Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin.
In the metabolism of angiotensin peptides by tissue angiotensinases, aminopeptidases A, B, M and leucine aminopeptidase have been identified as being particularly effective. Because the inhibitory actions of amastatin (AM) and bestatin (BE) are relatively specific for these aminopeptidases, we have examined the effects of these inhibitors on the binding, degradation and pressor activity of angiotensin II (AII) and angiotensin III (AIII). Within 30 min at 37 degrees C, significant metabolism of 125I-AII and 125I-AIII by homogenates of a block of tissue containing hypothalamus, thalamus, septum and anteroventral third ventricle regions of the brain was observed. A majority of 125I-AIII metabolism was due to soluble peptidases, whereas that of 125I-AII primarily resulted from membrane-bound peptidases. AM, BE and reduced incubation temperatures significantly decreased the metabolism of 125I-AII and 125I-AIII. After appropriate adjustments to reflect the proportion of intact radioligand bound, temperature- or inhibitor-induced decreases in metabolism were matched by corresponding increases in specific binding. Heat-treated bovine serum albumin, as a nonspecific peptidase inhibitor, had no effect on either the metabolism or binding of the ligands used. In accordance with their actions in vitro, i.c.v. administration of AM and BE prolonged the pressor activity of subsequently applied AII and AIII. Unexpectedly, the amplitude of the pressor response to AIII was increased by BE, whereas that to AII was decreased by AM. The results of this study indicate that the metabolism of AII and AIII by aminopeptidases is relatively specific and acts to modulate the actions of these peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Abhold
R H
RH
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman.
Sullivan
M J
MJ
Wright
J W
JW
Harding
J W
JW
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000805:Angiotensin III / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents; D001794:Blood Pressure / Q000187:drug effects*; D007457:Iodine Radioisotopes; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000900:Anti-Bacterial Agents; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D010455:Peptides; D000804:Angiotensin II; D000805:Angiotensin III; C016977:amastatin; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex