Natriuretic peptide receptors and the heart.

It is 20 years since de Bold reported that homogenates of normal atria stimulated a natriuresis and diuresis when administered intravenously to rats. This observation led to the isolation of atrial natriuretic peptide (ANP) from cardiac tissue. Subsequently other peptides with a similar ring structure and biological properties have been recognised, named in alphabetical order—BNP, CNP, and DNP—and termed the natriuretic peptide family. Initial studies of the biology of natriuretic peptides focused on their endocrine role—measuring circulating levels in response to different stimuli and looking at the effects of administering exogenous peptide to isolated tissues and whole animals. Most attention has been given to ANP and BNP. Both are synthesised by cardiac myocytes and their production is increased by factors that increase cardiac work—pressure and volume overload. Indeed, the cardiac synthesis of ANP and BNP has emerged as a sensor of cardiac strain, with increased synthesis the hallmark of myocyte hypertrophy in cell culture and raised plasma concentrations a biomarker of ventricle dysfunction in vivo. Both peptides relax isolated resistance vessels. Pharmacological infusions of either peptide reduce renin and aldosterone concentrations, promote renal sodium and water excretion, and lower blood pressure in humans and other animals. These actions are mediated through specific receptors. Three main natriuretic peptide receptors (NPR) have been cloned. NPR-A (or GC-A) and NPR-B (or GC-B) are guanylyl cyclase linked and utilise cyclic GMP as the intracellular messenger. A third receptor, known as NPR-C, is not linked to guanylyl cyclase and may act to clear the natriuretic peptides from the circulation (fig 1). The rank order of potency of the peptides for NPR-A is ANP > BNP >> CNP, and for NPR-B it is CNP > ANP > BNP. Consistent with a clearance role, NPR-C has less stringent structural requirements for binding, even tolerating D-amino acid substitutions. The demonstration of NPRs in the heart encouraged speculation that these peptides may have a paracrine or indeed an autocrine role in the myocardium. Autoradiographic studies show that the main NPR subtype in the heart is NPR-C and is located in the endocardium. However, analysis of mRNA transcripts, western blotting, and functional studies indicate that NPRs are also found in cardiac fibroblasts and cardiac myocytes. ANP inhibits collagen synthesis in cardiac fibroblasts and both attenuates the growth response to adrenergic stimuli in cultured neonatal cardiac myocytes and induces apoptosis. This raises the possibility that, in addition to protecting the heart by reducing workload, ANP and BNP act directly on the myocardium to inhibit myocyte hypertrophy and fibrosis.