The physiological and pathophysiological modulation of the endocrine function of the heart

Abstract

Under physiological conditions, the endocrine heart contributes to the maintenance of cardiovascular homeostasis through the polypeptide hormones ANF and BNP, which are members of the natriuretic peptide (NP) family. Given that NPs are of interest from the basic and clinical points of view, the genetic expression and secretion of ANF and BNP as well as the nature of the interaction of these hormones with their receptors has been the subject of extensive studies since the discovery of ANF in 1980. Following hemodynamic overload, increased secretion of NPs by the heart can be seen. This change may occur without an increase in gene expression as observed for atrial NPs following acute volume expansion, or it can occur with an increase in both ANF and BNP gene expression in atria only as seen in mineralocorticoid escape during which it is obvious that a critical decrease in hormone stores must be reached before transcriptional activation occurs. Chronic hemodynamic pressure or volume overload results in increased expression of NPs in atria and ventricles. Under these circumstances, the increased production of BNP by hypertrophic ventricles changes the normal plasma concentration ratio of ANF to BNP, a fact that has clinical diagnostic and prognostic implications. There are exceptions to this rule: chronic, severe L-NAME hypertension, which may occur without left ventricular hypertrophy, does not cause this effect and increased ventricular NP gene expression can occur in mineralocorticoid hypertension before detectable ventricular hypertrophy. Atrial and ventricular NP gene expression appears to be under different transcriptional control because pharmacological treatments such as chronic ACE inhibition or ET(A) receptor blockade can reverse the increased ventricular NP expression but has no detectable effect on atrial NP gene expression. This is not unlike the myosin heavy chain switch that is observed in certain pathologies, and can be pharmacologically reversed in a manner similar to NPs in the ventricles but it does not occur in atrial muscle. These observations made in vivo or using isolated adult atria often differ strikingly from results obtained using the mixed phenotype afforded by cardiocytes in culture, indicating that the kinds of questions addressed by each approach must be judiciously chosen. G-protein coupled receptor-mediated actions of neurohumors such as endothelin and phenylephrine are normally used to stimulate NP gene expression and release in different in vitro models. The main physiological stimulus for increased ANF release, atrial muscle stretch, also appears to rely on G-protein-coupled mechanisms. Alternative agonists and receptor types at play are suggested by the finding that circulating levels of BNP are selectively increased before and during overt cardiac allograft rejection episodes in human patients. The data suggest that enhanced BNP plasma levels could form a basis for a noninvasive test for cardiac allograft rejection. However, the molecular mechanism by which expression of NPs are ...

BNP controls early load-dependent regulation of SERCA through calcineurin

“…This indicates that serum ANP might predominantly have extracardiac functions. The increase in ANP 6 h after load might be explained by the release of stored ANP in the granula of the atrial myocytes [6]. Reason for the lack of systemic ANP on myocardial SERCA regulation could be the higher degradation of ANP in the heart.…”

The heart as an endocrine organ

“…Many of the agonists of cNPs secretion, such as ET1, angiotensin II (AII) and PE, signal through the receptors coupled to Gq proteins, although other subclasses may also be used (42, 43) and stimulate the RAS/c-Raf-1 and the phosphoinositide signalling pathways leading to the recruitment and activation of effector molecules such as those found in MAP kinase cascades (44, 45). Gi/o inhibition by pertussis toxin (PTX) abolishes stretch-secretion coupling without affecting baseline secretion through a mechanism that is independent of Gq signalling, suggesting that PTX sensitive Gi/o proteins are involved in stretch-induced secretion in atria.…”

Brain Natriuretic Peptide Production and Secretion in Inflammation

“…The advent of the more sensitive radioimmunoassay techniques to measure these NPs revealed that they were also present in ventricular muscle albeit at much lower concentrations than in the atria. Transcript abundance reflects this difference [5, 10, 11]. In addition, in both atria and ventricles, ANF is always more abundant than BNP [12, 13].…”