Abstract-Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEPknockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved biological activity. Consequently, in vivo experiments with the meprin inhibitor actinonin successfully elevated plasma BNP concentration in rats. We further demonstrated that the generation of mBNP7-32 is the prerequisite to catabolize BNP and identified NEP as the peptidase degrading the truncated BNP. Thus, the cooperative, successive action of the 2 transmembranal peptidases meprin A and NEP is crucial for rapid renal BNP inactivation. Therefore, the inhibition of meprin A could be a potent tool for increasing circulating BNP levels. Key Words: B-type natriuretic peptide Ⅲ natriuretic peptides Ⅲ meprin Ⅲ neutral endopeptidase Ⅲ peptide degradation N atriuretic peptides, as essential regulators of cardiovascular function in health and disease, are emerging as a focus of circulation research. Natriuretic peptides are naturally occurring cyclic peptide hormones with relevance to cardiovascular, endocrine, and renal homeostasis. They serve as functional antagonists of the renin-angiotensin system and counteract fibrosis, cardiac hypertrophy, and remodeling in the heart. 1-3 Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted by cardiomyocytes in response to stretch or hormonal stimuli (angiotensin II, endothelin-1). 2 C-Type natriuretic peptide (CNP) is mainly produced by endothelium and brain and acts as a local regulator of vascular tone and remodeling. 4 The propeptides of the natriuretic peptides must be activated by limited proteolysis. Essentially involved in this activating process are serine peptidases, especially corin (S1 family) for ANP and furin (S8 family) for BNP and CNP. 5-7 All 3 natriuretic peptides share a highly conserved 17-aa ring structure formed by a Cys-Cys disulfide bridge. This intact ring system is essential for biological activity. 8 ANP and BNP mediate their functions via the natriuretic peptide receptor A (NPRA) and CNP via the natriuretic peptide receptor B (NPRB); both receptors are linked to a guanylyl cyclase, which leads to the production of...

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.

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