Recent evidence demonstrates that the fragment of angiotensin II, angiotensin II (3-8) termed angiotensin IV, binds with high affinity to a specific binding site, the AT4 receptor. Intracerebroventricular injection of AT4 receptor agonists improves the performance of rats in passive avoidance and spatial learning paradigms. AT4 receptors and cholinergic neurons are closely associated in regions involved in cognitive processing, such as the hippocampus and neocortex. We therefore postulated that AT4 receptors affect cognitive processing by modulating cholinergic neurotransmission. To test this, we examined the effect of AT4 receptor ligands, angiotensin IV and LVV-hemorphin-7, on potassium-evoked [3H]acetylcholine ([3H]ACh) release from rat hippocampal slices. Hippocampal slices from male Sprague-Dawley rats were incubated with [3H]choline chloride, perfused with Krebs-Henseleit solution and [3H]ACh release was determined. Angiotensin IV and LVV-hemorphin-7 both potentiated depolarisation-induced [3H]ACh release from the rat hippocampus in a concentration-dependent manner with the maximal dose (10-7M) of each inducing an increase of 45±7.5% (P<0.01) and 95.8±19% (P<0.01) above control, respectively. Potentiation of release by both agonists was attenuated by the AT4 receptor antagonist, divalinal-Ang IV. Angiotensin IV-induced potentiation was not affected by AT1 and AT2 receptor antagonists. These results indicate that stimulation of AT4 receptors can potentiate depolarisation-induced release of ACh from hippocampal slices and suggest that potentiation of cholinergic transmission may be a mechanism by which AT4 receptor ligands enhance cognition.
- Ang IV
- AT receptor