Metabolism of angiotensin II is required for its in vivo effect on dopamine release in the striatum of the rat.
The effect of angiotensin (Ang) IV, an inhibitor of insulin-regulated aminopeptidase (IRAP), on extracellular dopamine levels in the striatum of freely moving rats was examined using in vivo microdialysis. The Ang IV was administered locally in the striatum through the microdialysis probe. A concentration-dependent (10-100 microm) increase in extracellular striatal dopamine was observed. The effect of Ang II (10-100 microm), which has only a weak affinity for IRAP, was similar to that observed for Ang IV. The effects of both peptides could not be blocked by the AT1 antagonist candesartan (10 nm and 1 microm) nor by the AT2 antagonist S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenyl-acetyl)-4,5,6,7-tetrahydro-1H-amidazo(4,5-c) pyridine-6-carboxylic acid (1 microm), suggesting that the observed effects are both AT1 and AT2 independent. The effect of Ang II could be blocked by the aminopeptidase-A inhibitor (S)-3-amino-4-mercaptobutylsulphonic acid as well as the aminopeptidase-N inhibitor 2-amino-4-methylsulphonylbutane thiol, indicating that the effect of Ang II is mediated via metabolism into Ang IV. Other IRAP inhibitors, such as Divalinal-Ang IV and LVV-haemorphin-7, had similar effects on extracellular dopamine levels as compared with Ang IV. We propose a role for IRAP as mediator for the effects of Ang IV and related peptides on extracellular dopamine levels in the striatum of the rat.
Department of Pharmaceutical Chemistry and Drug Analysis, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
Bart
B
Stragier
Sophie
S
Sarre
Patrick
P
Vanderheyden
Georges
G
Vauquelin
Marie-Claude
MC
Fournié-Zaluski
Guy
G
Ebinger
Yvette
Y
Michotte
D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006454:Hemoglobins / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists; D013451:Sulfonic Acids / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
C472311:2-amino-4-methylsulfonyl butane thiol; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C101968:EC 33; D006454:Hemoglobins; D007093:Imidazoles; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013451:Sulfonic Acids; D013777:Tetrazoles; C114974:divalanal-angiotensin IV; D000804:Angiotensin II; C073402:PD 123319; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D009271:Naltrexone; C074309:LVV-hemorphin-7; D008715:Methionine; C081643:candesartan; D004298:Dopamine