Functional compartmentation of endocrine actions of cardiac natriuretic peptides

The endocrine function of the heart is to secrete Atrial and Brain natriure tic peptides (ANP and BNP). These peptides are biologically active via part iculate guanylate cyclases which generate cyclic GMP, the second intracellu lar messenger. A polysaccharide antagonist, HS-142-1 has been recently desc ribed by a Japanese Group. Cyclic GMP is partly secreted from the target ce lls into the extra cellular medium in which its accumulation is proportiona l to the concentration of the natriuretic peptide. Neutral Endopeptidase (N EP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides . NEP is absent in plasma but present on the surface of endothelial and smo oth muscle cells. NEP is mainly expressed at the apical pole of the epithel ial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is asso ciated with the oversecretion of natriuretic peptides. This chronic phenome non involves the recruitment of ail the cardiac myocytes to express natriur etic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic pep tides correlate with the level of the hemodynamic stress. Therefore the pla sma levels of natriuretic peptides are good pronostic markers in both exper imental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also correlated with the plasm a and urinary levels of cyclic GMP. The plasma level of cyclic GMP is corre lated with the endothelial concentration of cyclic GMP but not with the cyc lic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells a nd is related to particulate guanylate cyclase activity. In contrast natriu retic peptides do not modulate vascular wall cyclic GMP content. The natriu retic action of ANP is probably due to the interaction of the filtered pept ide with the particulate guanylate cyclase at the apical pole of the epithe lial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urina ry compartment. It is also by a urinary pathway via the macula densa that A NP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP co rrelate with the degree of salt retention in congestive heart failure, prov ides evidence for chronic desensitization of the system. An up-regulation o f Na+, K+, 2Cl(-) expression associated with experimental congestive hear? failure has recently been shown. Similarly, a modulation of the different s odium transporter systems along the nephron could be one of the counter-reg ulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted b y the heart, transported in the plasma, filtered by the glomeruli and activ e at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mecha nism of desensitization remains to be elucidated.