Mechanisms of hypoxic cerebral vasodilatation

Hypoxia activates multiple mechanisms that influence cerebrovascular tone. Through actions on non-vascular cerebral elements, hypoxia stimulates the production of a wide variety of vasodilator metabolites, the most important of which are potassium and hydrogen ions, prostaglandins and adenosine. Hypoxia also promotes the neuronal release of excitatory amino acids, which stimulates overall cerebral metabolism and further enhances the release of vasodilator metabolites. Altogether, the combined action of these metabolites, many of which remain unidentified, account for approximately half the vasodilatation associated with moderate to severe hypoxia. The remaining vasodilatation is attributable to direct effects of hypoxia on cerebral arteries. One component of the direct vascular effects of hypoxia involves the endothelium, which can release at least three different vasodilating factors (prostacyclin, nitric oxide and hyperpolarizing factor) and two different contracting factors (indomethacin-sensitive and indomethacin-resistant) in response to hypoxia. In cerebral arteries, the net contribution of endothelial factors to hypoxic vasodilatation appears to be modest, although the exact profile of factors released by hypoxia appears to depend on both species and artery type. Within the vascular smooth muscle cells of cerebral arteries, hypoxia activates membrane ATP-sensitive potassium channels, resulting in hyperpolarization of the smooth muscle membrane and reduced calcium permeability. In addition, hypoxia also appears capable of retarding flux through the inositol phosphate cascade and reducing the second messenger stimulus for release of intracellular calcium. Both of these latter influences, which may be caused by hypoxic changes in intracellular ATP, ADP and hydrogen ion concentrations, act to lower the free cytosolic calcium concentration available to support contraction. Hypoxia also appears to reduce the calcium sensitivity of contractile proteins. Combined, these mechanisms exert a powerful and multifaceted inhibitory influence on cerebrovascular tone.