ACTIONS OF D-AMINO ACID-SUBSTITUTED ANALOGS OF DES-ASP-ANGIOTENSIN-I ON THE CENTRAL PRESSOR ACTION OF ANGIOTENSIN-III

The ability of intracerebroventricularly (i.c.v.) administered D-amino acid-substituted analogues of des-Asp-angiotensin I to attenuate the central presser action of angiotensin III in the rat was investigated. Of the 9 D-amino acid-substituted analogues, only D-tyrosine-des-Asp- angiotensin I was active. I.c.v. D-tyrosine-angiotensin I but not i.c. v. D-isoleucine-angiotensin I (when prevented from degradation by angi otensin converting enzyme with captopril) also attenuated the central presser action of angiotensin III. In vitro incubation of angiotensin I, D-tyrosine-angiotensin I and D-isoleucine-angiotensin I with brain homogenate resulted in the formation of des-Asp-angiotensin I, D-tyros ine-des-Asp-angiotensin I and D-isoleucine-des-Asp-angiotensin I, resp ectively. This shows that i.c.v. angiotensin I and D-tyrosine-angioten sin I were converted by brain aminopeptidase to des-Asp-angiotensin I and D-tyrosine-des-Asp-angiotensin I, respectively, which then attenua ted the presser action of angiotensin III. When compared to the findin gs of similar D-substitution studies carried out with angiotensin II a nd [Sar(1),Ile(8)]angiotensin II by other investigators, des-Asp-angio tensin I has a stringent structural-activity relationship. These findi ngs suggest that, at the physiological level, des-Asp-angiotensin I is formed from angiotensin I and that the nonapeptide probably acts on a distinct subtype of angiotensin receptors.