Effect of Cortisol on C-Type Natriuretic Peptide in Ovine Pregnancy: Differential Responses in Fetal and Placental Tissues

Abstract

ABSTRACT:We have used aminoterminal pro C-type natriuretic peptide (NTproCNP)-a stable marker of CNP secretion-to study the effect of cortisol on CNP secretion and fetal growth. In ovine pregnancy, maternal plasma NTproCNP (largely sourced from the placenta) increases at the end of the first trimester and then decreases abruptly preterm during the phase of fetal surge in cortisol secretion. Postulating that increases in cortisol, as occurs in the fetal or maternal circulation in late pregnancy, will reduce CNP secretion, we studied the fetal and maternal responses in NTproCNP to sustained low-dose infusions of cortisol (1.2 mg/d/kg for 11 d) delivered to the fetus from d 117 gestation. Fetal plasma NTproCNP was progressively reduced during fetal cortisol infusions, whereas fetal girth growth was unchanged. In contrast, maternal NTproCNP was unaffected by cortisol. We conclude that fetal but not placental tissue production of CNP is reduced by small increments in fetal cortisol. Failure to reduce maternal NTproCNP may relate to the continuing presence of the placental barrier to cortisol at this stage of pregnancy. (Pediatr Res 68: 462-465, 2010) C -type natriuretic peptide (CNP) is an important growth factor expressed in a wide range of tissues (1) during development (2) and postnatal life (3). Although shown to be essential to postnatal linear growth in both rodents (4) and humans (5), CNP production has also been found to correlate strongly with linear growth velocity in lambs and throughout all phases of linear growth in humans (6 -8). In rapidly growing lambs, catabolic interventions such as caloric restriction (9) and high doses of glucocorticoids (7), well-recognized inhibitors of linear growth, rapidly and reversibly reduce circulating forms of CNP and markers of bone formation. Similar reductions in CNP forms occur in the fetus during maternal caloric restriction (10) or glucocorticoid administration (6). However, the effect of physiological increments in fetal cortisol on CNP synthesis is unknown.Recent studies of ovine pregnancy show that both CNP and the bio inactive aminoterminal fragment of pro CNP 1-103 (NTproCNP) (11) are secreted by the placenta and circulate at high concentrations in maternal plasma from the end of the first trimester (12). In contrast, the ovine placenta does not seem to contribute to circulating fetal CNP concentrations, which are much lower than maternal concentrations (12). Nonetheless, as in the human fetus (13), fetal CNP synthesis is likely to be high, as shown by the very high concentrations of NTproCNP in fetal plasma. Fetal CNP forms are clearly regulated independently of maternal concentrations (10), but the sites of synthesis and the source of NTproCNP in the fetal circulation remain to be determined.A striking feature of the pattern of maternal plasma CNP forms in healthy pregnant ewes is the sudden decline in both NTproCNP and CNP within the last week of pregnancy (12)-a phase of rapidly increasing fetal cortisol production (14). Mindful of the inhibitory effects o...

Acute inflammation in young children inhibits C-type natriuretic peptide

“…Both CNP production and linear growth can be rapidly reduced in lambs or children by factors known to impair growth, such as nutrient deficiency (21) or high doses of glucocorticoids (3). Because small (contrived) increases in plasma cortisol for a period of 10 d in fetal lambs also lower NTproCNP (22), stress associated increases in cortisol could contribute to the suppressed levels of CNP we observed. However, the close inverse association of CNP values with CRP and fever suggest that inflammatory cytokines are more likely to be involved.…”