Role of aminopeptidase activity in the regulation of the pressor activity of circulating angiotensins.
Aminopeptidase A (AmA; EC 3.4.11.7) can convert angiotensin II (AII) to angiotensin III (AIII), and aminopeptidase M (AmM; EC 3.4.11.2) has been shown to degrade AIII. The present study investigated angiotensin metabolism by AmA and AmM activities in rat plasma. Plasma AmA and AmM activities hydrolyzed glutamyl-2-naphthylamide and alanyl-2-naphthylamide at rates of 10.6 and 30.0 nmol/min/ml, respectively. Plasma hydrolysis of AII (4.1 +/- 0.5 nmol/min/ml) was only one-third as rapid as AIII (13.3 +/- 1.7 nmol/min/ml). The Km of AII and AIII for AmA and AmM were 90.3 +/- 14.3 and 29.5 +/- 8.2 microM, respectively. The aminopeptidase inhibitor amastatin was 40-fold more potent as an inhibitor of AmM activity (IC50 = 0.2 microM) than of AmA activity (IC50 = 8 microM). In order to examine metabolism in vivo, blood pressure responses to angiotensins were obtained in anesthesized rats before and during infusion of amastatin (16 nmol/min i.v.). Amastatin specifically inhibited plasma AmM and AmA activities 81 and 10%, respectively. Consistent with the lower inhibition of AmA, the potency of angiotensin I and AII were only slightly increased after amastatin. However, the potency of AIII and des(Asp1)angiotensin I were significantly increased regarding both maximal change in blood pressure and duration of action. These data support an important role for both AmA and AmM activities in the metabolism of circulating angiotensins and establish both the value and limitations of amastatin as an inhibitor of peripheral angiotensin metabolism.
Ahmad
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Department of Physiology, Ohio State University, Columbus.
Ward
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PE
D000626:Aminopeptidases / Q000502:physiology*; D000809:Angiotensins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents; D001794:Blood Pressure / Q000187:drug effects*; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides; D051381:Rats; D011919:Rats, Inbred Strains
D000809:Angiotensins; D000900:Anti-Bacterial Agents; D009842:Oligopeptides; D010455:Peptides; C016977:amastatin; D000626:Aminopeptidases; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase