Basal cerebral blood flow is dependent on the nitric oxide pathway in elderly but not in young healthy men

doi:10.1016/j.exger.2004.04.001

Experimental Gerontology

Volume 39, Issue 8, August 2004, Pages 1245-1248

https://doi.org/10.1016/j.exger.2004.04.001 Get rights and content

Abstract

Objective. Brain perfusion is tightly regulated over a wide range of blood pressures by local regulation of cerebral blood flow (CBF). Ageing is associated with impaired CBF and impaired nitric oxide mediated vasodilator responses. The role of nitric oxide in the regulation of basal CBF in young and older subjects was investigated, using the nitric oxide synthase inhibitor l-NMMA as pharmacological tool.

Methods. We used a gradient echo phase-contrast magnetic resonance imaging technique to investigate the role of nitric oxide in the regulation of cerebral blood flow in young (25±7.1 years; n=8) and old (78±6.6 years; n=7) volunteers. The study was performed in a double-blinded fashion and consisted of two study days. On one day the effects of the intravenously infused L-NMMA on CBF and blood pressure was measured and on the other day the effects of a matching placebo.

Results. Basal CBF was significantly lower in old compared to young subjects (590±20 vs 704±20 ml/min), while the cerebral vascular resistance (CVR) levels were significantly higher (0.15±0.01 (arbitrary units) vs 0.12±0.01, respectively). Infusion of l-NMMA significantly increased mean arterial pressure in both groups (2.8±1.2 mmHg; p=0.02 in the young and in the old subjects 5.6±1.1 mmHg; p<0.001). Infusion of l-NMMA significantly decreased CBF (49±12 ml/min; p<0.001) and increased CVR (0.02±0.004; p<0.001) in the old subjects but did not significantly influence cerebral circulation in the young subjects.

Conclusion. We conclude that compared to young subjects, in old people CBF is impaired, and dependent on the intactness of the nitric oxide pathway.

Introduction

Brain perfusion is tightly regulated over a wide range of blood pressures by local regulation of cerebral blood flow (CBF) (Paulson et al., 1990). Nevertheless, ageing is associated with impaired CBF (Buijs et al., 1998).

Possible explanations for this age dependent impairment of CBF, is a reduction in cerebral metabolism or loss of cerebral tissue at old age (atrophy) (Folkow and Svanborg, 1993, Marin, 1995). Alternatively, this reduced cerebral perfusion at old age could be a pathological condition, caused by vascular damage, e.g. atherosclerosis and lipohyalinosis. In contrast to the first two possibilities, the latter pathological state would cause a potential imbalance between oxygen supply and demand of the brain, triggering auto regulatory mechanisms to induce cerebral vasodilation. An important mechanism to regulate CBF at a local level is the nitric oxide pathway (for review see Toda and Okamura, 2003).

Nitric oxide is produced by the endothelium from l-arginine upon various triggers, amongst others hypoxia and hypercapnia, both important stimuli to increase cerebral perfusion (Toda and Okamura, 2003). Both ageing and atherosclerosis are associated with impaired endothelial function and consequently impaired nitric oxide mediated vasodilation (Folkow and Svanborg, 1993, Lyons et al., 1997, Toda and Okamura, 2003). Since cerebral vascular disease is a disorder of the elderly it is possible that endothelial dysfunction might be the cause of a relative hypoperfusion of the brain at old age, causing ischaemic damage. This relative hypoperfusion would cause an imbalance between oxygen supply and demand, triggering the endothelium to enhance the production and release of nitric oxide.

In the present study we examined the role of nitric oxide in the regulation of basal cerebral vascular tone in older and young subjects. We used the nitric oxide synthase inhibitor l-NMMA as pharmacological tool.

Section snippets

Subjects

Eight young (mean age 25±7.1 years) and 7 old (mean age 78±6.6 years) non-smoking healthy male volunteers, participated in this study after giving informed consent. Physical and routine blood examinations, ECG and conventional MRI scans of the brain (T2-weighted fast spin echo and fluid attenuated inversion recovery (FLAIR)) revealed no major abnormalities. Exclusion criteria were current smoking, use of drugs and more than three alcoholic drinks a day, body mass index greater than 26 kg/m²,

Results

The clinical characteristics of the volunteers at the day of screening are listed in Table 1. Baseline MAP was significantly higher in the old subjects (91±13 mmHg) compared to the young individuals (74±27 mmHg; p<0.05). Baseline CBF in the old subjects (590±53 ml/min) was significantly lower compared to the young individuals (704±57 ml/min; p<0.05; Table 2). Consequently, baseline CVR was significantly higher in the old subjects compared to the young individuals (Table 2). In both groups l

Discussion

The main finding of our study is that in elderly individuals basal total CBF is dependent on the nitric oxide pathway, whereas in younger individuals this is not the case, suggesting that in old age the range of cerebral auto regulation is impaired.

Total CBF is kept constant over a wide range of systemic blood pressure by local regulation of vascular tone. This auto regulation of CBF is controlled by a combination of myogenic, neurogenic, and metabolic mechanisms (Heistadt and Kontos, 1983).

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Basal cerebral blood flow is dependent on the nitric oxide pathway in elderly but not in young healthy men

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Mech. Ageing Dev.

Effect of age on cerebral blood flow: measurement with ungated two-dimensional phase-contrast MR angiography in 250 adults

Radiology

Physiology of cardiovascular aging

Physiol. Rev.

Cerebral circulation

Impaired nitric oxide-mediated vasodilation and total body nitric oxide production in healthy old age

Clin. Sci.

Cerebral autoregulation

Cerebrovasc. Brain Metab. Rev.