Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep

Abstract

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 μg h⁻¹) were significantly greater in the DEX group (10 ± 1 mmHg at 1 μg 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.