Characterization of natriuretic peptide production by adult heart atria

Abstract

The cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are synthesized and costored by atrial cardiocytes and share receptors and many biologic properties. Although some aspects of their synthesis and release are specific for each peptide, it is not clear whether they share intracellular sorting and secretory mechanisms. In the present work we take advantage of a stable isolated rat atrial preparation that allows, for the first time, long-term study of synthesis, trafficking, targeting, and secretion of ANF and BNP by adult atrial muscle. Three model stimuli of secretion were used: increased intra-atrial pressure, endothelin-1 (ET-1), and phenylephrine (PE), representing mechanical, hormonal, and α1-adrenergic stimuli, respectively. To gain further insight into the secretory process under basal and agonist-induced secretion, we employed agents known to inhibit protein synthesis (cycloheximide) or to interfere with the vectorial transport of protein targeted for secretion (brefeldin A and monensin). All these agents induced significant changes in ANF and BNP release. Cycloheximide decreased natriuretic peptide secretion under basal and stimulated conditions. Brefeldin A dramatically increased basal as well as stimulated secretion of ANF and BNP. Monensin partially decreased basal ANF and BNP secretion and completely blocked stimulated secretion. None of these agents modified proteolytic processing as assessed by reverse-phase HPLC analysis. Double-label pulse-chase experiments using [3H]- and [14C]leucine demonstrated that the secretory response to ET-1, in contrast to the response to muscle stretch, is based on peptide other than newly synthesized or relatively newly stored ANF. It is concluded that, in adult atrial cardiocytes, ANF and BNP are sorted to constitutive and regulated pathways in a manner that is substantially unique for atrial cardiocytes. In particular, it appears that basal and stimulated ANF and BNP secretion may have a large “constitutive-like” component, as previously defined in other endocrine systems. This type of secretion is based on the preferential release of hormone through vesicles arising from immature secretory granules. The capacity of the atria to release ANF and BNP in response to stimuli, therefore, may depend more on stimulation of the rate of formation of immature granules than on the amount of stored hormone.

Phospholipase C signaling tonically represses basal atrial natriuretic factor secretion from the atria of the heart

“…7, where the classical constitutive, exocytotic, and constitutive-like release of ANF is shown. The latter type of release is the main vectorial transport pathway for stimulated ANF secretion, as demonstrated by previous investigations from this laboratory (37).…”

Ras dexamethasone-induced protein 1 is a modulator of hormone secretion in the volume overloaded heart

“…21) as may be observed by increasing intraatrial distension resulting from a normal (e.g., head-out water immersion) or pathological increase in venous return (e.g., congestive heart failure; Refs. 25,28). Increased atrial distension by volume overload (VO) is also accompanied by an increased expression and secretion of both NPs.…”

Natriuretic peptide gene expression in DOCA-salt hypertension after blockade of type B endothelin receptor

“…These investigations showed that whereas modulation of ventricular NP production by hormones in vivo resembles that which is obtained in vitro using cultures of neonatal cardiocytes, modulation of atrial NP production in vivo is largely independent of the endocrine factors so far tested. Atrial NP production, however, appears mainly determined by atrial wall stretch as modified by changes in blood volume (38) although in in vitro preparations such as the isolated atrial preparation (27), it is possible to modify atrial NP production with agents such as endothelin albeit at fairly high concentrations.…”