Organs/Systems Potentially Involved In One Model Of Programmed Hypertension In Sheep

Abstract

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.

Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology

“…The programming of glucose-insulin dyshomeostasis only occurs when glucocorticoids are administered in the final week of gestation (47), whereas the programming of hypertension is less time constrained (10, 35). Similar findings have been reported with DEX in sheep (10,20,28,35) and guinea pig (30, 52), although the particular windows of vulnerability appear species specific.In terms of mechanism, although prenatal DEX-programmed glucose intolerance is associated with permanently increased hepatic expression of a key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) (47), the basis of DEX programming of hypertension remains unknown, although some data in sheep have implicated the renin-angiotensin-aldosterone system (RAS) (21,46). Importantly, in adult rats, glucocorticoids regulate all of the principle components of the RAS, including renin secretion (17), angiotensinogen synthesis (16), ANG-converting enzyme activity (43), ANG II (56), and mineralocorticoid receptor expression (55).…”

“…The programming of glucose-insulin dyshomeostasis only occurs when glucocorticoids are administered in the final week of gestation (47), whereas the programming of hypertension is less time constrained (10, 35). Similar findings have been reported with DEX in sheep (10,20,28,35) and guinea pig (30, 52), although the particular windows of vulnerability appear species specific.…”

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

“…Previous studies in our laboratory demonstrated that highdose dexamethasone treatment administered to pregnant ewes (240 µg/kg maternal body weight per day), and thus their fetuses, for 2 days, early in pregnancy (26-28 days of gestation), has profound effects on adult cardiovascular function (Dodic et al 1998(Dodic et al , 1999(Dodic et al , 2001b(Dodic et al , 2002a. Also, this 2 day high-dose dexamethasone treatment causes significant changes in gene expression in the kidney, brain and hearts of twin ovine fetuses, killed at 130 days of gestation (Dodic et al 2001a, Hantzis et al 2001). In addition, several studies in rats have demonstrated high blood pressure associated with lower nephron number and altered renal function in an adult as a consequence of previous exposure to prenatal dexamethasone treatment (Celsi et al 1998, Ortiz et al 2001.…”

Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

“…At 7 yr of age, similarly exposed offspring displayed left ventricular hypertrophy and cardiac dysfunction (9). Further studies of this ovine model of fetal programming have demonstrated that adult offspring exposed to dexamethasone early in gestation have organ-specific alterations in renin-angiotensin system gene expression (7). There appears to be a critical window that allowed persistent programming of the hypertensive phenotype, since exposure to the same maternal dose at 64 days gestation failed to result in hypertensive offspring (8).…”