@misc{oai:repo.qst.go.jp:00069782,
 author = {Takuwa, Hiroyuki and Matsuura, Tetsuya and Bakalova-Zheleva, Rumiana and Obata, Takayuki and Kanno, Iwao and 田桑 弘之 and 松浦 哲也 and バカロバ ルミアナ and 小畠 隆行 and 菅野 巖},
 month = {Jul},
 note = {Objectives: The tight spatial and temporal coupling of synaptic activity with local cerebral blood flow (known as neurovascular coupling) is a hallmark of brain function. Any obstruction of the neurovascular coupling mechanism disturbs brain homeostasis and provokes brain pathology and cell death. To clarify and find ways to control the key molecular targets underlying the regulation of neurovascular coupling could be an important way to increase the life of brain cells, to overcome neurodegenerative diseases, and to delay the processes of senescence.
The present study was designed to clarify whether nitric oxide participates in the regulation of neurovascular coupling during hypoxia. Hypoxia is a characteristic of many brain disorders (e.g., stroke, infraction, inflammation, necrosis, etc.) and its control is of outstanding importance for brain homeostasis.
Methods: Seventeen male Sprague-Dawley rats (385.4g) were used to investigate the effect of hypoxia and LNA [N-nitro-L-arginine: a selective inhibitor of nitric oxide synthase (NOS)] on the evoked regional cerebral blood flow response (rCBF) to hind-paw stimulation. The rats were anesthetized with isoflurane during the surgery and alpha-chloralose during the measurements. The animals were ventilated with a respirator using a mixture of air and oxygen to achieve physiological arterial blood levels of PaO2 and PaCO2 (PaO2 was ~110-130 mmHg; PaCO2 ~33-40 mmHg), as well as to induce hypoxia (PaO2 ~ 45-49 mmHg, PaCO2 ~33-40 mmHg). To avoid side-effects of systematic changes, the experimental protocol was designed to ensure hypoxia and normotension conditions. The rCBF response to hind-paw stimulation was measured by laser-Doppler flowmetry (LDF) with stimulus frequency of 5 Hz, current 1.5 mA, and duration 5 sec before and after induction of hypoxia, as well as before and after intravenous infusion of LNA. The field potentials were also recorded using an Ag-AgCl indifferent electrode.
Results: Hypoxia was accompanied by an enhancement of the baseline (~18%) and rCBF response to hind-paw stimulation. The peak-amplitude of the rCBF response curve increased significantly (~31%), while the rise-time and termination-time were constant. The infusion of LNA completely abolished the effect of hypoxia on the baseline and evoked rCBF response. During hypoxia, the peak-amplitude of the evoked rCBF decreased significantly after LNA infusion (~48%) to a value even lower than that obtained during normoxia without LNA administration. The infusion of LNA was accompanied by vasoconstriction and hypertension. The termination time of the rCBF response curve decreased slightly (~15%) after LNA infusion during hypoxia, while the rise-time was constant. The field potential was constant for all experimental protocols.
Conclusions: The data confirm the major role of nitric oxide in the regulation of neurovascular coupling during hypoxia. Since the hypoxia is accompanied by abnormal generation of reactive oxygen species,1 e.g., superoxide radicals known to interact rapidly with nitric oxide, we hypothesize that the resulting peroxinitril radical is the most likely candidate for regulation of neurovascular coupling during hypoxia and hypoxia-induced vasodialtion.
References:
1Packer L.,et al, (1992) Free Radicals in the Brain: Aging, Neurological and Mental Disorders, Springer-Verlag, Berlin., XXIVth International Symposium on Cerebral Blood Flow, Metabolism and Function & VIth International Conference on Quantification of Brain Function with PET},
 title = {Nitric Oxide as a Major Mediator of Neurovascular Coupling in Hypoxia: Free Radical Hypothesis},
 year = {2009}
}