Central pressor actions of aminopeptidase-resistant angiotensin II analogs: challenging the angiotensin III hypothesis.
Intracerebroventricular administration of angiotensins causes pronounced pressor and dipsogenic responses. The suggestion that angiotensin III rather than angiotensin II is the active peptide in the brain spawned what we call The Angiotensin III.


OBJECTIVE
To test this hypothesis, 5 angiotensin II analogs containing zero or one position substitutions conferring resistance to aminopeptidases were administered intracerebroventricularly to determine their pressor and dipsogenic efficacies. Two aminopeptidase-resistant analogs caused significantly greater pressor responses than angiotensin II, whereas 3 analogs caused pressor responses similar to angiotensin II. Latency to cause a pressor response for 4 of the 5 aminopeptidase-resistant angiotensin II analogs was the same as for angiotensin II. There was no detectable formation of (125)I-angiotensin III from 1 of the intracerebroventricularly administered analogs, (125)I- N-Methyl-l-Asp(1)-angiotensin II, indicating its aminopeptidase resistance. Latency to drink also did not differ between the angiotensins. After the initial dipsogenic response, water was removed until 25 minutes after angiotensin administration to avoid interfering with the pressor response. The dipsogenic stimulus was sustained 25 minutes after intracerebroventricular injection of angiotensin II and its aminopeptidase-resistant analogs. Comparison of angiotensin III and angiotensin II showed equivalent pressor responses with similar latencies and durations. The latency to drink was similar for angiotensin III and angiotensin II. However, there was no dipsogenic response to angiotensin III 25 minutes after intracerebroventricular injection. These data do not support The Angiotensin III Hypothesis and suggest that conversion of exogenously applied angiotensin II to angiotensin III is not necessary to cause brain-mediated pressor or dipsogenic responses.
Kokje
Ranjita J
RJ
Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Wilson
Wendy L
WL
Brown
Travis E
TE
Karamyan
Vardan T
VT
Wright
John W
JW
Speth
Robert C
RC
D000626:Aminopeptidases / Q000494:pharmacology*; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000187:drug effects*; D000805:Angiotensin III / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004327:Drinking Behavior; D007276:Injections, Intraventricular; D008297:Male; D011311:Pressoreceptors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000805:Angiotensin III; D000626:Aminopeptidases