Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis

Abstract

Although there is a large body of knowledge on protein synthesis, the available data on protein catabolism, although quite substantial, are still inadequate. This is due to the marked differences in the activity of proteolytic enzymes, compounded by different substrate specificities and multiple environmental factors. Understanding enzyme behavior under physiological and pathological conditions requires the identification of specific proteolytic activities, such as aminopeptidases, as able to degrade certain peptidergic hormones or neuropeptides. Another requirement is the isolation, purification and characterization of the enzymes involved. In addition, systematic studies are needed to determine each enzyme's subcellular location, tissue distribution, and the influence of environmental factors such as diurnal rhythm, age, gender, diet, cholesterol, or steroids. Central and peripheral aminopeptidases may play a role in the control of blood pressure by coordinating the effect of the different peptides of the renin-angiotensin system cascade, acting through the AT(1), AT(2), and AT(4) receptors. Our review of the available data suggests the hypothesis that cholesterol or steroids, particularly testosterone, significantly influence aminopeptidase activities, their substrate availability and consequently their functions. These observations may have relevant clinical implications for a better understanding of the pathophysiology of cardiovascular diseases, and thus for their treatment with aminopeptidase inhibitors.

Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights

“…Moreover, such asymmetry is not static but dynamic and adjustable depending on the variability in exogenous conditions such as light or dark conditions (Ramirez et al 2004) or endogenous environment like type and level of sex steroids (Ramirez et al 2008;Rueda et al 2016), stress (Lee et al 2014), brain dopamine content (Banegas et al 2009 or drug treatments involving the RAS, such as ACE inhibitors (Segarra et al 2012.…”

Brain, Heart and Kidney Correlate for the Control of Blood Pressure and Water Balance: Role of Angiotensinases

“…Additionally, these correlations may also indicate secretory processes for angiotensinases in the neuroeffector junction from nerve terminals and/or from tissue cells under these circumstances. The enzymes would then be activated or not, depending on whether an appropriate biochemical environment surrounding their peptide substrates was reached [9,27,28,29]. We suggested early the functional importance of aminopeptidase activities (including angiotensinases) in nerve terminals and synaptic events [27,30] exhibiting different functional roles depending on whether the Sol or MB fraction was analyzed [30,31].…”

“…The activities of such enzymes can focus on a specific substrate by various mechanisms including a specific biochemical environment such as a precise pH or Km affinity for the substrate. The presence of endogenous or exogenous activators or inhibitors, such as levels of steroids or drug treatments [9], could also be involved. Furthermore, according to the present results, the status of activation of the ANS appears to play a major role.…”

“…RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of their active peptides [9]. …”

“…The enzymatic activities analyzed [measured in their soluble (Sol) and membrane-bound (MB) forms by fluorimetric methods] were: aspartyl aminopeptidase (AspAP) which metabolizes Ang I to Ang 2-10, glutamyl aminopeptidase (GluAP) which metabolizes Ang II to Ang III and cholecystokinin, alanyl aminopeptidase (AlaAP) which transforms Ang III to Ang IV, an enzyme that also acts as an enkephalinase, and finally cystinyl aminopeptidase (CysAP), identified as insulin-regulated aminopeptidase and AT 4 receptor (in its MB form), which also hydrolyzes vasopressin or oxytocin [9] (fig. 1).…”