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 reg ulated, to a large extent, by the level of membrane potential. At physiolog ical levels of arterial pressure, cerebral arterial muscle is maintained in an active state owing to membrane depolarization, compared with zero press ure load. As arterial pressure changes, so does membrane potential. The mem brane 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 Ca2+-activated K+ channel (K-Ca) is dependent upon th e level of 20-HETE produced by arterial muscle. As arterial pressure increa ses. so does cytochrome P450 (P4504A) activity. P4504A enzymes catalyse ome ga-hydroxylation of arachidonic acid and formation of 20-hydroxyeicosatetra enoic acid (20-HETE). 20-HETE is a potent inhibitor of Kc, which maintains membrane depolarization and muscle cell activation. Astrocytes also metabol ize AA via P450 enzymes of the 2C11 gene family to produce epoxyeicosatrien oic acids (EETs). Epoxyeicosatrienoic acids are released from astrocytes by glutamate which 'spills over' during neuronal activity. These locally rele ased EETs shunt blood to metabolically active neurones providing substrate to support neuronal function. This short paper will discuss the findings wh ich 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.