Programming of Hypertension

Abstract

Abstract-Animal models suggest that explanations for the association of low birthweight with adult hypertension may include chronic activation of the hypothalamic-pituitary-adrenal or renin-angiotensin-aldosterone axes. In humans, low birthweight predicts elevated plasma cortisol, but associations with aldosterone have not been reported. We measured aldosterone in serum samples from 205 men and 106 women from 67 to 78 years of age, from Hertfordshire, UK, for whom birthweight was recorded. Participants underwent an overnight low-dose (0.25 mg) dexamethasone suppression test and a low-dose (1 g) ACTH (corticotropin) stimulation test and were genotyped for the -344 C/T polymorphism of the CYP11B2 gene encoding aldosterone synthase. Median aldosterone was 6.22 ng/dL (range 0.15 to 38.74) and was higher in men than women (PϽ0.0001). Higher aldosterone levels after both dexamethasone and ACTH stimulation were associated with higher blood pressure (rϭ0.20, Pϭ0.001; rϭ0.33, PϽ0.0001, respectively) and with lower birthweight (rϭϪ0. 16, Pϭ0.008; rϭϪ0.21, Pϭ0.001, respectively). These associations remained significant after adjusting for age, gender, obesity, and genotype. Our findings supplement previous evidence that aldosterone is an important regulator of blood pressure and suggest that factors in early life that retard fetal growth and program activation of the hypothalamic-pituitary-adrenal axis in humans result not only in higher glucocorticoid activity but also in increased mineralocorticoid activity. Key Words: programming Ⅲ hypertension Ⅲ aldosterone Ⅲ mineralocorticoid Ⅲ glucocorticoid E pidemiological studies have shown that low birthweight, a marker of an adverse intrauterine environment, is associated with development of hypertension in adulthood. 1 One hypothesis to explain this phenomenon is excessive activity of glucocorticoids. 2 Treatment of pregnant rats with dexamethasone reduces birthweight and leads to permanent hypertension and increased hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. [2][3][4] Similarly, in men and women of low birthweight and with cardiovascular risk factors, including hypertension, we observed increased fasting cortisol, increased excretion of urinary glucocorticoid metabolites, and increased cortisol responses to ACTH stimulation. 5-8 Thus, it has been proposed that elevated glucocorticoid activity resulting from activation of the HPA axis may explain the link between low birthweight and high blood pressure.Chronic activation of the HPA axis may also increase mineralocorticoid activity. This mechanism has been invoked, for example, to explain higher aldosterone levels in subjects with polymorphisms in CYP11B1 and CYP11B2 that associate with lower 11␤-hydroxylase activity, reduced cortisol secretion, and compensatory HPA axis activation. 9 There is substantial evidence implicating mineralocorticoids in the pathogenesis of hypertension. For example, data from the Framingham Offspring Study showed that higher aldosterone levels within the normal range predict...

Impaired Cardiovascular Structure and Function in Adult Survivors of Severe Acute Malnutrition

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Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension

“…[15][16][17] More broadly, aldosterone is linked to the development and progression of cardiorenal disease, including endothelial dysfunction, proteinuria, left ventricular hypertrophy, target-organ fibrosis and inflammation, congestive heart failure, stroke, and recently the severity of obstructive sleep apnea. 18 -30 Mineralocorticoid receptor-blocking agents, such as spironolactone and eplerenone, prevent aldosterone from binding with the mineralocorticoid receptor.…”

Mineralocorticoid receptor activation in obesity hypertension

“…Aldosterone as well as glucocorticoid is suggested to be involved in the mechanisms, possibly because of the activation of the hypothalamus-pituitary-adrenal axis. 66 Aldosterone excess has also been reported in several animal models of obesity and metabolic syndrome. For example, obese, heart failureprone SHHF/Mcc-fa cp is documented to have a higher plasma aldosterone level compared with +/+ control (209.4 ± 14.3 vs. 107.0±17.0 ng l À1 ; Po0.05).…”