Effects of Acute Hyperhomocysteinemia on the Neurovascular Coupling Mechanism in Healthy Young Adults

Abstract

Background and Purpose-Hyperhomocysteinemia is a vascular risk factor that infers with the nitric oxide signaling pathway of endothelial vasoregulation. Most investigations in young healthy humans on the peripheral vasculature using a standardized methionine challenge demonstrated altered vascular reactivity. In contrast, the cerebral autoregulation mechanism was shown to be unaffected by the same methionine load. To obtain additional insight into the compensatory range of the cerebral vasculature during a methionine challenge, we tested the neurovascular coupling mechanism that adjusts cerebral blood flow in accordance with cortical activity. Methods-Fifteen healthy young adults (age, 24.7Ϯ2.3 years; 7 men) were tested with a functional transcranial Doppler test before and 3, 8, and 24 hours after administration of placebo, 20 mg folic acid, 20 mg folic acid and 0.1 g/kg body weight L-methionine, or L-methionine alone. Evoked blood flow response was evaluated according to a control system approach. Plasma concentrations of homocysteine, resting blood flow velocities, and control system parameters of flow velocity change were compared for each time point using a multiple analysis of variance test. Results-Homocysteine levels increased significantly compared with baseline (before, 7.6Ϯ1.9 mol/L; 3 hours, 22 Key Words: endothelium Ⅲ homocyst(e)ine Ⅲ ultrasonography, Doppler Ⅲ vasodilation T he neurovascular coupling (NC) mechanism adjusts local cerebral blood flow in accordance with the underlying cortical activity. [1][2][3][4] Whereas the detailed mechanisms remain to be resolved, there is good evidence that the biological elements of the NC mechanism functionally resemble a complex and cascaded control system. 1,2,4 -8 The vascular endothelium and its nitric oxide system play a crucial role in the NC-related vasoregulation. 4,9 -13 Hyperhomocysteinemia is an emerging vascular risk factor leading to endothelial dysfunction, atherosclerosis, and consequently parenchymal ischemia. 10 -13 The term "endothelial dysfunction" is assumed to describe in general a functional alteration of the vasculature, depending on some vasoregulative mechanism. 14,15 Under acute hyperhomocysteinemia, it is hypothesized to be caused by a decrease in availability of nitric oxide. 16 -19 Several studies in healthy young volunteers undergoing an oral methionine loading of 0.1 g/kg body weight demonstrated an impaired peripheral vascular reactivity. 20 -24 However, some reports found neither an altered peripheral vascular reactivity 25,26 nor a change in arterial rigidity under the same homocysteine challenge. 27 Similarly, for the cerebral autoregulation (CA) mechanism that maintains constant cerebral perfusion despite changes in arterial blood pressure, it was demonstrated that vascular reactivity was affected only in aged but not in young healthy subjects. 28 An attenuation of the endothelium-dependent cerebrovascular reactivity was found consistently only in animal experiments using high concentrations of homocysteine (1 mmol/L)...

Active, passive, and motor imagery paradigms: component analysis to assess neurovascular coupling

“…The initial temporal pattern of CBFv response, involving a steep bilateral increase, is consistent with former TCD studies using a broad variety of brain activation paradigms (4,14,15,22,24,29,30,32,37). In keeping with our results, Duscheck et al (15) found the effects of BP on CBFv responses during arithmetic processing were also more pronounced during the first second of the response.…”

The effect of levodopa treatment on cerebral hemodynamics in patients with Parkinson's disease: Serial transcranial Doppler studies

“…However, this finding is in agreement with previous results of the change in cerebral blood flow velocities after a standardized methionine challenge. Rosengarten and colleagues reported that although homocysteine levels increased significantly after a methionine loading, no significant changes were observed in the resting cerebral flow velocities [11]. It is known that the cerebral vasculature differs in many functional and morphological aspects from the peripheral vasculature, having a wider compensatory range to maintain adequate blood flow than peripheral vasculature [11].…”

“…Rosengarten and colleagues reported that although homocysteine levels increased significantly after a methionine loading, no significant changes were observed in the resting cerebral flow velocities [11]. It is known that the cerebral vasculature differs in many functional and morphological aspects from the peripheral vasculature, having a wider compensatory range to maintain adequate blood flow than peripheral vasculature [11]. This compensatory capacity of cerebral vasculature may result in no gross alteration of cerebral blood flow velocities and PI even after increased serum homocysteine levels.…”

Plasma and Cerebrospinal Fluid Homocysteine, Nitric Oxide and Malondialdehyde Levels in Acute Ischemic Stroke: Possible Role of Free Radicals in the Development of Brain Injury

“…In recent years, numerous studies have identified a strong, independent and doserelated association between elevated Hcy levels and vascular diseases, including stroke (11)(12)(13)(14)(15)(16)(17)(18). The exact mechanisms responsible for this association is still under investigation.…”

“…Endothelial dysfunction is hypothesized to be caused by the potency of Hcy to interfere with the action of endothelial vasodilators such as NO (14). It is postulated that NO is scavenged by superoxide anion generated in the metabolic pathway of Hcy (16). When NO formation is reduced, excessive Hcy may further damage the endothelium by generation of ROS (15,17), thereby increasing lipid peroxidation (18).…”