Abstract
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.
Highlights
Using object recognition as a model of memory and learning, we have shown that angiotensin IV causes significant enhancement in mice
The object recognition test involves exposing the animals to an open field (60 × 40 cm) in which are placed two identical ethanol-cleaned porcelain objects that are novel to the mice, and of sufficient weight that they cannot be moved or displaced by the subjects
The salient points of their argument are: the effects of enzyme inhibition and accumulation of endogenous peptides are slow, in the order of hours or days, whilst the onset of action of angiotensin IV in some tissues is within seconds; the concentrations of angiotensin IV required to produce biological, that is, cognitive effects, are well below the concentrations required to inhibit insulin-regulated aminopeptidase (IRAP); and there is dispute as to whether angiotensin IV is a competitive substrate of IRAP or whether it binds allosterically
Summary
Using object recognition as a model of memory and learning, we have shown that angiotensin IV causes significant enhancement in mice. The salient points of their argument are: the effects of enzyme inhibition and accumulation of endogenous peptides are slow, in the order of hours or days, whilst the onset of action of angiotensin IV in some tissues is within seconds; the concentrations of angiotensin IV required to produce biological, that is, cognitive effects, are well below the concentrations required to inhibit IRAP; and there is dispute as to whether angiotensin IV is a competitive substrate of IRAP or whether it binds allosterically If it is a competitive substrate, it would be difficult to explain the observed effects of the AT4 receptor antagonist divalinal, which is known to block the effects of angiotensin IV, and have detrimental effects on learning and memory: does divalinal enhance IRAP activity?. The conclusion is that oxytocin is unlikely to be involved with the cognitive actions of angiotensin IV, and that the resistance of BKW strain mice to the cognitive effects of angiotensin IV is unlikely to be due to an inherent disorder of oxytocin
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