© 2000 American Heart Association, Inc.
Integrative Physiology |
Production of 20-HETE and Its Role in Autoregulation of Cerebral Blood Flow
From the Cardiovascular Research Center, Department of Physiology (D.G., A.R.L., T.F.L., M.R.T., J.N., H.O., R.J.R., D.R.H.), Department of Pharmacology and Toxicology (K.N., W.B.C.), and Department of Anesthesiology (A.G.H.), Medical College of Wisconsin, Milwaukee, Wis; School of Veterinary Medicine (E.K.B.), University of Pennsylvania, Kennett Square, Pa; and Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to David R. Harder, PhD, Professor and Director, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. dharder@post.its.mcw.edu
Abstract—In the brain, pressure-induced myogenic constriction of cerebral arteriolar muscle contributes to autoregulation of cerebral blood flow (CBF). This study examined the role of 20-HETE in autoregulation of CBF in anesthetized rats. The expression of P-450 4A protein and mRNA was localized in isolated cerebral arteriolar muscle of rat by immunocytochemistry and in situ hybridization. The results of reverse transcriptase–polymerase chain reaction studies revealed that rat cerebral microvessels express cytochrome P-450 4A1, 4A2, 4A3, and 4A8 isoforms, some of which catalyze the formation of 20-HETE from arachidonic acid. Cerebral arterial microsomes incubated with [14C]arachidonic acid produced 20-HETE. An elevation in transmural pressure from 20 to 140 mm Hg increased 20-HETE concentration by 6-fold in cerebral arteries as measured by gas chromatography/mass spectrometry. In vivo, inhibition of vascular 20-HETE formation with N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), or its vasoconstrictor actions using 15-HETE or 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), attenuated autoregulation of CBF to elevations of arterial pressure. In vitro application of DDMS, 15-HETE, or 20-HEDE eliminated pressure-induced constriction of rat middle cerebral arteries, and 20-HEDE and 15-HETE blocked the vasoconstriction action of 20-HETE. Taken together, these data suggest an important role for 20-HETE in the autoregulation of CBF. (Circ Res. 2000;87:60-65.)
Key Words: cerebral blood flow • homeostasis • HETE • cytochrome P-450 • arachidonic acid
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