Intracerebroventricularly infused [D-Arg1]angiotensin III, is superior to [D-Asp1]angiotensin II, as a pressor agent in rats.

Abstract Two d -amino acid substitution angiotensin analogues were compared against native angiotensin II (AII) and angiotensin III (AIII) for their resistance to brain tissue-induced degradation and for pressor potency when intracerebroventricularly (i.c.v.) infused in Sprague-Dawley rats. The in vitro results indicate that [ d -Asp 1 ]AII was very resistant to degradation, AII and [ d -Arg 1 ]AIII were degraded at similar rates, while AIII was the most rapidly degraded. In vivo results revealed that AII, AIII and [ d -Arg 1 ]AIII produced greater pressor responses than [ d -Asp 1 ]AII. Intracerebroventricular pretreatment with the aminopeptidase A inhibitor, amastatin, siginificantly reduced the subsequent pressor response to i.c.v. infused [ d -Asp 1 ]AII presumably by inhibiting its conversion to AIII. In contrast, pretreatment with the aminopeptidase B inhibitor, bestatin, potentiated the subsequent pressor response to i.c.v. infused [ d -Arg 1 ]AIII, presumably by inhibiting the conversion of [ d -Arg 1 ]AIII to the less active hexapeptide AII(3–8). Next, i.c.v. pretreatment with the specific angiotensin receptor antagonist, [Sar 1 , Thr 8 ]AII (Sarthran) was found to greatly diminish the subsequent pressor responses to i.c.v. infused [ d -Asp 1 ]AII and [ d -Arg 1 ]AIII, suggesting that these analogues are having their effect at the same brain angiotensin receptor site. These results support the hypothesis that AIII, or AIII-like ligands, may serve as the active form of brain angiotensin.