Gard Paul R
School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton, UK.
BMC Neurosci. 2008 Dec 3;9 Suppl 2(Suppl 2):S15. doi: 10.1186/1471-2202-9-S2-S15.
Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out.
血管紧张素IV是强效血管收缩剂血管紧张素II的衍生物，研究表明，在动物学习和记忆模型中，经中枢或外周给药时，血管紧张素IV可增强记忆的获得、巩固和回忆。旨在破坏人体外周肾素-血管紧张素系统的心血管药物的认知效应是否源于血管紧张素IV活性的变化仍未确定，但血管紧张素IV似乎是药物研发计划中值得考虑的候选药物。尽管血管紧张素IV的AT4受体已被确认为胰岛素调节的氨基肽酶，即催产素酶和胎盘亮氨酸氨基肽酶，但其作用机制仍存在争议。据推测，血管紧张素IV可能与胰岛素调节的氨基肽酶相互作用，以增强神经元对葡萄糖的摄取，防止其他神经活性肽的代谢，诱导细胞外基质分子的变化，或诱导乙酰胆碱和/或多巴胺的释放。所有这些都可能是其对认知产生有益影响的原因，但均未得到证实。重要的是，小鼠对血管紧张素IV反应的品系差异表明，一些个体可能从针对AT4受体的药物中获益，而另一些个体可能无效。因此，目前看来，基线认知最差的个体可能获益最大，但不能排除对血管紧张素IV反应存在潜在基因差异的可能性。
