Aminopeptidase A inhibitors as potential central antihypertensive agents.
Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT(1)) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT(1) receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.
Reaux
A
A
Institut National de la Santé et de la Recherche Médicale, Unité 36, Collège de France, Chaire de Médecine Expérimentale, 3 rue d'Ulm, 75005 Paris, France.
Fournie-Zaluski
M C
MC
David
C
C
Zini
S
S
Roques
B P
BP
Corvol
P
P
Llorens-Cortes
C
C
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000378:metabolism; D000805:Angiotensin III / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043384:Glutamyl Aminopeptidase; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D000805:Angiotensin III; D000626:Aminopeptidases; D043384:Glutamyl Aminopeptidase