Altered cardiovascular haemodynamics and baroreceptor‒heart rate reflex in adult sheep after prenatal exposure to dexamethasone

Abstract

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.

Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up

“…Steroids may lead to microvascular dysfunction by altering vascular responses to vasoconstrictors, including induction of endothelin vasoconstriction and attenuating endothelium-dependent vasorelaxation [34,35]. A central mechanism has been proposed with alteration of baroreceptor centres in the brainstem [36]. However, despite these findings, Dalziel et al found no increased risk of hypertension in their 30-year follow-up after antenatal exposure to betamethasone [37].…”

Glucocorticoid programming of adult disease

“…Both produce hypertension in the adult sheep offspring (Dodic et al 1998(Dodic et al , 2002b and both produce a decrease in nephron number after nephrogenesis is completed (Wintour et al 2003a,b;Moritz et al 2004). However, as shown in (Dodic et al 1999), whereas that attributable to cortisol is dependent upon increased peripheral resistance (McAlinden et al 2004). In addition, the long-term changes in gene expression in various sections of the brain also differ (Fig.…”

“…When dexamethasone or cortisol is infused early into the ewe (from 26-28 days of gestation; term is 145-150 days), all offspring are hypertensive from 3-5 months (Dodic et al 1998(Dodic et al , 2002aRoghair et al 2005). In the case of dexamethasone treatment, the hypertension is associated with an increased cardiac output and no change in peripheral sensitivity to infused angiotensin II (Dodic et al 1998(Dodic et al , 1999Roghair et al 2005). The in vitro responsiveness of mesenteric arteries of hypertensive offspring is actually less responsive to angiotensin II, whereas the coronary arteries show increased vasoconstriction to ang II and other second-messenger-dependent vasoconstrictors (Dodic et al 1998;Roghair et al 2005).…”

Adverse prenatal environment and kidney development: implications for programing of adult disease

“…Short-term infusions of glucocorticoids during early-or midgestation culminate in hypertension in both sheep (Dodic et al 2002) and rat offspring respectively (Ortiz et al 2003, Singh et al 2007a. Interestingly, the outcome is highly dependent upon the timing of exposure as the same level of glucocorticoid exposure did not result in hypertension when administered at other stages of development (Dodic et al 1999, Ortiz et al 2003. Models of uteroplacental insufficiency have been developed to explore the long-term effects of reduced placental function in late gestation in the rat, which coincides with the period of rapid fetal growth.…”