Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs

Abstract

Abstract-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 Hypothesis. 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. Key Words: brain angiotensin receptors Ⅲ intracerebroventricular Ⅲ dipsogenesis Ⅲ metabolism T he brain rennin-angiotensin system (RAS) is distinct from the peripheral RAS and regulated independently. [1][2][3] Hyperactivity of the brain RAS is known to cause hypertension. 4 Angiotensin II (Ang II) receptors in circumventricular organs (which respond to both blood-borne and centrally produced Ang II), as well as in the hypothalamus and brain stem, cause cardiovascular, endocrine, and behavioral effects. 5 Centrally administered angiotensins stimulate both angiotension II type 1 (AT 1 ) and type 2 (AT 2 ) receptor subtypes in the brain, but the cardiovascular effects arise from AT 1 receptor-mediated vasopressin, oxytocin and aldosterone release, activation of sympathetic neuronal activity, and enhanced thirst and salt appetite. 6,7 Fitzsimons demonstrated that angiotensin III (Ang III) which is des Asp 1 Ang II also acts in the brain, to cause thirst. 8 Subsequent studies demonstrated that intracerebroventricular (ICV) Ang II and Ang III were equipotent at causing dipsogenic and pressor responses. 9 Harding and Felix 10 were able to increas...

Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis

“…It is now well accepted that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over blood pressure [11,12]. The socalled Ang III hypothesis, which suggests that Ang III rather than Ang II is the active peptide in the brain responsible for pressor and dipsogenic responses, has recently been challenged [13].…”

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

“…The interpretation of these results has been challenged recently. 27 Aminopeptidase-resistant Ang II analogs were injected ICV into alert normotensive rats and caused an increase in BP because of AT 1 receptor activation, leading the authors to postulate that Ang II, rather than Ang III, is the main active form controlling BP in the brain. However, the finding that ICV injection of exogenous Ang II analogs exhibiting a very slow degradation rate and binding efficiently with AT 1 receptors was expected to increase BP.…”

Brain AT1Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

“…This peptide caused short-latency pressor and dipsogenic responses at a time when there was no discernible formation of 125/127 I-Ang III. Other aminopeptidase-resistant analogs of Ang II also showed agonistic properties with potencies equal to or greater than Ang II, with latencies equal to or shorter than Ang II (Kokje et al, 2007). This argues strongly against the second unlikely scenario, that Ang II could be an antagonist of the brain AT 1 receptor.…”

“…Previous work from this laboratory (Kokje et al, 2007) using aminopeptidase-resistant analogs of Ang II included an experiment in which a 125/127 I-labeled aminopeptidaseresistant Ang II analog, N-methyl L-Asp 1 Ang II, was administered intracerebroventricularly to rats. This peptide caused short-latency pressor and dipsogenic responses at a time when there was no discernible formation of 125/127 I-Ang III.…”

“…This takes on great importance considering the ongoing debate regarding the main effector peptide of the brain renin-angiotensin system-Ang II versus the heptapeptide Ang III (Harding and Felix, 1987;Zini et al, 1996;Kokje et al, 2007;Bodineau et al, 2008;Speth and Karamyan, 2008). Moreover, if only Ang III can activate brain AT 1 receptors (the angiotensin III hypothesis), then Ang II either does not bind to AT 1 receptors in the brain, or it binds to the brain AT 1 receptors without causing a response (Kokje et al, 2007;Speth and Karamyan, 2008).…”