Use of aminopeptidase M as a hypotensive agent in spontaneously hypertensive rats.
The present investigation determined that a commercially available aminopeptidase M (AmM, Sigma Chemical) can be utilized to lower blood pressure in normotensive and hypertensive rats. In vitro analyses indicated that the predominant peptidase present in this preparation was AmM; however, it also contained some aminopeptidase A (AmA) and less DAP IV. Although no DAP IV-mediated metabolism of angiotensin II (AII) or angiotensin III (AIII) was measured, both AmM and AmA metabolized AII and AIII. Upon further examination, it appeared that AII could be converted to AIII by either AmM or AmA; however, Arg was cleaved from the N-Terminal of AIII predominantly by AmM. The aminopeptidase inhibitors actinonin (AC), amastatin (AM), and bestatin (BE) effectively blocked the AmM-induced hydrolysis of the Asp-Arg bond of AII, and the Arg-Val bond of AIII. The activity of AmA was inhibited by AM but was relatively resistant to inhibition by AC and BE. Next, exogenous aminopeptidase replacement was employed in the anesthetized spontaneously hypertensive rat (SHR) in an attempt to temporarily correct a hypothesized brain deficiency of receptor-associated peptidases and lower blood pressure. Third-ventricle infusion of AmM produced significant drops in blood pressure and heart rate in both SHRs and Wistar-Kyoto normotensive controls. Pretreatment with AC or BE was particularly effective at interfering with the subsequent AmM-induced hypotensive effect, while AM was less effective. The central mechanisms underlying these effects are in need of further investigation; however, they are at least partially dependent upon the brain angiotensin system.
Department of Psychology, Washington State University, Pullman 99164-4820.
J W
JW
Wright
H Z
HZ
Amir
C E
CE
Murray
K A
KA
Roberts
J W
JW
Harding
S
S
Mizutani
P E
PE
Ward
D000626:Aminopeptidases / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018826:CD13 Antigens; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D007123:Immunoelectrophoresis, Two-Dimensional; D007263:Infusions, Parenteral; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D000959:Antihypertensive Agents; D000626:Aminopeptidases; D018826:CD13 Antigens