Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor

Abstract

The brain angiotensin (Ang) system plays an important role in the central control of vasopressin release. Using EC33, a selective aminopeptidase A inhibitor which blocks the metabolism of Ang II in Ang III, we previously reported that vasopressin release was under the control of Ang III and not Ang II. To determine accurately the action of EC33, the effects of intracerebroventricular injection of Ang peptides or EC33 on extracellular unit activity of vasopressinergic neurons in the supraoptic nucleus of urethane-anaesthetized rats were examined. Angiotensin II (15-30 ng) or Ang III (15 ng) increased the firing rate of all neurons tested. Conversely, EC33 (10 microg) reduced or completely abolished (30-60 microg) the basal firing rate for 4-6 min in all eight neurons tested. EC33 (30 microg) also inhibited the activity induced by 30 ng Ang II. It was concluded that the observed activity of Ang II required its conversion to Ang III and that endogenous Ang III may exert a tonic control on the basal firing level of vasopressinergic neurons.

Aminopeptidase A inhibitors as potential central antihypertensive agents

“…In an attempt to define the respective roles of brain AngII and AngIII in the central control of cardiovascular functions, we recently have developed highly selective APA and APN inhibitors: the compound EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] specifically inhibits APA whereas the compounds EC27 [(S)-2-amino-pentan-1,5-dithiol] and PC18 (2-amino-4-methylsulfonyl butane thiol) specifically inhibit APN (22)(23)(24). Using these new tools, we demonstrated previously that AngIII and not AngII, as shown at the periphery, is one of the main effector peptides of the brain RAS in the central control of vasopressin release and supraoptic vasopressinergic neuron activity (21,22,25).…”

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

“…1). We developed specific and selective APN and APA inhibitors, PC18 and EC33, respectively (23,24), and used these tools to demonstrate that AngIII, but not AngII as shown in the periphery, is one of the main effector peptides of the brain RAS in the control of vasopressin release (25)(26)(27). Moreover, brain AngIII exerts a tonic stimulatory action on the control of BP in the conscious SHR (26), suggesting that APA, generating brain AngIII, could constitute a new candidate target for the treatment of hypertension.…”

Structural Insights into Central Hypertension Regulation by Human Aminopeptidase A

“…In particular, a high-level central RAS, accompanied by a low-level systemic RAS, has been described in some hypertensive patients who are resistant to treatments targeting the systemic RAS (10). The major effector peptide for blood pressure regulation in the brain is angiotensin III (13)(14)(15). Angiotensin III is produced by the action of APA on angiotensin II and is converted to angiotensin IV by APN (Fig.…”

“…Finally, aminopeptidase N (APN) cleaves the N-terminal arginine from angiotensin III to produce angiotensin IV. Interestingly, angiotensin peptides play different roles in the central and systemic RASs: in the systemic RAS, angiotensin II is the main effector peptide that increases blood pressure, whereas in the central RAS, angiotensin III plays this role (13)(14)(15). Renin and ACE in the systemic RAS are among the main targets for antihypertensive drugs (11).…”