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Articles in PresS, published online ahead of print November 14, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00326.2002
Submitted on June 5, 2002
Accepted on November 10, 2002
1 Psychology, Washington State University, Pullman, WA, USA
2 Pharmacochimie Moleculaire et Structurale, Institut National de la Sante et de la Recherche Medicale, Unite 266, Paris, Cedex, France
3 Medecine Experimentale, College de France, Institut National de la Sante de la Recherche Medicale, Unit 36, Paris, France
4 Veterinary & Comparative Anatomy, Pharmacology, and Physiology, Program in Neuroscience, Washington State University, Pullman, WA, USA
* To whom correspondence should be addressed. E-mail: wrightjw{at}wsu.edu.
The present investigation measured the relative pressor potencies of intracerebroventricularly (icv) infused angiotensin II (AngII), angiotensin III (AngIII) and the metabolically resistant analogs D-Asp1AngII and D-Arg1AngIII in alert freely-moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A (APA) inhibitor EC33, or the aminopeptidase N (APN) inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5 min infusion period. However, D-Asp1AngII revealed significantly extended durations of pressor effects prior to return to baselevel MAP. Pretreatment icv infusion with EC33 blocked the pressor activity induced by the subsequent infusion of D-Asp1AngII; while EC33 had no effect on the pressor response to subsequent infusion of D-Arg1AngIII. In contrast, pretreatment infusion with PC18 extended the duration of the D-Asp1AngII pressor effect by approximately 2-3X, and the duration of D-Arg1AngIII's effect by approximately 10-15X. Pretreatment with the specific AT1 receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT1 receptor subtype. These results suggest that the brain AT1 receptor may be designed to preferentially respond to AngIII, and AngIII's importance as a centrally active ligand has been underestimated.
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