Heart as an Endocrine Organ
The endocrine activity of the heart comprises the release of various natriuretic peptide hormones from the cardiomyocytes. The atrial natriuretic peptide family includes three structurally similar peptides, i.e., atrial natriuretic peptide (ANP), brain or B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).
The secretion of these17.1.2 Mechanism of Synthesis
The genes encoding different natriuretic peptides were evolved from the ancestral natriuretic peptide gene. Natriuretic peptide A precursor (NPPA), natriuretic peptide B precursor (NPPB), and natriuretic peptide B precursor (NPPC) genes, respectively, encode the ANP, BNP, and CNP. Initially those are synthesized as preprohormones (preproANP, preproBNP, and preproCNP). The proteolytic cleavage of signal peptides from preprohormones results in the production of prohormones that are stored as vesicles. Subsequent endoproteolytic action of serine proteases such as corin and furin acts on prohormones to produce mature hormones that are released through exocytosis. All three types of natriuretic peptides contain a 17-aminoacid residues ring linked by a disulfide bridge, which is essential for their biological activity.
Know More...
• Type C natriuretic peptide has a broken 17-aminoacid ring and hence cannot exert natriuretic effects.
• Birds and reptiles do not possess ANP.
17.1.3 Mechanism of Action
The target effects of natriuretic peptides are mediated by cell membrane-bound receptors coupled with guanylyl cyclase. Three different types of receptors were identified: NPR-A, NPR-B, and NPR-C. ANP and BNP exert their biological effects by binding to NPR-A. The binding of ANP or BNP to NPR-A results in a conformational change with consequent activation of the intracellular guanylyl cyclase domain. The cGMP formed from GTP in the presence of guanylyl cyclase is regarded as the secondary messenger in the signal transduction mechanism.
The elevated cGMP levels affect various cGMP-dependent protein kinases (PKGs), cGMP gated ion channels, and cGMP-regulated phosphodiesterases to bring about specific target effects. Kidneys, blood vessels, and the adrenal cortex are regarded as the principal target tissues of natriuretic peptides.17.1.4 Biological Effects
The natriuretic peptides (except CNP) are responsible for lowering the blood volume by enhancing the renal excretion of water (diuresis) and sodium (natriuresis). Apart from kidneys, they also cause the relaxation of vascular smooth muscles thereby bringing down the arterial pressure. They act on the pituitary gland, adrenal cortex, and small intestine to inhibit ADH, aldosterone secretion, and sodium absorption, respectively.
17.1.4.1 Effect on Kidneys: Aldosterone Escape
The increased intracellular levels of cGMP result in the activation of PKGs to cause a simultaneous dilation of afferent arterioles and constriction in efferent arterioles. The increased blood flow to the kidneys is correlated with an increase in glomerular filtration rate and filtration fraction. Moreover, the hampered reabsorption of sodium and water in proximal tubules and distal tubules hastens sodium and water excretion (Fig. 17.1). Further, the inhibitory role of ANP on renin secretion from the kidneys is well documented. Altogether, the natriuretic and diuretic effects of ANP/BNP override the effects of aldosterone on the circulatory volume, generally referred to as the aldosterone escape.
Fig. 17.1 Effects of natriuretic peptides on circulatory volume. [ANP/BNP released due to the stretch of heart musculature will lead to the increased excretion of sodium along with water and decreases the blood volume to normal level. " = increase, () = Feedback inhibition]
17.1.4.2 Effects on the Vasculature
The increased intracellular levels of cGMP cause a decrease in the levels of Ca+2 ions.
As calcium ions play a significant in smooth muscle contraction, a decrease in their intracellular levels leads to the relaxation of smooth muscles present in blood vessels and alters their permeability. The resultant vasodilation in the arterial tree and venous systems leads to a decrease in the peripheral resistance and preload, thereby reducing cardiac output. In addition, ANP has an antiproliferative effect on vascular smooth muscles, fibroblasts, and cardiac cells.17.2.2 MechanismofAction
The activation of erythropoietin receptors (EPOR) when bound with EPO results in their dimerization and phosphorylation by Janus kinase 2 (JAK2). The transphosphorylation of EPOR initiates the phosphorylation of signal transducer and activator of transcription 5 (STAT5), PI3K/AKT, and SHC/MAPK pathways to regulate cellular proliferation and survival. The EPOR is distributed majorly in erythrocyte progenitor cells residing in the bone marrow, thus making them the primary target tissue.
17.1.5 RegulationofSecretion
The natriuretic peptides, especially ANP and BNP, are secreted in response to an increase in blood volume. The increased stretch of atrial muscle cells due to the rise in venous returns causes the secretion of ANP/BNP. Since the natriuretic and diuretic effects produced by natriuretic peptides are pressure induced, they are also known as pressure natriuresis and pressure diuresis. The vasoactive peptides such as endothelin 1 (ET-1), angiotensin II, and catecholamines are also implicated in increasing the expression of ANP in cardiomyocytes.
17.2