Role of endopeptidase‐24.11 in the inactivation of atrial natriuretic peptide

Abstract

The circulating form of atria1 natriuretic factor is a 28-residue peptide containing a 17-residue disulphide-linked ring. It has important actions on the kidney, largely on its haemodynamics, and at other sites including the adrenal cortex and CNS. It has a short half-life in vivo and is rapidly inactivated when incubated with kidney microvillar membranes. Of the battery of peptidases present in that membrane, only one, endopeptidase-24.11, is responsible for initiating the attack, and this commences with hydrolysis of the Cys'-PheS bond within the ring. Hydrolysis at this and other points has been shown to inactivate the peptide and this information has pointed the way to the synthesis of resistant analogues.Atria1 natriuretic peptide; Membrane peptidase; Neuropeptide; Endopeptidase-24.11 DISCOVERY OF ATRIAL NATRIURETIC FACTORAtria1 natriuretic factor (ANF) comprises a family of peptides with powerful natriuretic, diuretic and hypotensive activities which are present in storage granules of atrial muscle. The existence of these granules and their resemblance to secretory granules of other cells were reported more than 20 years ago [1,2] Abbreviations: ANF, atria1 natriuretic factor; ANP, atrial natriuretic peptide (l-28) the prefixes h and r indicating human and rat; could be affected by changes in the intake of water and sodium [3] and that injections of extracts of atria or granules promoted diuresis and natriuresis [4] and by 1983 it was becoming clear that these activities resided in a group of related peptides (for review and nomenclature see [S]). Several low-M, peptides have been isolated from rat atria, e.g. atriopeptins I, II and III and cu-rat atria1 natriuretic peptide (cu-rANP), all of which possess a disulphide-linked loop of 17 amino acid residues, with short N-and C-terminal extensions. However, the major circulating form of ANF in the rat appears to be the 28-residue peptide [6,7] which is derived from a high-M,, 152-residue precursor, rat pre-pro ANP (see [5]). Human atria also release a 28-amino acid peptide @-human atrial natriuretic peptide, a-hANP; [8]; fig.1) which differs from a-rANP by only one residue, Met" for Ilei* [9]. REGULATION OF RELEASE OF ANPSeveral factors have been found to stimulate

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

“…The kidney, which contains the highest NEP activity, seems also to be a major site of atrial natriuretic peptide (ANP) metabolism (23). And, as several peripheral effects of circulating ANP are regulated mainly by NEP ectopeptidase, we postulate that sialorphin may help potentiate the physiological actions of ANP at periphery, especially at the renal site (23,24).…”

Urodilatin: a new approach for the treatment of therapy‐resistant acute renal failure after liver transplantation

“…The mechanisms underlying this strong natriuretic potency in the kidney have not yet been clarified. URO is resistant to proteolytic degradation by metallo-endo-protease EC 24.1 1 located in the apical membrane of the proximal tubule where the circulating CDD/ANP-99-126 is degraded [37,38]. Thus, a possible way of acting at the luminal membrane of collecting duct cells is that URO inhibits the entry of sodium through apical sodium channels [39,40].…”

Radiocontrast‐induced natriuresis associated with increased urinary urodilatin excretion

“…However, the therapeutic/prophylactic administration of atrial natriuretic peptide was not nephroprotective in high risk patients receiving radiocontrast [21]. This could be related to the rapid degradation of atrial natriuretic peptide by a tubular brush border endopeptidase [6] limiting its efficacy as a natriuretic agent. In contrast, urodilatin is much less subject to inactivation by this renal endopeptidase [5].…”