A common pathway for regulation of nutritive blood flow to the brain: arterial muscle membrane potential and cytochrome P450 metabolites.
Perfusion pressure to the brain must remain relatively constant to provide rapid and efficient distribution of blood to metabolically active neurones. Both of these processes are regulated by the level of activation and tone of cerebral arterioles. The active state of cerebral arterial muscle is regulated, to a large extent, by the level of membrane potential. At physiological levels of arterial pressure, cerebral arterial muscle is maintained in an active state owing to membrane depolarization, compared with zero pressure load. As arterial pressure changes, so does membrane potential. The membrane is maintained in a relatively depolarized state because of, in part, inhibition of K+ channel activity. The activity of K+ channels, especially the large conductance Ca(2+)-activated K+ channel (KCa) is dependent upon the level of 20-HETE produced by arterial muscle. As arterial pressure increases, so does cytochrome P450 (P4504A) activity. P4504A enzymes catalyse omega-hydroxylation of arachidonic acid and formation of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent inhibitor of KCa which maintains membrane depolarization and muscle cell activation. Astrocytes also metabolize AA via P450 enzymes of the 2C11 gene family to produce epoxyeicosatrienoic acids (EETs). Epoxyeicosatrienoic acids are released from astrocytes by glutamate which 'spills over' during neuronal activity. These locally released EETs shunt blood to metabolically active neurones providing substrate to support neuronal function. This short paper will discuss the findings which support the above scenario, the purpose of which is to provide a basis for future studies on the molecular mechanisms through which cerebral blood flow matches metabolism.
Harder
D R
DR
Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA.
Roman
R J
RJ
Gebremedhin
D
D
Birks
E K
EK
Lange
A R
AR
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D002536:Cerebral Arteries / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*
D003577:Cytochrome P-450 Enzyme System