RESUMEN
An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life "programming". Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, alpha-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.
Asunto(s)
Dexametasona/toxicidad , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Hidrocortisona/toxicidad , Insulina/metabolismo , Preñez , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Peso al Nacer/efectos de los fármacos , Glucemia/análisis , Evaluación de Medicamentos , Femenino , Edad Gestacional , Crecimiento y Desarrollo/efectos de los fármacos , Secreción de Insulina , Masculino , Exposición Materna/efectos adversos , Embarazo , OvinosRESUMEN
Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT1) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular (I.C.V.) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h(-1); n = 7), CORT (5 mg h(-1), n = 6) or SAL (n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 microg h(-1)) were significantly greater in the DEX group (10 +/- 1 mmHg at 1 microg h(-1)) compared with SAL (6 +/- 1 mmHg) or CORT (6 +/- 1 mmHg) animals (P < 0.05). I.C.V. infusion of the AT1 antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT1 receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.
Asunto(s)
Angiotensina II/farmacología , Antiinflamatorios/farmacología , Dexametasona/farmacología , Efectos Tardíos de la Exposición Prenatal , Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Femenino , Edad Gestacional , Frecuencia Cardíaca/efectos de los fármacos , Hidrocortisona/farmacología , Inyecciones Intraventriculares , Losartán/administración & dosificación , Losartán/farmacología , Masculino , Embarazo , Sistema Renina-Angiotensina/efectos de los fármacos , Ovinos , Factores de Tiempo , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacologíaRESUMEN
Low-dose dexamethasone treatment is used in pregnancies where the fetus is suspected to be at risk of congenital adrenal hyperplasia (CAH). In order to see if such treatment had long-term effects, pregnant ewes were treated with dexamethasone (20 micro g/kg maternal body weight) or saline from 25 to 45 days of gestation and blood pressure and renal function studied in offspring at 2 Years of age. There were 11 animals from dexamethasone treatment (six females and five males) and nine lambs from saline treatment (five females and four males). We aimed to study blood pressure and heart rate in the adult animals of both genders, and renal function only in the adult female animals. In both females and males, blood pressure and heart rate were similar between the two groups of animals. The excretion rates of sodium and potassium were similar between the two groups of animals. In addition, glomerular filtration rate was not different between the two groups of animals (112+/-11 ml/kg per h (S.E.M.) in saline-treated females vs 112+/-10 ml/kg per h in dexamethasone-treated females). There were no differences in body weight or weights of the kidney and heart between the treatments in both females and males. In conclusion, these results are reassuring for patients similarly exposed to prenatal dexamethasone treatment for CAH, as in our animal model no evidence of altered renal function or predisposition to adult hypertension was found.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Dexametasona/farmacología , Glucocorticoides/farmacología , Riñón/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Hiperplasia Suprarrenal Congénita/prevención & control , Animales , Femenino , Tasa de Filtración Glomerular , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Modelos Animales , Embarazo , OvinosRESUMEN
The concept that 'life before birth' or the 'first environment' is important in determining subsequent risk for the development of cardiovascular/metabolic disease is now gaining acceptance. There are substantial data from animal experiments that complement and enhance the epidemiological data from human studies. We argue that any factor which disrupts nephrogenesis, and lowers nephron number, during the period of active nephrogenesis, will induce malapadaptive changes in the future functioning of that kidney and predispose to the onset of adult hypertension. Such factors include exposure of the mother, to a particular low-protein diet, excess synthetic or natural glucocorticoid at certain critical periods, mild vitamin A deficiency, elevated blood glucose, unilateral nephrectomy during the period of nephrogenesis, as well as the deletion of one allele of a gene (GDNF) involved in normal metanephric development. All of these stresses are associated with a reduction (20-40 per cent) in total nephron number in the adult, and the development of hypertension. In some hypertensive models, (rats) there is evidence of alterations in the components of the hippocampal/hypothalamic/pituitary/adrenal axis, whereas in others (sheep) there are alterations in the expression of angiotensinogen (hypothalamus) and angiotensin II receptor type I (AT(1)) in the medulla oblongata. The surprising finding is that the period when the kidney and brain are most vulnerable is very early in development, when both organs are in an extremely primitive state of development.
Asunto(s)
Encéfalo/embriología , Sistema Cardiovascular/embriología , Hipertensión/embriología , Hipertensión/etiología , Riñón/embriología , Angiotensinas/fisiología , Animales , Encéfalo/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Glucocorticoides/administración & dosificación , Glucocorticoides/fisiología , Humanos , Riñón/efectos de los fármacos , Masculino , Embarazo , OvinosRESUMEN
There is some evidence, mainly from rodent studies, that any factor which alters the final total number of nephrons formed, during nephrogenesis, will result in hypertension in adult life. Sheep, programmed to become hypertensive by exposure to synthetic glucocorticoid (dexamethasone, 0.48 mg h-1, for 48 h) early in development (~27 days of gestation), were killed at 7 years of age, and had nephron counting performed by unbiased stereology. Mean arterial pressure was 83 +/- 4 mmHg in the dexamethasone (DEX) group (n = 5), and 73 +/- 5 in the control (CON; n = 7; P < 0.05). The total nephron number, in the right kidney (249 070 +/- 14 331; n = 5) was significantly lower (P < 0.01) than that of controls (402 787 +/- 30 458; n = 7). Mean glomerular volume was larger in the DEX than the CON group (P < 0.01), but there was no significant difference in the sclerosis index between the two groups. Low nephron number was associated with grossly enlarged and dilated proximal tubules and greater accumulation of collagen type I and type III in the tubular interstitium and periadventitia of the renal cortical vessels. These data suggest that the hypertensive programming effect of glucocorticoid treatment, early in kidney development, results, at least in part, from impaired nephrogenesis.
Asunto(s)
Glucocorticoides/farmacología , Hipertensión/patología , Nefronas/patología , Efectos Tardíos de la Exposición Prenatal , Ovinos/fisiología , Algoritmos , Animales , Peso Corporal/fisiología , Colágeno/metabolismo , Dexametasona/farmacología , Femenino , Glomeruloesclerosis Focal y Segmentaria/patología , Hipertensión/inducido químicamente , Riñón/patología , Glomérulos Renales/patología , Tamaño de los Órganos/efectos de los fármacos , EmbarazoRESUMEN
There is evidence to suggest that an individual's susceptibility to cardiovascular disease cannot be entirely explained by differences in life style factors (i.e., low physical activity, high fat/salt diet), or genetic causes, but may also be influenced by factors encountered during intrauterine life. Epidemiological studies found the link between low birth weight for gestational age (a broad index of sub-optimal intrauterine environment) and increased incidence of cardiovascular and metabolic diseases in adulthood. Many animal models in which the intrauterine environment was altered during early/late or throughout gestation demonstrated long-term effects on adult health. In general stress in early gestation is more likely to be associated with adult cardiovascular disease including hypertension, whereas late gestation stress may also be associated with adult hypotension in addition to metabolic/endocrine abnormalities. Two systems have been widely hypothesised to serve as mechanisms via which adverse prenatal influences impinge on adult cardiovascular and metabolic disease; hippocampal-hypothalamo-pituitary-adrenal axis (HHPA) and renin-angiotensin system (RAS). Interestingly, at least in our animal model of adult hypertension after brief/early prenatal glucocorticoid exposure, HHPA axis is not altered when studied either in late gestation or at several stages during adulthood. However, our more recent results, using the same animal model, suggest a major role for the central and renal RAS. This review will mainly focus on animal models and potential mechanisms via which a perturbed intrauterine environment (undernutrition or steroid exposure) lead to adult cardiovascular and/or metabolic disease.
Asunto(s)
Enfermedades Cardiovasculares/embriología , Glucocorticoides/fisiología , Factores de Edad , Animales , Enfermedades Cardiovasculares/genética , Modelos Animales de Enfermedad , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/fisiología , Femenino , Glucocorticoides/toxicidad , Humanos , Enfermedades Renales/embriología , Sistema Hipófiso-Suprarrenal/embriología , Sistema Hipófiso-Suprarrenal/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Ovine fetuses exposed to high concentrations of synthetic (dexamethasone, D) or naturally occurring glucocorticoids (cortisol, F) in utero during early gestation develop high blood pressure in adulthood. To investigate potential mechanisms involved, we examined the role of the renal renin-angiotensin system (RAS). Ewes were infused with isotonic saline (S, n = 11), D (n = 12, 0.48 mg/h), or F (n = 5, 5 mg/h) for 48 h between d 26 and 28 of gestation (term = 150 d). Ewes carrying twins (S, n = 5; D, n = 6; F, n = 5) were killed at 130 d of gestation. The mRNA levels for angiotensinogen, the AT(1) receptor and AT(2) receptor, were increased in the fetal kidneys after D treatment. Prenatal infusions of F produced similar effects on the AT(1) receptor. Single fetuses (S, n = 6; D, n = 6) were cannulated and infused with angiotensin II for 3 d beginning at 127 d of gestation. Basal blood pressure was similar in both groups and increased similarly with angiotensin II infusion. However, increases in urine flow and glomerular filtration rate were significantly reduced and kidney weights increased in the D-treated group. These results indicate that treatment with D very early in gestation causes significant alterations in the RAS in the fetal kidney 100 d later with functional consequences. Changes in the RAS in the developing kidney may be an important mechanism in the development of adult disease.
Asunto(s)
Glucocorticoides/efectos adversos , Riñón/embriología , Intercambio Materno-Fetal , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina II/administración & dosificación , Angiotensinógeno/genética , Animales , Presión Sanguínea/efectos de los fármacos , Western Blotting , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Diuresis/efectos de los fármacos , Femenino , Edad Gestacional , Tasa de Filtración Glomerular/efectos de los fármacos , Glucocorticoides/administración & dosificación , Hidrocortisona/administración & dosificación , Hidrocortisona/efectos adversos , Hipertensión/inducido químicamente , Inmunohistoquímica , Riñón/fisiología , Hibridación de Ácido Nucleico , Tamaño de los Órganos/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Embarazo , Efectos Tardíos de la Exposición Prenatal , ARN Mensajero/análisis , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/genética , OvinosRESUMEN
Low-dose dexamethasone (D) treatment is used in pregnancies where the fetus is suspected to be at risk of congenital/virilizing adrenal hyperplasia. To study if this treatment had any immediate or long-term effects in normal fetuses, pregnant ewes were treated with D (20 microg/kg maternal body weight x d) or saline (S), from d 25-45 of gestation. Tissue was collected from fetuses killed at 45 d (S = 6; D = 8), 130 d (S = 8; D = 8), or lambs at 2 months of age (S = 6; D = 6) and mRNA levels measured using real-time PCR. D treatment reduced adrenal wt at 45 d (S, 12.2 +/- 0.7 mg; D, 6.3 +/- 0.4 mg) and significantly decreased adrenal mRNA for P(450scc). At 130 d, fetuses from the D treatment were growth retarded (S, 3.2 +/- 0.1 kg; D, 2.5 +/- 0.1 g), but the adrenals were appropriate for the body weight. mRNA levels of angiotensinogen, the AT(1) receptor and mineralocorticoid receptor (MR) and GR were similar in kidney and brain (hypothalamus, hippocampus, medulla oblongata) except for hippocampal expression of MR and GR, which was significantly decreased by D treatment. By 2 months, BW and hippocampal MR and GR mRNA levels were similar, and lambs were normotensive (S, 83 +/- 3 mm Hg; D, 78 +/- 3 mm Hg). Thus, there were no persistent, long-term effects of prolonged low-dose D treatment in normal ovine fetuses.
Asunto(s)
Dexametasona/toxicidad , Feto/efectos de los fármacos , Líquido Amniótico/metabolismo , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calibración , Cartilla de ADN , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Frecuencia Cardíaca/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Embarazo , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , OvinosRESUMEN
AIM: To examine cardiovascular, hormonal and other physiological responses of 2-month-old lambs to rubber-ring castration and tail docking. METHODS: Twenty-two male lambs, well accustomed to handling and prepared with femoral artery and jugular vein cannulae, were studied during a 5 h control period and, at least 2 days later, for 1 h before and 4 h after castration and tail docking using rubber rings. Pressure recordings were made via femoral cannulae and blood samples for analysis of plasma constituents were taken from jugular cannulae. RESULTS: Mean systolic, diastolic and mean arterial blood pressure, heart rate and the plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol all increased markedly during the first 1 h after ring castration and tail docking. Although plasma ACTH and cortisol concentrations had returned to control levels by 2.5-3 h, blood pressures and heart rate were still elevated 4 h after ring application. In contrast, there were no significant changes in mean plasma concentrations of renin, electrolytes, minerals, glucose, lactate, urea, creatinine, total carbon dioxide and total proteins, plasma osmolality or the haematocrit after ring application. There were no significant changes in the mean values for any parameter during the 5 h control period or the 1 h period before ring application. CONCLUSION: Systolic, diastolic and mean arterial blood pressure and heart rate may be more sensitive than plasma ACTH or cortisol concentrations as indices of low-grade pain induced by ring castration and tail docking. Alternatively, it is possible that by 4 h after ring placement a small shift in sympathetic tone still persists in the absence of low-grade pain.
RESUMEN
1. When pregnant ewes and their fetuses are exposed to the synthetic glucocorticoid dexamethasone for 2 days early in pregnancy (days 26-28; term 145-150 days), female offspring have increased blood pressure relative to a control group. In one series, this was shown to be due to increased cardiac output, concomitant with a reset mean arterial pressure/heart rate reflex. The first group of such animals had, by the age of 7 years, left ventricular hypertrophy and reduced cardiac functional capacity. 2. The elevation in blood pressure is not maintained by any change in the peripheral renin-angiotensin system (RAS). 3. There is, however, preliminary evidence that some aspects of local RAS (particularly in the kidney and brain) could have participated in the 'programming' event. The levels of mRNA for angiotensin II receptors (AT1, AT2) and angiotensinogen are increased in the kidney of such dexamethasone-treated fetuses in late gestation (130 days), some 100 days after steroid treatment. Similar increases in AT1 mRNA in the medulla oblongata of the fetal brain and large increases of mRNA for angiotensinogen occur in the hypothalamus. 4. These findings, together with evidence from the literature, suggest that both the kidney and parts of the brain are affected by events that also 'program' high blood pressure in the offspring of animals in which the intra-uterine environment has been perturbed at some stage.
Asunto(s)
Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Riñón/anomalías , Efectos Tardíos de la Exposición Prenatal , Sistema Renina-Angiotensina/fisiología , Animales , Presión Sanguínea , Femenino , Hipertensión/inducido químicamente , Riñón/crecimiento & desarrollo , Modelos Animales , Embarazo , Sistema Renina-Angiotensina/efectos de los fármacos , Factores Sexuales , Ovinos , Esteroides/farmacologíaRESUMEN
We have shown that exposure of pregnant ewes to dexamethasone (11.5 mg/d for 2 days) at 27 days of gestation (term, 150 days) led to increased blood pressure and cardiac output in adult offspring. In this study, we hypothesized that dexamethasone-induced hypertension is associated with left ventricular hypertrophy and a reduced cardiac functional reserve (CO(max-0)). Six control animals (group C) and five dexamethasone-exposed animals (group D) were volume-loaded with Hemaccel until the wedge pressure was 13 mm Hg (baseline). The wedge pressure was held constant during an infusion of dobutamine at incremental doses (0.4 to 12 microgram/kg/min) while blood pressure and cardiac output were measured. The same protocol was repeated in each animal 5 days later under mild general anesthesia (1.5% isoflurane), when transthoracic echocardiography (M-mode) was obtained. Group D showed a reduced CO(max-0) in response to dobutamine during both conscious (89+/-22 versus 150+/-25 mL/kg/min in control; P<0.01) and anesthetized states (91+/-38 versus 156+/-56 mL/kg/min in control; P<0.05). Reduced CO(max-0) in group D was associated with higher left ventricular mass index compared with group C (2.6+/-0.67 versus 1.8+/-0.51 g/kg; P<0.05). In addition, group D showed a reduced cardiac contractility reserve (FS(max-0)) in response to dobutamine (21+/-22% versus 54+/-34% in group C; P<0.05). An impaired cardiac functional reserve in group D was associated with increased left ventricular type I collagen content. In conclusion, brief prenatal exposure to dexamethasone led to the development of hypertension, left ventricular hypertrophy, and reduced cardiac functional reserve in adult life.
Asunto(s)
Dexametasona/efectos adversos , Hipertensión/inducido químicamente , Hipertrofia Ventricular Izquierda/inducido químicamente , Hipertrofia Ventricular Izquierda/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Colágeno/análisis , Modelos Animales de Enfermedad , Dobutamina , Ecocardiografía , Femenino , Gelatina/administración & dosificación , Glucocorticoides/efectos adversos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico , Infusiones Intravenosas , Contracción Miocárdica/efectos de los fármacos , Miocardio/química , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Polímeros/administración & dosificación , Embarazo , Arteria Pulmonar/fisiopatología , Presión Esfenoidal Pulmonar/efectos de los fármacos , OvinosRESUMEN
1. Fetal exposure to an adverse intrauterine environment has been linked with cardiovascular and metabolic disease later in life. We have shown previously, in sheep, that brief exposure (48 h) to maternally administered dexamethasone (0.28 mg/kg per day) at 27 days of gestation (prenatal treatment group (PTG) 1; term approximately 150 days), but not at 64 days of gestation (PTG2), produced hypertensive offspring at 40 months of age. The present study aimed to determine whether the elevated blood pressure in these sheep was associated with an altered peripheral renin-angiotensin system (RAS). 2. Measurements of the basal levels of the RAS components (renin, angiotensinogen, angiotensin (Ang) I, angiotensin- converting enzyme (ACE), AngII and Ang-(1-7)) were made. In addition, we studied the effect of a peripherally administered AngII type 1 (AT1) receptor antagonist (irbesartan at 1.02 mg/kg per h) on mean arterial pressure (MAP) over 4.5 h. 3. There was no significant difference in basal plasma concentrations of the components of the RAS measured between control (n = 7) and PTG1 (n = 5) or PTG2 (n = 6) animals. The MAP in PTG1 was significantly higher than in the control group during both vehicle infusion and AT1 receptor blockade. The effect of 4.5 h irbesartan (1.02 mg/kg per h) infusion on blood pressure was similar between the groups. 4. In conclusion, intrauterine exposure for 48 h to maternally administered dexamethasone at 27 days of gestation caused elevated blood pressure in adult sheep that does not appear to be associated with an alteration in the peripheral RAS.
Asunto(s)
Angiotensinógeno/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Dexametasona/farmacología , Glucocorticoides/farmacología , Hipertensión/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Sistema Renina-Angiotensina/efectos de los fármacos , Renina/efectos de los fármacos , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina , Angiotensinógeno/sangre , Animales , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea/fisiología , Femenino , Hipertensión/sangre , Irbesartán , Embarazo , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Renina/sangre , Sistema Renina-Angiotensina/fisiología , Ovinos , Tetrazoles/farmacología , Vasoconstrictores/farmacologíaRESUMEN
BACKGROUND: At 27 days of gestation in the ovine fetus (term = 145 to 150 days), the only kidney is the mesonephros, and allantoic fluid represents fetal urine. The hypothesis tested in this study was that functional glucocorticoid receptors (GRs) are present in this early mesonephric kidney. METHODS: Pregnant ewes, between 26 and 30 days, were infused with saline, dexamethasone (0.48 mg/hour), cortisol (5 mg/hour), or aldosterone (10 microg/hour) for 48 hours and were then killed for collection of fetuses and fetal fluids. GR mRNA was measured by real-time polymerase chain reaction in whole fetuses, and the location of gene expression was determined by hybridization histochemistry. RESULTS: Significant changes in allantoic fluid composition were produced by the exposure of the fetus to maternally infused synthetic (dexamethasone) and natural (cortisol) glucocorticoids, over a period of two days, compared with fetuses of ewes infused with vehicle (isotonic saline; N = 8) or aldosterone (N = 8). Volume of fluid was unchanged by any treatment, but both dexamethasone (N = 10) and cortisol (N = 8) caused significant (P < 0.05) decreases in sodium and chloride concentrations and increases in concentrations of potassium, urea, glucose, and fructose. GR mRNA was detected in equivalent concentrations in the whole fetuses of saline, dexamethasone, and cortisol treatments. The GR mRNA levels were significantly decreased in the aldosterone group. By hybridization histochemistry, GR mRNA was detected in most of the tubular cells of the mesonephros. CONCLUSION: These results suggest that functional GRs are present in the early ovine mesonephros.
Asunto(s)
Feto/metabolismo , Mesonefro/metabolismo , Receptores de Glucocorticoides/metabolismo , Ovinos/embriología , Alantoides/metabolismo , Líquido Amniótico/metabolismo , Animales , Líquidos Corporales/efectos de los fármacos , Líquidos Corporales/metabolismo , Sistemas de Computación , Dexametasona/farmacología , Femenino , Glucocorticoides/farmacología , Histocitoquímica , Hidrocortisona/farmacología , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Embarazo , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/genética , Ovinos/sangreRESUMEN
Numerous epidemiological studies have related an increased risk of adult-onset cardiovascular and metabolic disease to an adverse intra-uterine environment at critical periods. We have shown that fetal sheep exposed to dexamethasone for only 2 days at 27 days of gestation (term approximately 150 days) became hypertensive adults, whereas those exposed at 64 days of gestation remained normotensive, as did controls. In the same sheep, now nearly 5 years old, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to study the insulin sensitivity of glucose, amino acid and non-esterified fatty acid metabolism. Glucose tolerance, calculated as the area under the curve, after intravenous administration of bolus glucose and insulin secretion in response to a glucose challenge were not altered in any group. There were no significant differences in the insulin sensitivity of net whole-body glucose or amino acid uptake. However, suppression of lipolysis by insulin, measured as the proportional decrease in the circulating concentration of non-esterified fatty acids during the hyperinsulinaemic clamp, was 69+/-1.2% at steady-state plasma insulin levels ( approximately 1000 m-units/l) in the group exposed to dexamethasone at 27 days of gestation, but only 50.8+/-6.5% in the controls (P<0.05). In the group exposed to dexamethasone at 64 days of gestation, the decrease was 66.4+/-5.1%, which did not reach significance compared with the controls (P=0.10). Thus brief dexamethasone exposure during early gestation programmed hypertension independently of insulin resistance of glucose or amino acid metabolism; however, it did lead to increased insulin sensitivity of the inhibition of lipolysis, which may increase susceptibility to the development of obesity postnatally.
Asunto(s)
Dexametasona/efectos adversos , Edad Gestacional , Glucocorticoides/efectos adversos , Hipertensión/embriología , Resistencia a la Insulina/fisiología , Efectos Tardíos de la Exposición Prenatal , Aminoácidos/metabolismo , Animales , Glucemia/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Hipertensión/sangre , Hipertensión/inducido químicamente , Intercambio Materno-Fetal , Embarazo , OvinosRESUMEN
1. There is considerable evidence to support the idea that steroid hormones have the potential to increase blood pressure that may not always be via 'classical' mineralocorticoid or glucocorticoid action. 2. Epidemiological studies, together with the evidence from studies in animals, proposed the link between an adverse intra-uterine environment (i.e. undernutrition or excess exposure to glucocorticoids) and the early onset of cardiovascular and metabolic diseases later in life. 3. We tested this by treating pregnant ewes (and foetuses) with excess steroid early in pregnancy. The mean ages at which the prenatal exposure to glucocorticoid (dexamethasone 0.48 mg/h for 48 h) occurred were 22 +/- 0.4 to 29 +/- 0.4 days (prenatal treatment group 1; PTG1) and 59 +/- 2 to 66 +/- 2 days (PTG2), respectively. Basal blood pressures and hormones and the vascular responsiveness to graded doses of angiotensin II and noradrenaline, or to a 5-day adrenocorticotropin hormone treatment (ACTH), in lambs at 4, 10 and 19 months of age were studied. 4. Basal mean arterial pressure in PTG1 group (80 +/- 1 mmHg at 4 months; 83 +/- 1 mmHg at 10 months; and 89 +/- 1 mmHg at 19 months; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 +/- 2 mmHg at 4 months; 76 +/- 1 mmHg at 10 months; and 81 +/- 1 mmHg at 19 months; n = 7). Prenatal glucocorticoid exposure did not alter vascular responsiveness to noradrenaline, angiotensin II and ACTH in these sheep at any of the ages studied. 5. These results suggest that foetal exposure to maternal dexamethasone during defined developmental stage or 'window' programmes elevated blood pressure, which persists later in life.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Dexametasona/toxicidad , Glucocorticoides/toxicidad , Hipertensión/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Hormona Adrenocorticotrópica/farmacología , Angiotensina II/farmacología , Animales , Femenino , Hipertensión/etiología , Norepinefrina/farmacología , Embarazo , Ovinos , Vasoconstrictores/farmacologíaRESUMEN
Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset of cardiovascular and metabolic diseases later in life. We were the first to show that sheep exposed to dexamethasone (0.28 mg.kg-1.day-1 for only 2 days) at the end of the first month of pregnancy (PTG1), but not those exposed at the end of the second month of pregnancy (PTG2), had a higher basal mean arterial pressure (MAP) 19 months after birth. In the present study we report the MAP, cardiovascular haemodynamics and baroreflex sensitivity in these animals at 40 months of age. MAP in the PTG1 group was significantly higher than in the control group (91+/-1 mmHg and 81+/-1 mmHg respectively; P<0.001) and also when compared with the PTG2 group (82+/-1 mmHg; P<0.001). There was a significant increase in cardiac output in the PTG1 group compared with the control group (108+/-2 and 96+/-4 ml.min-1.kg-1 respectively; P<0.05). The increase in cardiac output in the PTG1 group was due to an increase in stroke volume (1.82+/-0.08 ml.kg-1. beat-1, compared with 1.46+/-0.06 ml.kg-1.beat-1 in the control group; P<0.05), but not in heart rate. In the hypertensive group of animals (PTG1), there was a rightward shift of the baroreflex curve. In group PTG2 (the normotensive group of animals), a lower gain was found before and during propranolol treatment. The decrease in gain of the baroreflex was not associated with changes in heart rate range, suggesting an impairment in the central processing of the baroreceptor signals. Thus sheep fetuses exposed to dexamethasone for only 2 days at the end of the first month of gestation have high blood pressure (dependent upon the increase in cardiac output) and a reset of the baroreflex at 40 months of age. Animals that have received prenatal dexamethasone closer to mid-gestation, although normotensive with normal cardiac output, showed an altered baroreceptor-heart rate response.
Asunto(s)
Barorreflejo/efectos de los fármacos , Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Embarazo , Efectos Tardíos de la Exposición Prenatal , OvinosRESUMEN
For many years, both human and animal studies correlated changes in behaviour of the young offspring with the degree of maternal stress or glucocorticoid exposure of the foetus/neonate. In the past ten years there has been overwhelming epidemiological evidence to suggest that growth retardation in utero is a very important risk factor for the development of cardiovascular and metabolic disease in adult life. More recently, it has been shown that one important, even key, determinant is the exposure of the foetus to excess glucocorticoid. Even a brief period (48 h) of dexamethasone exposure very early in pregnancy was able to programme permanently hypertensive adult sheep. Understanding how such programming works, and the underlying physiological changes that occur, provides one of the most exciting challenges in contemporary endocrinology and developmental biology.
RESUMEN
Hydrops fetalis, with or without oligo- or polyhydramnios, is associated with very high fetal mortality. In many cases the causes are unknown. Chronically cannulated ovine fetuses have been used as animal models to study the regulation of fetal fluid balance. This study reports that the mid-gestation ovine fetus (70 +/- 1 d of gestation; term = 145-150 d) is susceptible to the development of fetal abnormalities (excess allantoic fluid--hydrallantois, with or without hydrops and hydranencephaly), when blood vessels in the neck are cannulated. Cannulation of one carotid artery and one jugular vein, or cannulation of a single jugular vein resulted in 5 out of 12 fetuses having abnormalities 1 wk later. In contrast, six fetuses at 115 d of gestation that had both carotids and one jugular vein ligated cranially and cannulated, developed hydranencephaly but no hydrops or hydrallantois. In the mid-gestation fetus hydrallantois [760 +/- 140 mL (n = 5) versus 104 +/- 23 mL (n = 7 controls), p < 0.001] occurred without alterations in the plasma concentrations of ACTH, cortisol, atrial natriuretic peptide, or aldosterone, as well as without anemia. Although the causes of the fluid abnormalities were not resolved, it is important to note the developmental differences in vulnerability.
Asunto(s)
Cateterismo/efectos adversos , Hidropesía Fetal/etiología , Hidropesía Fetal/fisiopatología , Equilibrio Hidroelectrolítico/fisiología , Hormona Adrenocorticotrópica/sangre , Aldosterona/sangre , Animales , Factor Natriurético Atrial/sangre , Arterias Carótidas , Modelos Animales de Enfermedad , Femenino , Sangre Fetal/metabolismo , Edad Gestacional , Humanos , Hidrocortisona/sangre , Hidropesía Fetal/sangre , Venas Yugulares , Embarazo , OvinosRESUMEN
1. Recent studies in animals have linked fetal exposure to excess maternal glucocorticoids with the later occurrence of cardiovascular disorders, particularly hypertension. 2. To test the hypothesis that prenatal treatment could impact on adult blood pressure two groups of pregnant ewes were transported from the farm to the Institute at either 22-29 days of pregnancy (pretreatment group 1) or 59-66 days of pregnancy (pretreatment group 2), subjected to 48 h treatment with dexamethasone (0.28 mg day-1 kg-1 for 2 days) and then returned to the farm. The control group remained at the farm for the entire pregnancy. Lambs were then studied at approximately 4, 10 and 19 months after birth. 3. The basal mean arterial pressure in pretreatment group 1 (80 +/- 1 mmHg at 124 days; 83 +/- 1 mmHg at 309 days and 89 +/- 1 mmHg at 558 days; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 +/- 2 mmHg at 110 days; 76 +/- 1 mmHg at 323 days and 81 +/- 1 mmHg at 568 days; n = 7). However, prenatal glucocorticoid exposure did not alter vascular sensitivity to noradrenaline, angiotensin II and adrenocorticotropic hormone in these sheep at any of the ages studied, nor did it affect basal or adrenocorticotropic hormone-induced concentrations of cortisol or basal plasma renin concentrations in the lambs at any age. 4. These data support the hypothesis that excess glucocorticoid exposure in early pregnancy, during a critical developmental stage or 'window', programmes higher blood pressure that persists in later life.
Asunto(s)
Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Hipertensión/etiología , Efectos Tardíos de la Exposición Prenatal , Hormona Adrenocorticotrópica/farmacología , Angiotensina II/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Edad Gestacional , Hidrocortisona/sangre , Hipertensión/sangre , Norepinefrina/farmacología , Embarazo , OvinosRESUMEN
These studies investigated whether treatment with carbenoxolone (CBX), an inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), resulted in an enhanced mineralocorticoid response to endogenous or infused cortisol. In conscious sodium replete sheep with a parotid fistula, infusion of CBX (40 mg/h for 10 days) did not increase mean arterial pressure, or change sodium and potassium status or plasma renin concentration, but significantly increased the half-life of 1,2[3H] cortisol from 18.6 +/- 4.0 to 38.8 +/- 3.9 min (p < 0.05) and reduced the blood clearance rate of cortisol (BCR) from 31 +/- 3 to 15 +/- 4 L/h (p < 0.01). The reduction in cortisol BCR was associated with reduction in cortisol secretion rate from 433 +/- 116 to 181 +/- 79 nmol/h (p < 0.01). Cortisol (8 mg/h) for 5 days increased mean arterial pressure (from 83 +/- 2 to 101 +/- 5 mmHg, p < 0.001) and caused natriuresis, hypokalaemia and hyperglycaemia. These responses were unaltered when cortisol was infused from the fifth to the tenth day of CBX infusion. These findings suggest that in sheep, carbenoxolone is either a less potent inhibitor of 11 beta-HSD2 than in other species or 11 beta-HSD2 may not be the only mechanism, which determines the specificity of the MR.