Actions of D-amino acid-substituted analogues 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 pressor 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 angiotensin converting enzyme with captopril) also attenuated the central pressor 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-tyrosine-des-Asp-angiotensin I and D-isoleucine-des-Asp-angiotensin I, respectively. This shows that i.c.v. angiotensin I and D-tyrosine-angiotensin I were converted by brain aminopeptidase to des-Asp-angiotensin I and D-tyrosine-des-Asp-angiotensin I, respectively, which then attenuated the pressor action of angiotensin III. When compared to the findings of similar D-substitution studies carried out with angiotensin II and [Sar1,Ile8]angiotensin II by other investigators, des-Asp-angiotensin I has a stringent structural-activity relationship. These findings 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.
Radhakrishnan
R
R
Department of Pharmacology, National University of Singapore, Singapore.
Sim
M K
MK
D000596:Amino Acids / Q000494:pharmacology*; D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000805:Angiotensin III; C011437:angiotensin I, des-Asp(1)-; D000803:Angiotensin I