Intracerebroventricularly infused [D-Arg1]angiotensin III, is superior to [D-Asp1]angiotensin II, as a pressor agent in rats.
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-Asp1]AII was very resistant to degradation, AII and [D-Arg1]AIII were degraded at similar rates, while AIII was the most rapidly degraded. In vivo results revealed that AII, AIII and [D-Arg1]AIII produced greater pressor responses than [D-Asp1]AII. Intracerebroventricular pretreatment with the aminopeptidase A inhibitor, amastatin, significantly reduced the subsequent pressor response to i.c.v. infused [D-Asp1]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-Arg1]AIII, presumably by inhibiting the conversion of [D-Arg1]AIII to the less active hexapeptide AII(3-8). Next, i.c.v. pretreatment with the specific angiotensin receptor antagonist, [Sar1, Thr8]AII (Sarthran) was found to greatly diminish the subsequent pressor responses to i.c.v. infused [D-Asp1]AII and [D-Arg1]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.
Wright
J W
JW
Department of Psychology, Washington State University, Pullman 99164.
Roberts
K A
KA
Cook
V I
VI
Murray
C E
CE
Sardinia
M F
MF
Harding
J W
JW
D000626:Aminopeptidases / Q000378:metabolism / Q000502:physiology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000805:Angiotensin III / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007276:Injections, Intraventricular; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides; D051381:Rats; D011919:Rats, Inbred Strains
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; D000804:Angiotensin II; D000805:Angiotensin III; C016977:amastatin; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex