Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum

Abstract

We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in midgestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1·5-to 2-fold postpartum (P<0·01). At term, ANP content in right (8·7 1·2 vs 12·7 1·1 µg/mg protein, P<0·04) and left (3·5 0·6 vs 8·5 2·0 µg/mg protein, P<0·01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2-and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.

Pregnancy alters nitric oxide synthase and natriuretic peptide systems in the rat left ventricle

“…This decrease in cGMP may have resulted from downregulated natriuretic peptides and their GC receptors, as well as upregulated clearance receptors, which act as a buffering system, reducing the effective pool of natriuretic peptides. Decline of LV OTR, eNOS, iNOS and ER , and, as we have reported previously, plasma ANP (Mukaddam-Daher et al 2002) may also contribute to cGMP reduction in the LV. The reduced levels of cGMP at term favor a shift of balance toward enhanced heart work at the onset of labor.…”

“…The actions of estrogens and progesterone are mediated by specific binding sites in vascular tissue and in the heart. Their hormonal effects include changes in the synthesis or release of cardiac natriuretic peptides, and in the oxytocin system (Mukaddam-Daher et al 2002, Wang et al 2003 as well as NOS and cGMP regulation (Weiner et al 1994, Linke et al 2002. In addition, direct interaction between these systems may also be involved in pregnancy-associated cardiac remodeling.…”

“…Cardiac ANP expression is influenced by elevated estradiol during pregnancy and postpartum (Jankowski et al 2001, Mukaddam-Daher et al 2002. Brown et al (1993) have shown that the transcriptional downregulation of heart natriuretic peptide receptors is associated with the development of hypertrophic cardiac pathology in the rat.…”

Peptidergic Activation of Locomotor Pattern Generators in the Neonatal Spinal Cord

“…Membranes then were incubated for 2 hr at room temperature with 10% fat-free milk in Tris-buffered saline containing Tween-20 (TBS-T) composed of 20 mM Trizma-base (Sigma), 0.15 M sodium chloride, 0.1% polyoxyethylene-sorbitan monolaurate (Sigma). A well characterized rabbit V 1a receptor antibody (1 g/ml; Chemicon, Temecula, CA) (Hurbin et al, 2002;Clerget-Froidevaux and Pittman, 2003) or OXT receptor antibody (5 g/ml; RDI, Flanders, NJ) (Mukaddam-Daher et al, 2002) were used. After 2 hr of incubation with the primary antibody the membrane was washed with TBS-T and incubated with goat antirabbit IgG conjugated with horseradish peroxidase (1:4000) (Santa Cruz Biotechnology, Santa Cruz, CA) for 1 hr at room temperature.…”

Effects of oxytocin on cardiomyocyte differentiation from mouse embryonic stem cells

“…New functions have recently been reported for oxytocin as a positive and negative regulator of cell proliferation in different tissues [3] and a differentiation factor for myoepithelial cells in the mouse mammary gland [4]. Recent studies have indicated the role of oxytocin in cardiac development as the oxytocin receptor increases at the protein level in the murine heart from day 7 of gestation, when cardiac differentiation starts [5]. Furthermore, oxytocin has been found to be a potent inducer of P19 and cardiomyocyte differentiation of adult stem cells [6,7].…”