Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Metabolism of angiotensin II is required for its in vivo effect on dopamine release in the striatum of the rat. 1531 80

Intracerebroventricular (i.c.v.) administration of angiotensin IV (Ang IV) or Leu-Val-Val-haemorphin 7 (LVV-H7) improves memory performance in normal rats and reverses memory deficits in rat models for cognitive impairment. These memory effects were believed to be mediated via the putative 'AT4 receptor'. However, this binding site was identified as insulin-regulated aminopeptidase (IRAP). Correspondingly, Ang IV and LVV-H7 were characterised as IRAP inhibitors. This study investigates whether and how IRAP may be involved in the central effects of Ang IV and LVV-H7. We determined the effects of i.c.v. administration of Ang IV or LVV-H7 on hippocampal neurotransmitter levels using microdialysis in rats. We observed that Ang IV modulates hippocampal acetylcholine levels, whereas LVV-H7 does not. This discrepancy was reflected in the observation that Ang IV binds with micromolar affinity to the AT1 receptor whereas no binding affinity was observed for LVV-H7. Correspondingly, we demonstrated that the AT1 receptor is involved in the effects of Ang IV on hippocampal neurotransmitter levels and on spatial working memory in a plus maze spontaneous alternation task. However, the AT1 receptor was not involved in the spatial memory facilitating effect of LVV-H7. Finally, we demonstrated that Ang IV did not diffuse to the hippocampus following i.c.v. injection, suggesting an extrahippocampal site of action. We propose that AT1 receptors are implicated in the neurochemical and cognitive effects of Ang IV, whereas LVV-H7 may mediate its effects via IRAP.
 ...
PMID:Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVV-haemorphin 7 on hippocampal neurotransmitter levels and spatial working memory. 2002 50

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Ang IV also acts as a weak agonist for the Ang II-receptor (AT1), implying the need for stable and highly selective Ang IV-analogues. Here we present the screening of novel Ang IV-analogues, selected on basis of high affinity for IRAP, high selectivity (compared to aminopeptidase N and the AT1 receptor) and resistance against proteases. The selected compound IVDE77 possesses a number of advantages compared to Ang IV: (i) it has a 40 times higher affinity for IRAP (Ki 1.71 nM), (ii) it does not activate the AT1 receptor, (iii) it is easily radiolabeled with tritium and (iv) it is resistant to proteolysis, even in human plasma. In addition, pre-treatment of intact CHO-K1 cells with IVDE77 led to a virtually complete inhibition of subsequent intracellular accumulation of [(3)H]IVDE77-IRAP complexes. IVDE77 thus represents the first Ang IV-analogue able to abolish IRAP-availability completely at the cell surface in vitro. In summary, IVDE77 is a useful tool for the detection of IRAP under physiological conditions, and may contribute to elucidating the mechanism of Ang IV to ascertain which functions are IRAP-dependent.
 ...
PMID:[3H]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase. 2337 57

It is quite well established that activation of the so-called protective arms of the renin-angiotensin system (RAS), involving both AT2 and Mas receptors, provides a counter-regulatory role to AT1 receptor overactivity that may drive pathological changes in the cardiovascular system. In this brief review, we will focus on recent evidence that identifies at least three different pathways that may be effective in the setting of stroke and may be complementary with AT1 receptor blockade. Such mechanisms include AT2 receptor stimulation, Mas receptor stimulation and insulin-regulated aminopeptidase blockade. This report highlights recent data demonstrating striking neuroprotective effects in preclinical models of stroke targeting each of these pathways, which may pave the way for translational opportunities in this field.
 ...
PMID:The protective arms of the renin-angiontensin system in stroke. 2481 74