Paul Gard

The role of angiotensin II in cognition and behaviour

Polymorphisms of the renin-angiotensin system are associated with cardiovascular disorders, possibly as a consequence of increased brain angiotensin II activity. Within the brain, angiotensin controls blood pressure, fluid balance and hormone secretion; it also influences behaviour: reduction of central angiotensin function has both antidepressant-like and axiolytic-like actions. Evidence concerning the role of the renin-angiotensin system in learning and memory is contradictory, although more studies support the proposal that angiotensin reduces cognitive function. Studies of renin-angiotensin system genotype and psychological status have suggested an association between the angiotensin-converting enzyme deletion allele and age related cognitive decline, but a greater prevalence of the insertion allele in Alzheimers disease. The deletion allele has also been associated with depressive illness, as has the M allele of the angiotensinogen gene although other studies have failed to replicate these findings. The role of the brain renin-angiotensin system in human psychopathology remains to be fully explored.

Angiotensin as a target for the treatment of Alzheimer's disease, anxiety and depression

The brain renin–angiotensin system (RAS), which is comprised of a variety of peptides including angiotensin II, angiotensin III and angiotensin IV acting on AT1, AT2 and AT4 receptors, is important in cognition and anxiety. Perturbation of the RAS improves basal cognition and reverses age-, scopolamine-, ethanol- and diabetes-induced deficits. In studies of dementias and Alzheimer’s disease (AD), some studies have shown that antihypertensive drugs, including angiotensin-converting enzyme inhibitors, have some moderate effects on cognitive decline, but that the angiotensin receptor antagonist losartan has a significantly beneficial effect. These findings suggest that angiotensin receptor ligands may have potential in the prevention or even reversal of vascular dementias and AD. With respect to depression and anxiety, there is similar experimental evidence from animal models that drugs acting on the RAS may be antidepressant or anxiolytic, but insufficient clinical data exist. Such effects, if proven, could promote the use of such agents in the treatment of hypertension coexisting with depression or anxiety.

Evidence of a possible role of altered angiotensin function in the treatment, but not etiology, of depression.

BACKGROUND Angiotensin-converting enzyme inhibitors are reportedly effective in the treatment of depression; furthermore, antidepressants decrease angiotensin function. It appears therefore that reduced angiotensin function may be important in the treatment of depression. The aims of this study were to elucidate the actions of antidepressants on angiotensin receptors; to investigate the antidepressant potential of an angiotensin antagonist; and to study angiotensin receptors in depressed puerperal women. METHODS The effects of antidepressant drugs on angiotensin receptors and the relationship between mood and platelet receptors in puerperal women were investigated using radioligand binding. The antidepressant potential of the angiotensin antagonist losartan was assessed using the mouse forced swim test. RESULTS Desipramine, but neither fluoxetine nor tranylcypromine, displaced angiotensin from its receptor; however, there was no significant relationship between receptor number and depressed mood. In the forced swim test losartan was shown to possess antidepressant like activity. CONCLUSIONS These findings indicate that antidepressants differ in the mechanism by which they reduce angiotensin function, but the link between antidepressants and angiotensin is reiterated by the demonstration that losartan possesses antidepressant like activity. There is, however, no evidence of abnormal angiotensin receptors in women with depressed mood postpartum.

Cognitive-enhancing effects of angiotensin IV.

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.

Captopril and Enalapril Improve Cognition and Depressed Mood in Hypertensive Patients

UNLABELLED In this study, we evaluate the effects of two angiotensin converting enzyme inhibitors (ACEIs), captopril and enalapril given chronically as antihypertensive treatment, on certain cognitive and emotional processes in humans. Thirty-nine subjects with mild to moderate hypertension and fifteen normotensive controls were divided into four groups consisting of normotensive and hypertensive subjects taking captopril, enalapril, or no medication at all. The Rey Auditory Verbal Learning Test and the Wechsler Memory Scale were used to evaluate their cognitive functioning. Mood changes in all subjects were assessed using the Beck Depression Inventory and the Hopkins Symptom Check- list (HSC). RESULTS Untreated hypertensive patients scored lower than normotensive controls in cognitive tests and significantly worse in cumulative recall (P < 0.05) and paired words association (P < 0.01). When compared with normotensive subjects, untreated hypertensive patients also scored significantly higher on the depression with anxiety subscale in HSC (P < 0.05). No significant influence of hypertension was found in any other examined aspect of cognition and mood. In most cases captopril improved and enalapril reversed the adverse memory effects of hypertension. High arterial blood pressure is significantly associated with an impairment of cognition and the occurrence of depression with anxiety in humans. Enalapril and, to a lesser extent, captopril reversed these deficits.

Renin- angiotensin- system gene polymorphisms and depression

Given the abundance of the renin-angiotensin system (RAS) components in the brain, their importance in behavior and cognition, and the data that implicates them in the etiology and treatment of depression, it is possible that those RAS gene polymorphisms associated with increased RAS activity may also be associated with depression. The frequencies of common polymorphisms of genes encoding for components of the RAS, namely angiotensinogen (M235T), angiotensin converting enzyme (ACE) (insertion, I; deletion, D), angiotensin receptor type I (A1166C), and angiotensin receptor type II (C3123A) were determined in DNA extracted from buccal cells from a Lebanese population of 132 depressed patients and their first-degree relative case-controls. The angiotensin receptor type 1 (A1166C) CC genotype was significantly associated with depression (p=0.036). None of the other common RAS-associated polymorphisms were significantly associated. The results support the hypothesis that increased RAS activity may increase relative risk of depression in that the angiotensin receptor type 1 (A1166C) CC genotype is associated with increased responsiveness to angiotensin II.

Hip subluxation and dislocation in cerebral palsy – a prospective study on the effectiveness of postural management programmes

BACKGROUND AND PURPOSE Hip subluxation and dislocation are common sequelae in children with bilateral cerebral palsy and are currently managed by surgical interventions. This study aimed to investigate the effectiveness of early postural management programmes on hip subluxation and dislocation at five years, and the need for treatment in children with bilateral cerebral palsy, and to compare these findings with a historical control group. METHODS A prospective cohort study followed 39 children who commenced using postural management equipment under 18 months of age. Levels of ability, type and amount of equipment use and treatments were recorded every three months. At 30 and 60 months, the hips were X-rayed and the hip migration percentage was measured. The results were compared with the historical control group. RESULTS Children who used equipment at recommended and moderate levels had significantly less chance of both hips being subluxed than those using equipment at minimal levels (two-tailed Fishers exact chi(2) p = 0.024). The frequency of children with hip problems was significantly less in the intervention group in comparison to the historical control group at five years (chi(2) = 11.53, df = 2, p = 0.006). The frequency of children receiving bilateral or unilateral treatments, i.e. surgery, use of a hip and spinal orthosis and/or botulinum toxin injections, in the intervention group was significantly less compared to the historical control group (two-tailed Fishers exact p = 0.001). CONCLUSION The early provision of postural management equipment has a role to play in reducing the number of hip problems and therefore the need for treatment of hip subluxation/dislocation in cerebral palsy at five years of age.

Angiotensin and Alzheimer's disease: therapeutic prospects

This review describes the features of Alzheimer´s disease and discusses the evidence that antihypertensive therapies may be beneficial in its treatment and prevention. Drugs acting via the reninangiotensin system are considered and it is suggested that these drugs may produce their effects via mechanisms other than by their antihypertensive actions. Using evidence from animal studies, the role of angiotensin as a neurotransmitter and its involvement in the control of normal cognitive function is described. Studies of angiotensin and human cognition are reviewed along with studies investigating the possible link between disorders of the system, either inherited or acquired, and the symptoms of Alzheimer´s disease. The therapeutic potential of screening for markers of reninangiotensin abnormality for the prediction of Alzheimer´s disease is considered, as is the potential use of agents known to influence the renin–angiotensin system in the treatment or prevention of the disease.

Strain differences in the anxiolytic effects of losartan in the mouse.

Anxiolytic effects of the angiotensin AT(1) receptor antagonist losartan were studied in the elevated plus maze (EPM) and the light/dark test (LDT) in different mouse strains as were responses to angiotensin II and acetylcholine in isolated ascending colon. There were no significant strain differences in behaviour on the EPM, and diazepam was anxiolytic in C57BL/6, DBA/2 and BKW mice. Losartan was anxiolytic in BKW only. In the LDT, there were significant strain differences, with BKW mice exhibiting greatest anxiety-like behaviour; losartan was ineffective in this test. In vitro responses to angiotensin II and acetylcholine were significantly smaller in BKW than in C57BL/6 and DBA/2. These results indicate that the mouse strain exhibiting least angiotensin receptor function is the most responsive to the anxiolytic effects, suggesting a possible relationship between angiotensin receptor function and anxiolytic response to losartan.

Hypertension and inflammation in Alzheimer's disease: close partners in disease development and progression!

Alzheimers disease (AD) is by far the most common sporadic neurodegenerative disorder. Clinically it is associated with cognitive and other neuropsychological impairments, and neuropathologically it is distinguished by presence of amyloid-β plaques and neurofibrillary tangles. Hypertension has been traditionally associated with the etiology of vascular dementia, however, vascular risk factors including hypertension are increasingly being implicated in AD. Likewise, the importance of neuroinflammation in AD pathogenesis is also widely recognized. Data from animal and non-AD human studies suggest a close reciprocal relationship between hypertension and inflammatory systems. Much less is known on the potential pathological interaction between hypertension and inflammation in AD and its subsequent effects on amyloid and tau misfolding, aggregation, and propagation, events recognized as critical for the development and progression of AD. This review summarizes what is known about the mechanistic interactions between hypertension and inflammatory mediators and assesses their potential synergistic/additive role in AD genesis. Increasing our understanding of the pathological interactions between the recognized risk factors for AD is a worthwhile endeavor in a condition which currently has limited treatment options but an increasing number of potential preventative measures.