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.

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

“…The secretion of insulin, the counterbalancing hormone for glucagon, proceeds through activation of AC (Gao et al 2002), so the heterologous augmentation of AC signaling caused by CPF exposure is likely to amplify the physiologic effect of a superimposed deficiency in the glucagon response. It is now recognized that diseases that occupy a distinct cluster-hypertension, obesity, and diabetes-may have significant dependence on prenatal stress and/or toxicant exposures (Dodic et al 1999(Dodic et al , 2001Nyirenda and Seckl 1998;Power and Jefferis 2002;Slikker and Schwetz 2003;Toschke et al 2002). The present results point to the possibility that otherwise subtoxic, nonsymptomatic developmental exposure may provide predisposition to these types of diseases, with a specific component of delayed-onset effects.…”

“…The "Barker Hypothesis" originally drew a connection between fetal growth retardation and the subsequent incidence of coronary artery disease and diabetes (Barker 2003;Phillips 2002), and there is also significant literature on the long-term consequences of prenatal stress and the role of glucocorticoid hormones (Dodic et al 1999(Dodic et al , 2001Nyirenda and Seckl 1998). More recently, there are suggestions that environmental toxicants may play an important contributory role in such disorders as hypertension, diabetes, and obesity, beyond neural contributions (Power and Jefferis 2002;Slikker and Schwetz 2003;Toschke et al 2002).…”

Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

“…Oophorectomized offspring (group SA, nϭ6; group DA, nϭ5) have been studied extensively before being killed at 7 years of age for tissue collection. [11][12][13]21 Both male and female animals from the first cohort had basal blood pressure measurements. Blood pressure response to testosterone was studied after basal blood pressure measurements only in males from the same cohort.…”

“…[11][12][13] Animals (both male and female) were between 16Ϯ1 and 24Ϯ4 months of age. The pressure was corrected to compensate for the height of transducer above the level of the heart.…”

“…This hypertension amplifies with age and is associated with an increased cardiac output. 12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied.…”