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Departments of 1 Psychology, 2 Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Program in Neuroscience, Washington State University, Pullman, Washington 99164-4820; 3 Department de Pharmacochimie Moleculaire et Structurale, Institut National de la Santé et de la Recherche Médicale, Unite 266, Centre National de la Recherche Scientifique, UMR 8600, 75270 Paris, Cedex 06; and 4 Institut National de la Santé et de la Recherche Médicale, Unit 36, College de France, Chaire de Medecine Experimentale, 75005 Paris, France
The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs D-Asp1ANG II and D-Arg1ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N 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-Asp1ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of D-Asp1ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of D-Arg1ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the D-Asp1ANG II pressor effect by about two to three times and the duration of D-Arg1ANG III's effect by ~10 to 15 times. 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 ANG III, and ANG III's importance as a centrally active ligand has been underestimated.
blood pressure; D-Asp1Angiotensin II; D-Arg1Angiotensin III
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