Prolonged low-dose dexamethasone treatment, in early gestation, does not alter blood pressure or renal function in adult sheep

Dodic, Miodrag; Jefferies, Andrew J.; Wintour, E. M.; Moritz, Karen M.

doi:10.1677/joe.0.1790275

Cited by 13 publications

(6 citation statements)

References 31 publications

(45 reference statements)

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“…Our data also agree with the findings that treatment of pregnant ewes very early in gestation with low dose of dexamethasone does not change the whole kidney GFR in adult female offspring (12). The lack of alterations in whole kidney GFR and renal blood flow in females suggests an increase in single nephron hemodynamics when taking into consideration the similarity in the reduced nephron number in males and females by antenatal dexamethasone exposure (15,32).…”

supporting

confidence: 91%

Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

Tang¹,

Carey²,

Bi³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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posure to clinically relevant doses of glucocorticoids during fetal life increases blood pressure in adult male and female sheep. The purpose of this study was to evaluate the effects of prenatal exposure to betamethasone at 80 -81 days of gestation on renal function in ewes and rams at 1.5 yr of age. In prenatal betamethasone-exposed males, compared with the vehicle-exposed animals, basal glomerular filtration rate (GFR) (1.93 Ϯ 0.08 vs. 2.27 Ϯ 0.10 ml ⅐ min Ϫ1 ⅐ kg body wt Ϫ1 ) and the ability to excrete an acute Na ϩ load (37.1 Ϯ 4.4 vs. 53.7 Ϯ 9.7%) were reduced. (P Ͻ 0.03 and P ϭ 0.03, respectively). In contrast, prenatal betamethasone exposure had no effect on basal GFR, Na ϩ excretion, or the percentage of the Na ϩ load excreted during the experiment in females. Systemic infusions of ANG-(1-7) at 9 ng⅐ min Ϫ1 ⅐ kg Ϫ1 for 2 h had minimal effects on basal GFR, renal plasma flow, and Na ϩ excretion in males but increased Na ϩ excretion in females. However, the percentage of Na ϩ load excreted during ANG-(1-7) infusion did not change in prenatal betamethasone-exposed females (113.1 Ϯ 14.2 vs. 98.1 Ϯ 12.2%) compared with the significant increase in vehicle females (139.2 Ϯ 22.3 vs. 92.2 Ϯ 7.5%) (P ϭ 0.01). The data indicate that antenatal betamethasone exposure produces gender-specific alternations in renal function and thus suggest that different mechanisms underlie the antenatal steroid-induced elevations in blood pressure in male and female offspring. prenatal steroid exposure; sodium load; glomerular filtration rate; sodium excretion; angiotensin-(1-7) SINCE ANTENATAL STEROID TREATMENT became the standard of care for enhancing fetal lung maturation in pregnancies threatened by premature labor between 24 and 34 wk of gestation, the use of corticosteroid therapy in the United States has increased from Ͻ15% of eligible pregnancies in 1990 to Ͼ75% in 1995 (1, 3). However, clinical epidemiological studies show an association between antenatal glucocorticoid administration and altered vascular function (7,46), suggesting that exposure to excess glucocorticoids in the prenatal period may have untoward consequences in adult offspring.We and others have shown using sheep and rat experimental models that prenatal steroid exposure results in elevated blood pressure in adulthood (8,10,14,36). Although there are likely multiple targets influencing the effect of steroids on blood pressure, several recent studies have suggested that altered kidney development induced by antenatal glucocorticoids may contribute to the elevations in arterial blood pressure (35,36,53). It is well known that the kidneys play a major role in the long-term regulation of arterial pressure and that change in renal function may lead to alterations in Na ϩ and water balance and blood pressure (19). In a rat model, Ortiz et al. (35,36) observed that prenatal exposure to dexamethasone on days 15 and 16 of gestation induced 30 and 20% reductions in glomerular number in offspring compared with controls when assessed at 60 -70 days and 6 -9 mo of age, ...

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supporting

confidence: 91%

Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

Tang¹,

Carey²,

Bi³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The hypertension induced by dexamethasone exposure at 26 -28 days gestation amplified with postnatal age and was associated with an increased cardiac output that was attributable to an increase in stroke volume (107). Interestingly, this programming effect was specific in timing as the same dose of dexamethasone administered for 48 h between 59 and 66 days gestation or a lower dose of dexamethasone given for a longer period (25-45 days gestation) did not produce hypertension in the offspring (110,111,350). Similarly in sheep, single or repeated maternal injections of betamethasone between 104 and 125 days gestation or repeated injections of dexamethasone, starting on day 103 of gestation, did not result in hypertension in the offspring at 5-12 mo of age (347,356).…”

Section: Sheepmentioning

confidence: 99%

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

McMillen

Robinson²

2005

Physiological Reviews

1,682

1,366

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The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

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“…However, in humans, a recent report found no significant effects of antenatal dexamethasone on detailed developmental outcomes [51]. An important difference may be that the majority of animal studies use doses that are one or two orders of magnitude above the doses recommended to treat pregnancies at risk for CAH [52].…”

Section: Antenatal Dexamethasone Therapy In Congenital Adrenal Hyperpmentioning

confidence: 99%

Adrenal Function of Low-Birthweight Children

Ong

2005

Abnormalities in Puberty

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During the neonatal period, increased stress due to infection or illness in low-birthweight infants may increase the importance of adequate adrenal cortisol secretion. Such low-birthweight infants often have transient cortisol insufficiency during the first few days of life, but then soon develop restored or even high cortisol levels. The pressure to enhance survival during this critical period could lead to either the programming of higher cortisol secretion, or the favorable selection of infants who are genetically predisposed to produce sufficient cortisol levels and activity. However, in long-term survivors of low birthweight, the maintenance of higher levels of cortisol secretion or action may contribute to increased hypertension and cardiovascular disease risk in later life. Similarly, low birthweight and subsequent rapid postnatal weight gain are associated with increased androgen secretion from the adrenal zona reticularis and this may contribute to disorders of hyperandrogenism and hyperinsulinemia before and after puberty. Precocious pubarche, the clinical manifestation of adrenal hyperandrogenism prepuberty, in girls is predictive of polycystic ovary syndrome, and is also associated with dyslipidemia, and increased central fat. In conclusion, long term consequences of low birthweight on both adrenal cortisol and adrenal androgen secretion could contribute to increased risks for the metabolic syndrome in later life.

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Prolonged low-dose dexamethasone treatment, in early gestation, does not alter blood pressure or renal function in adult sheep

Cited by 13 publications

References 31 publications

Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

Adrenal Function of Low-Birthweight Children

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