Angiotensin II Inhibits Cortical Cholinergic Function

Barnes, James L.; Barnes, NM; Costall, B.; Horovitz, Zola P.; Ironside, James; Naylor, R.J.; Williams, T J

doi:10.1097/00005344-199008000-00009

Cited by 62 publications

(33 citation statements)

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“…This hypothesis is based on two well-reported findings: First, scopolamine-induced impairment in memory and CBF is due to cholinergic hypofunction as increase in cholinergic activity (either by inhibiting ACh degradation or increasing its synthesis) ameliorated both the conditions (Jones et al 1991;Jeong et al 2008;Ogawa et al 1994;Tsukada et al 1997). Second, Ang II has been shown to inhibit ACh release in vitro from entorhinal cortex which was reversed by AT1 receptor antagonists (Barnes et al 1989(Barnes et al , 1990). Therefore, the improvement of cholinergic function leads to endothelium-dependent relaxation of cerebral arteries resulting into increased cerebral circulation (Faraci and Heistad 1998).…”

Section: Discussionmentioning

confidence: 99%

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

et al. 2012

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Rational Inhibition of renin-angiotensin system (RAS) improves cognitive functions in hypertensive patients. However, role of AT1 and AT2 receptors in memory impairment due to cholinergic hypofunction is unexplored. Objective This study investigated the role of AT1 and AT2 receptors in cerebral blood flow (CBF), cholinergic neurotransmission, and cerebral energy metabolism in scopolamineinduced amnesic mice. Methods Scopolamine was given to male Swiss albino mice to induce memory impairment tested in passive avoidance and Morris water maze tests after a weeklong administration of blocker of AT1 receptor, candesartan, and AT2 receptor, PD123, 319. CBF was measured by laser Doppler flowmetry. Biochemical and molecular studies were done in cortex and hippocampus of mice brain. Results Scopolamine caused memory impairment, reduced CBF, acetylcholine (ACh) level, elevated acetylcholinesterase (AChE) activity, and malondialdehyde (MDA). Administration of vehicle had no significant effect on any parameter in comparison to control. Candesartan prevented scopolamineinduced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. In contrast, PD123, 319 was not effective. However, the effect of AT1 receptor blocker on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2 receptor. Angiotensin-converting enzyme (ACE) activity, ATP level, and mRNA expression of AT1, AT2, and ACE remained unaltered. Conclusion The study suggests that activation of AT1 receptors appears to be involved in the scopolamine-induced amnesia and that AT2 receptors contribute to the beneficial effects of candesartan. Theses finding corroborated the number of clinical studies that RAS inhibition in hypertensive patients could be neuroprotective.

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Section: Discussionmentioning

confidence: 99%

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

et al. 2012

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“…Recently, Denny et al (t991) have reported the ability of angiotensin II to inhibit hippocampal long term potentiation, a model of enhanced synaptic efficacy believed to be involved in the formation of memory. Furthermore, an interaction of angiotensin II with the cholinergic system has also been implicated (Barnes et al 1990). While neither of these effects have yet been shown to be mediated through either AT1 or AT 2 receptors, either may provide possible underlying mechanisms mediating the cognitive enhancing effects of the ACE inhibitors or the AT1 receptor antagonists as reported in the present study and by others.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of scopolamine-induced spatial memory deficits in the rat by cholinomimetic and non-cholinomimetic drugs using a novel task in the 12-arm radial maze

Dennes¹,

Barnes²

1993

Psychopharmacology

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The effects of cholinomimetic and non-cholinomimetic agents on spatial memory using a novel task in the 12-arm radial maze were investigated. The task was designed to reduce the tendency to use non-spatial strategies. Animals were repeatedly trained to retrieve food rewards from three arms, until a criterion level of performance was reached. Scopolamine (0.03 and 0.1 mg/kg SC), but not N-methylscopolamine (0.1 mg/kg SC) disrupted performance of this task. Physostigmine (0.3 mg/kg SC) and pilocarpine (30 mg/kg SC) completely reversed the deficit of performance produced by scopolamine. Furthermore, the ACE inhibitor Hoe 288 (10 nmol ICV) and the angiotensin AT1 receptor antagonist losartan (10 mg/kg SC) also significantly attenuated the scopolamine-induced deficit. These results show that this novel task in the radial maze is sensitive to the disruptive effects of scopolamine and can identify cognitive enhancing effects of both cholinomimetic and non-cholinomimetic drugs. Thus, this maze task provides a useful model for the evaluation of novel cognitive enhancing agents.

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“…Thus it appears that ACE inhibition in the brain may actually have a cognitively beneficial effect. The apparent cognitive benefits of ACE inhibition in the brain may be due to increased cholinergic activity, because ACE activity is increased in AD brain (39 -41) and angiotensin II has been shown to inhibit acetylcholine release (42).…”

Section: Figure 8 Oral Administration Of Ece and Nep Inhibitorsmentioning

confidence: 99%

Regulation of Steady-state β-Amyloid Levels in the Brain by Neprilysin and Endothelin-converting Enzyme but Not Angiotensin-converting Enzyme

Eckman

Adams

Troendle

et al. 2006

Journal of Biological Chemistry

186

135

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The deposition of ␤-amyloid in the brain is a pathological hallmark of Alzheimer disease (AD). Normally, the accumulation of ␤-amyloid is prevented in part by the activities of several degradative enzymes, including the endothelin-converting enzymes, neprilysin, insulin-degrading enzyme, and plasmin. Recent reports indicate that another metalloprotease, angiotensin-converting enzyme (ACE), can degrade ␤-amyloid in vitro and in cellular overexpression experiments. In addition, ACE gene variants are linked to AD risk in several populations. Angiotensin-converting enzyme, neprilysin and endothelin-converting enzyme function as vasopeptidases and are the targets of drugs designed to treat cardiovascular disorders, and ACE inhibitors are commonly prescribed. We investigated the potential physiological role of ACE in regulating endogenous brain ␤-amyloid levels for two reasons: first, to determine whether ␤-amyloid degradation might be the mechanism by which ACE is associated with AD, and second, to determine whether ACE inhibitor drugs might block ␤-amyloid degradation in the brain and potentially increase the risk for AD. We analyzed ␤-amyloid accumulation in brains from ACE-deficient mice and in mice treated with ACE inhibitors and found that ACE deficiency did not alter steady-state ␤-amyloid concentration. In contrast, ␤-amyloid levels are significantly elevated in endothelin-converting enzyme and neprilysin knock-out mice, and inhibitors of these enzymes cause a rapid increase in ␤-amyloid concentration in the brain. The results of these studies do not support a physiological role for ACE in the degradation of ␤-amyloid in the brain but confirm roles for endothelin-converting enzyme and neprilysin and indicate that reductions in these enzymes result in additive increases in brain amyloid ␤-peptide levels.

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Angiotensin II Inhibits Cortical Cholinergic Function

Cited by 62 publications

References 0 publications

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

Attenuation of scopolamine-induced spatial memory deficits in the rat by cholinomimetic and non-cholinomimetic drugs using a novel task in the 12-arm radial maze

Regulation of Steady-state β-Amyloid Levels in the Brain by Neprilysin and Endothelin-converting Enzyme but Not Angiotensin-converting Enzyme

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