Involvement of insulin-regulated aminopeptidase and/or aminopeptidase N in the angiotensin IV-induced effect on dopamine release in the striatum of the rat.
Locally administered angiotensin IV causes a dose-dependent increase of the dopamine levels in the striatum of the rat. The aminopeptidases insulin-regulated aminopeptidase (IRAP) and/or aminopeptidase N (AP-N) are proposed to be involved in this effect since both enzymes are inhibited by angiotensin IV. In agreement with this hypothesis we demonstrate that by using the AP-N selective inhibitor 7B, about 60% of the aminopeptidase activity in striatal membranes could be attributed to AP-N (pK(i)=9.20). Higher concentrations of 7B are capable of inhibiting IRAP as well (pK(i)=7.26). Interestingly, in vivo, inhibition of IRAP or AP-N activity does not appear to be involved in the angiotensin IV-mediated effect in the striatum since 7B itself is not capable to induce dopamine release such as observed with angiotensin IV. However, 7B at a concentration selective for inhibition of AP-N (100 nM) potentiates the angiotensin IV-mediated increase of dopamine, suggesting that inhibition of AP-N lengthens the half-life of angiotensin IV. On the other hand, inhibition of both AP-N and IRAP by perfusion of 500 nM 7B completely abolishes the effect of angiotensin IV. We therefore hypothesize that the effect of angiotensin IV on dopamine release in the striatum is mediated via activation of IRAP and/or AP-N, possibly acting as receptors for angiotensin IV.
Stragier
Bart
B
Research Group Experimental Pharmacology, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel Laarbeeklaan 103 B-1090 Brussels, Belgium.
Demaegdt
Heidi
H
De Bundel
Dimitri
D
Smolders
Ilse
I
Sarre
Sophie
S
Vauquelin
Georges
G
Ebinger
Guy
G
Michotte
Yvette
Y
Vanderheyden
Patrick
P
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D018826:CD13 Antigens; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D004298:Dopamine