Functional hyperemia in the brain: hypothesis for astrocyte-derived vasodilator metabolites.
BACKGROUND
Cerebral blood flow is tightly coupled to neuronal metabolic activity, a phenomenon referred to as functional hyperemia. The mechanisms underlying functional hyperemia in the brain have been extensively studied, but the link between neuronal activation and nutritive blood flow has yet to be defined. Recent investigations by our laboratory and others have identified a potential role for astrocytes as an intermediary cell type in this process.


RESULTS
This short review will develop the hypothesis that cytochrome P450 epoxygenase activity in astrocytes catalyzes formation of epoxyeicosatrienoic acids (EETs), which act as potent dilators of cerebral vessels and are released in response to glutamate receptor activation within astrocytes. Neuronal activity stimulates release of arachidonic acid from the phospholipid pool of astrocytic membranes. We provide evidence that the arachidonic acid released on stimulation of glutamate receptors within astrocytes is metabolized by cytochrome P450 2C11 cDNA enzymes into EETs.


CONCLUSIONS
The EETs thus formed will be released and activate K+ channels, increase outward K+ current, and hyperpolarize the plasma membrane. The resulting membrane hyperpolarization inhibits voltage-gated Ca2+ channels and leads to arteriolar dilation, thereby increasing regional nutritive blood flow in response to neuronal activity.
Harder
D R
DR
Cardiovascular Research Center and Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA. dharder@mcw.edu
Alkayed
N J
NJ
Lange
A R
AR
Gebremedhin
D
D
Roman
R J
RJ
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001160:Arterioles / Q000502:physiology; D001189:Aryl Hydrocarbon Hydroxylases; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology*; D008563:Membrane Lipids / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010105:Oxygenases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism*
D001095:Arachidonic Acids; D015220:Calcium Channels; D008563:Membrane Lipids; D010743:Phospholipids; D017470:Receptors, Glutamate; D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D000090762:Cytochrome P-450 CYP2J2; D039181:Steroid 16-alpha-Hydroxylase; D015126:8,11,14-Eicosatrienoic Acid