*5.1. Inhibition of APA*

The icv administration of EC33, a specific APA inhibitor, prevented the BP increase produced by the icv administration of AngII in SHR animals, indicating that the central response to AngII requires its transformation into AngIII by APA. A marked BP decrease has also been observed in conscious SHR and DOCA-salt hypertensive rats after the icv infusion of EC33 [76,77]. In contrast, the peripheral iv infusion of EC33 did not reduce BP, indicating that EC33 does not cross the blood–brain barrier and/or is inactive in systemic circulation.

The BP of SHR rats increased after the central icv administration of APA [78], probably due to an increased endogenous generation of AngIII, whereas APA blockade with an antiserum attenuated the pressor response to AngII by around 60% [78]. It is interesting to note that a selective APA inhibitor (RB150) with antihypertensive properties can be given either intravenously [77] or orally [79] because it can cross the blood–brain barrier.

The peripheral activity of the AT1 receptor depends on the transformation of AngII into AngIII by APA [80]. Thus, antihypertensive effects were observed in SHR rats after the systemic administration of recombinant APA [81] at a dose that was one-tenth of the usual candesartan dose [82]; the joint i.v. administration of APA and APN attenuated the pressor effect of AngII in normal rats and treatment with APA reduced the BP of SHR rats to normal levels [83].

Considered together, these data clearly demonstrate that APA reduces BP, while abnormalities in APA activity promote hypertension, as supported by the lower renal APA activity in SHR versus WKY rats [84]. The administration of APA has therefore been proposed for the treatment of acute heart failure, acute hypertensive crisis, preeclampsia, and hypertensive encephalopathy, among other hypertensive emergencies [85,86].

#### *5.2. APN Blockade in the Treatment of Hypertension*

The administration of PC18, an inhibitor of APN, generates a pressor response through the accumulation of endogenous AngIII, which is mediated via the AT1 receptor. In this way, pretreatment with the AT1 blocker losartan can suppress the pressor response, while the AT2 antagonist PD123319 is unable to prevent the BP increase [87]. The enhanced proximal tubular sodium reabsorption of SHR rats is prevented by the intrarenal infusion of PC18 [88]. This finding indicates that the blockade of AngIII degradation achieved by APN inhibition improved sodium excretion in the proximal tubule of these rats when it was administered in the renal interstitium [89]. Hence, the transformation of AngII into AngIII is required for this natriuretic response, which is not affected by the AT1 blocker candesartan. Research on the usefulness of APN inhibitors to treat hypertensive patients is at an early stage, and further studies are required.
