Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats.
The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG 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-Asp(1)ANG 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-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.
Wright
John W
JW
Department of Psychology, Washington State University, Pullman, Washington 99164-4820, USA. wrightjw@wsu.edu
Tamura-Myers
Elizabeth
E
Wilson
Wendy L
WL
Roques
Bernard P
BP
Llorens-Cortes
Catherine
C
Speth
Robert C
RC
Harding
Joseph W
JW
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000804:Angiotensin II / Q000494:pharmacology*; D000805:Angiotensin III / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D043384:Glutamyl Aminopeptidase; D007276:Injections, Intraventricular; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013451:Sulfonic Acids / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C472311:2-amino-4-methylsulfonyl butane thiol; D057911:Angiotensin Receptor Antagonists; C101968:EC 33; D013451:Sulfonic Acids; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000805:Angiotensin III; D008715:Methionine; D000626:Aminopeptidases; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; D019808:Losartan