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...
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