dexamethasone treatment also decreased the sensitivity of baroreflex-mediated changes in HR in response to increases in MABP. Because the sympathetic response at birth is depressed in preterm compared with term lambs, we performed an additional study (n = 8) to determine if immature sheep are capable of mounting a sympathetic response to cold. In utero cooling produced rapid and sustained increases in MABP (20 +/- 4%), HR (26 +/- 6%), and RSNA (282 +/- 72%) (all P < 0.05), consistent with a generalized sympathoexcitation. These results suggest that sympathoexcitation is absent after premature delivery despite the presence of functional descending autonomic pathways. Furthermore, exogenous corticosteroids appear to have a maturational effect on the sympathetic response at birth, which may be one mechanism by which maternal steroid administration improves postnatal cardiovascular homeostasis.
Asunto(s)
Dexametasona/farmacología , Glucocorticoides/farmacología , Riñón/inervación , Efectos Tardíos de la Exposición Prenatal , Sistema Nervioso Simpático/fisiología , Angiotensina II/sangre , Animales , Animales Recién Nacidos , Arginina Vasopresina/sangre , Presión Sanguínea/efectos de los fármacos , Dióxido de Carbono/sangre , Cesárea , Epinefrina/sangre , Femenino , Edad Gestacional , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca Fetal/efectos de los fármacos , Hidrocortisona/sangre , Norepinefrina/sangre , Oxígeno/sangre , Embarazo , Ovinos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/embriologíaRESUMEN
The present study was designed to test the hypothesis that endogenous angiotensin II (ANG II) influences baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) early in life and to determine whether these actions are mediated by angiotensin AT1 or AT2 receptors. To test this hypothesis, we studied the effects of systemic and central administration of losartan, a selective AT1 receptor antagonist, and PD-123319, a selective AT2 antagonist, on baroreflex-mediated control of HR and RSNA in conscious newborn lambs. Systemic administration of losartan decreased resting mean arterial blood pressure (MABP) from 70 +/- 3 to 58 +/- 4 mmHg (P < 0.05) without producing reflex increases in HR or RSNA. The baroreflex response curves were shifted to the left as indicated by a decrease in the arterial pressure at the midpoint of the curve for HR (83 +/- 3 to 75 +/- 4 mmHg) and RSNA (74 +/- 2 to 69 +/- 3 mmHg; P < 0.05 for both). Losartan also reset HR and RSNA baroreflex curves when changes in baseline blood pressure were prevented by simultaneous infusion of phenylephrine. In contrast, a sustained decrease in arterial pressure of 10-12 mmHg with nitroprusside failed to shift the baroreflex function curves. PD-123319 had no effect on baseline HR, MABP, RSNA, or baroreflex responses. Lateral ventricle administration of losartan but not PD-123319 also produced a decrease in arterial pressure (81 +/- 4 to 73 +/- 3 mmHg, P < 0.05) and reset the baroreflex for HR and RSNA toward lower pressure. These results demonstrate that, early in life, endogenous ANG II exerts a tonic effect on baroreflex control of HR and RSNA to shift the curves toward higher pressure levels. The alterations in arterial baroreflex function appear independent of direct ANG II effects on arterial pressure and are mediated by AT1 receptors.
Asunto(s)
Angiotensina II/fisiología , Animales Recién Nacidos/fisiología , Arterias/fisiología , Barorreflejo/fisiología , Receptores de Angiotensina/fisiología , Angiotensina II/farmacología , Animales , Antihipertensivos/farmacología , Barorreflejo/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Fenómenos Fisiológicos Cardiovasculares , Imidazoles/farmacología , Losartán , Fenilefrina/farmacología , Ovinos , Tetrazoles/farmacologíaRESUMEN
The postnatal rise in renal Na+ reabsorption is associated with an increase in proximal tubule apical membrane Na+/H+ exchanger (NHE) activity in sheep. Inasmuch as circulating angiotensin II (ANG II) levels increase immediately after birth and ANG II is known to upregulate NHE activity in the adult proximal tubule, we postulated that ANG II plays a role in mediating maturational changes in NHE activity. We therefore studied the effects of ANG II infusion (10 micrograms/h) for 24 h on renal cortical NHE activity in chronically instrumented, twin ovine fetuses (129 +/- 2 days gestation, term is 145 days, n = 10 pairs); one twin of each pair served as a control. After 24 h, the fetuses were killed and brush-border membrane vesicles (BBMV) were prepared from the renal cortices. Postinfusion plasma ANG II levels were significantly higher and plasma renin activities were significantly lower in treated fetuses compared with controls. Kinetic analysis revealed an increase in NHE activity after ANG II treatment; however, the difference was not statistically significant: maximal velocity (in nmol.s-1.mg protein-1) control 1.65 +/- 0.50, treated 2.31 +/- 0.66 (P = 0.11, n = 9 pairs); Michaelis constant control 8.29 +/- 1.17 mM, treated 9.84 +/- 1.26 mM (P = 0.11). Northern blots of total RNA from the cortices of these animals were hybridized to a D-[32P]UTP-labeled antisense RNA probe prepared from a 1.3-kb rat NHE3 cDNA fragment. There were no differences between the groups in NHE3 mRNA levels (32P counts were control 413 +/- 54, treated 340 +/- 46). ANG II does not appear to play an important role in the regulation of NHE activity in the proximal tubule of the near-term sheep fetus.
Asunto(s)
Angiotensina II/farmacología , Feto/metabolismo , Corteza Renal/embriología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Arterias , Presión Sanguínea/efectos de los fármacos , Desarrollo Embrionario y Fetal , Femenino , Sangre Fetal/efectos de los fármacos , Feto/efectos de los fármacos , Feto/fisiología , Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca Fetal/efectos de los fármacos , Riñón/embriología , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/embriología , Túbulos Renales Proximales/metabolismo , Embarazo , Ratas , Ovinos/embriología , Intercambiadores de Sodio-Hidrógeno/genéticaRESUMEN
The present study was designed to test the hypothesis that the influence of circulating vasopressin (AVP) on the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) changes during development. To test this hypothesis, we studied arterial baroreflex-mediated control of HR and RSNA in the presence of increasing plasma levels of AVP in conscious, chronically instrumented fetal, newborn, and adult sheep. In fetal and newborn sheep, increasing plasma AVP levels (from < 10 to > 200 microU/ml) increased resting levels of mean arterial blood pressure (MABP) and decreased HR and RSNA. HR and RSNA baroreflex responses to variations of MABP with nitroprusside and phenylephrine infusion were not modified by elevated AVP levels in either newborn or fetal sheep, except for a small decrease in maximal HR response to nitroprusside infusion in the newborn animals. In contrast, in adults, AVP caused bradycardia and a decrease in RSNA without change in MABP, accompanied by resetting of the arterial baroreflex (decrease in maximal HR and RSNA, decrease in RSNA gain, and shift of HR to lower pressure). To test the hypothesis that the inability of AVP to reset the arterial baroreflex early during development was not secondary to maximal stimulation of V1 receptors during baseline conditions, we investigated the effect of V1-receptor blockade on baseline cardiovascular and arterial baroreflex function in newborn lambs. Administration of a V1-receptor antagonist produced no significant changes in resting MABP, HR, and RSNA and did not influence arterial baroreflex-mediated changes in HR and RSNA. These results indicate that, contrary to adults, circulating AVP does not modulate the arterial baroreflex in fetal and newborn sheep.
Asunto(s)
Animales Recién Nacidos/fisiología , Arginina Vasopresina/farmacología , Arterias/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Feto/fisiología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/sangre , Arterias/fisiología , Barorreflejo/fisiología , Sangre/metabolismo , Presión Sanguínea/efectos de los fármacos , Fenómenos Fisiológicos Cardiovasculares , Frecuencia Cardíaca/efectos de los fármacos , Riñón/embriología , Riñón/inervación , Fenilefrina/farmacología , Ovinos/embriología , Sistema Nervioso Simpático/fisiologíaRESUMEN
The influence of altered dietary sodium on angiotensinogen and renin gene expression was examined in young normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Artificial rearing was used to increase or decrease dietary sodium intake during the preweanling period. In normally reared control animals, renal renin and liver angiotensinogen mRNA decreased between 6 and 30 postnatal days of age. In contrast, in the central nervous system, angiotensinogen mRNA increased between 6 and 30 days of age, and renin mRNA remained stable. Dietary sodium manipulation between postnatal days (PD) 6 and 18 significantly influenced renal renin gene expression, with low-sodium diet increasing renin mRNA on PD12 and PD18 and high-sodium diet decreasing renin mRNA on PD18. Liver angiotensinogen mRNA decreased for animals on either diet on PD12 and PD18. Brain angiotensinogen and renin mRNA were not affected by dietary sodium levels. There were no strain-related differences in the response to high and low dietary sodium. These results demonstrate that 1) the peripheral and central renin-angiotensin systems do not have a common ontogenetic pattern of development, 2) they are independently regulated in response to dietary sodium variations, and 3) young WKY and SHR share very similar ontogenetic patterns of angiotensinogen and renin gene expression.
Asunto(s)
Angiotensinógeno/genética , Animales Lactantes/fisiología , Expresión Génica/efectos de los fármacos , Hipertensión/genética , Renina/genética , Sodio en la Dieta/farmacología , Animales , Peso Corporal , Encéfalo/metabolismo , Femenino , Hipertensión/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR/fisiología , Ratas Endogámicas WKY , Valores de ReferenciaRESUMEN
To further investigate the maturation of the cardiopulmonary baroreflex, we measured the effects of a 45-min blood volume expansion to an increase in right atrial pressure of approximately 4 mmHg in chronically instrumented newborn (n = 17) and older lambs (n = 14). Measurements included various parameters of endocrine, cardiovascular, and renal function and concomitant recording of renal sympathetic nerve activity (RSNA). During blood volume expansion, RSNA was inhibited to a similar extent in newborns and older lambs when atrial pressures were increased by approximately 4 mmHg. A sympathoinhibition persisted in newborns but was only transient in older lambs. In newborn lambs, heart rate decreased in response to blood volume expansion, whereas heart rate remained constant after blood volume expansion in older lambs. The renal and endocrine responses to blood volume expansion were, however, similar in newborns and older lambs. These data provide evidence that when atrial pressures are matched, the renal and endocrine responses to blood volume expansion are similar, but there are differential cardiovascular and RSNA responses. Any reduced ability of the newborn kidney to excrete a volume load is therefore probably related to maturational differences in its distribution between the capacitance vessels and the heart.
Asunto(s)
Animales Recién Nacidos/crecimiento & desarrollo , Volumen Sanguíneo , Fenómenos Fisiológicos Cardiovasculares , Glándulas Endocrinas/fisiología , Riñón/fisiología , Envejecimiento/fisiología , Animales , Función del Atrio Derecho , Factor Natriurético Atrial/sangre , Presión Sanguínea , Diuresis , Tasa de Filtración Glomerular , Frecuencia Cardíaca , Riñón/inervación , Sustitutos del Plasma/farmacología , Presión , Renina/sangre , Ovinos , Sistema Nervioso Simpático/fisiologíaRESUMEN
Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na+/H+ exchanger [NHE] and Na+/K+ATPase activity) by dopamine. To determine if impaired D1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses. A D1 agonist, SKF 81297, inhibited (37.6 +/- 4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure < 140 mm Hg, n = 7) but not in hypertensive F2s (n = 21). Furthermore, a D1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s (n = 3) without altering renal blood flow but was inactive in hypertensive F2s (n = 21). Since the major D1 receptor gene expressed in renal proximal tubules is the D1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D1A receptors. Systolic blood pressure was greater in homozygous (n = 6) and heterozygous (n = 5) mice compared to normal sex matched litter mate controls (n = 12); moreover, the mice lacking one or both D1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D1A alleles suggest a causal relationship of the D1A receptor gene with hypertension.
Asunto(s)
Hipertensión/genética , Receptores de Dopamina D1/fisiología , Animales , AMP Cíclico/metabolismo , Femenino , Hipertensión/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Intercambiadores de Sodio-Hidrógeno/fisiologíaRESUMEN
We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.
Asunto(s)
Angiotensinógeno/fisiología , Barorreflejo/fisiología , Hipertensión/fisiopatología , Presorreceptores/fisiología , Renina/fisiología , Animales , Frecuencia Cardíaca , Ratones , Ratones TransgénicosRESUMEN
The present studies were designed to assess the contribution of onset of respiration, separation from the placenta, and a decrease in environmental temperature on the increase in renal sympathetic nerve activity (RSNA) that occurs at birth. In the first series of experiments, heart rate (HR), mean arterial blood pressure (MABP), and RSNA were recorded in chronically instrumented near-term fetal sheep (n = 12) before and during in utero ventilation (V), V + oxygenation (V + O), and V + O + umbilical cord occlusion (V + O + CO). RSNA increased by 49 +/- 16% during V alone (P < 0.05), whereas no additional changes were seen with V + O or V + O + CO. HR and MABP did not change with any intervention. In a second series of experiments (n = 10), changes in fetal HR, MABP, and RSNA in response to in utero cooling were recorded. Cooling of the fetal core temperature by -3.1 +/- 0.2 degree C produced a rapid and sustained increase in RSNA (330 +/- 155%), HR (25 +/- 11%), and MABP (10 +/- 2%) consistent with generalized sympathoexcitation. In a third series of studies (n = 3), we found that brain stem transection between the rostral pons and posterior hypothalamus abolishes the increases in RSNA seen at birth. These results suggest that cooling is a major contributor to the postnatal rise in RSNA and that brain centers at the level of or above the hypothalamus are involved in mediating sympathoexcitation at birth.
Asunto(s)
Animales Recién Nacidos/fisiología , Parto Obstétrico , Riñón/inervación , Sistema Nervioso Simpático/fisiología , Animales , Animales Recién Nacidos/sangre , Arterias , Tronco Encefálico/fisiología , Frío , Constricción , Desnervación , Femenino , Sangre Fetal/metabolismo , Feto/fisiología , Hemodinámica , Oxígeno/sangre , Embarazo , Respiración , Ovinos , Cordón Umbilical/fisiologíaRESUMEN
Previous studies have shown that angiotensin II subtype 2 (AT2) receptors appear early during renal embryonic development. Factors involved in the regulation of AT2 receptors during renal development, however, have not been investigated. The present study was designed 1) to characterize the ontogeny of renal AT2 gene expression during the last half of gestation in fetal sheep and newborn lambs, 2) to compare changes in AT1 and AT2 gene expression during renal development, 3) to determine the influence of AII in modulating renal AT1 and AT2 gene expression during fetal life, and 4) to characterize the role of cortisol in modulating renal AT2 gene expression during the last trimester of gestation in fetal sheep. To perform these studies, we first isolated and cloned a polymerase chain reaction product that has 92 and 90% homology with the cDNA encoding the human and rat AT2 receptors, respectively. Using this sheep AT2 cDNA probe, we demonstrated that the sheep AT2 gene was encoded in a single locus. In addition, we showed that renal AT2 mRNA expression was high early during fetal life (60-90-d gestation) and decreased rapidly thereafter. In contrast, the expression of renal AT1 receptor gene was low at 60-d gestation and increased during the last trimester of gestation. We found that a continuous i.v. infusion (1 mL/h) of AII (9.5 mM/n) for 24 h, which raised plasma AII levels from 84 +/- 9 pg/mL to 210 +/- 21 pg/mL, decreased the expression of both renal AT1 and AT2 genes in third trimester fetal sheep. On the other hand, we observed that cortisol, known to decrease AT1 gene expression in the fetus, had no effect on AT2 gene expression. In summary, this study demonstrates that AII, but not glucocorticoids, contributes to the regulation of renal AT2 gene expression during development and that there is differential regulation of AT1 and AT2 receptors.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica/fisiología , Riñón/metabolismo , Receptores de Angiotensina/fisiología , Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Secuencia de Bases , ADN Complementario/genética , Desarrollo Embrionario y Fetal/genética , Edad Gestacional , Humanos , Hidrocortisona/fisiología , Riñón/efectos de los fármacos , Ratones , Datos de Secuencia Molecular , ARN Mensajero/biosíntesis , Ratas , Renina/genética , Ovinos , Especificidad de la EspecieRESUMEN
It is generally accepted that the etiology of essential hypertension is due to a complex interplay of genetic and environmental factors. A great deal of research effort over the past ten years has been focused on the identification of genes the variants of which predispose individuals to high blood pressure. Consequently, transgenic and knockout animals have become important research tools, providing experimental systems in which defined genetic manipulations can be introduced on uniform genetic backgrounds while minimizing environmental variation. These animal models have provided the means by which candidate genes thought to be involved in blood pressure regulation have been studied. Furthermore, these models can be used to test the significance of genes and gene variants identified via genome-wide searches as potential causes of hypertension. The purpose of this review is to provide a brief discussion of transgenic and knockout methodology and its application to study the genetic basis of hypertension.