Evidence that 20-HETE contributes to the development of acute and delayed cerebral vasospasm.
Recent studies have indicated that arachidonic acid (AA) is metabolized by the cytochrome P450 4A (CYP4A) enzymes in cerebral arteries to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and that this compound has effects on cerebral vascular tone that mimic those seen following subarachnoid hemorrhage (SAH). In this regard, 20-HETE is a potent constrictor of cerebral arteries that decreases the open state probability of Ca(2+)-activated K(+) channels through activation of protein kinase C (PKC). It increases the sensitivity of the contractile apparatus to Ca(2+) by activating PKC and rho kinase. The formation of 20-HETE is stimulated by angiotensin II (AII), endothelin, adenosine triphosphate (ATP) and serotonin, and inhibited by NO, CO and superoxide radicals. Inhibitors of the formation of 20-HETE block the myogenic response of cerebral arterioles to elevations in transmural pressure in vitro and autoregulation of cerebral blood flow (CBF) in vivo. 20-HETE also plays an important role in modulating the cerebral vascular responses to vasodilators (NO and CO) and vasoconstrictors (AII, endothelin, serotonin). Recent studies have indicated that the levels of 20-HETE in cerebrospinal fluid (CSF) increase in rats, dogs and human patients following SAH and that inhibitors of the synthesis of 20-HETE prevent the acute fall in CBF in rats and reverse delayed vasospasm in both dogs and rats. This review examines the evidence that an elevation in the production of 20-HETE contributes to the initial fall in CBF following SAH and the later development of delayed vasospasm.
Roman
Richard J
RJ
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. rroman@mcw.edu
Renic
Marija
M
Dunn
Kathryn M J
KM
Takeuchi
Kazuhiko
K
Hacein-Bey
Lotfi
L
D000208:Acute Disease; D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D002536:Cerebral Arteries / Q000378:metabolism* / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013997:Time Factors; D014661:Vasoconstriction / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D020301:Vasospasm, Intracranial / Q000378:metabolism* / Q000503:physiopathology*
D006893:Hydroxyeicosatetraenoic Acids; D014665:Vasodilator Agents; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid