Onset of pulmonary ventilation in fetal sheep produces pial arteriolar constriction dependent on cytochrome p450 omega-hydroxylase activity.
With the onset of ventilation at birth, cerebral blood flow decreases as oxygenation increases, but the mechanism of cerebral vasoconstriction is unknown. Cytochrome P-450 omega-hydroxylase activity metabolizes arachidonic acid to 20-HETE, a potent vasoconstrictor, in a physiologically relevant O(2)-dependent manner. We tested the hypothesis that the omega-hydroxylase inhibitor, 17-octadecynoic acid (17-ODYA), reduces cerebral vasoconstriction during in utero ventilation with O(2) in fetal sheep. In anesthetized pregnant sheep near term, the fetal head was exposed with the rest of the body remaining in utero. Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window superfused with vehicle or 17-ODYA. Mechanical ventilation of the fetal lungs with a high O(2) mixture to increase arterial Po(2) from approximately 20 to approximately 90 Torr markedly decreased pial arteriolar diameter by 24 + or - 3% (+ or - SE) without a change in arterial pressure. In contrast, superfusion of 17-ODYA completely blocked the decrease in diameter (2 + or - 3%) with increased oxygenation. Vasoconstriction to hypocapnia was intact after returning to the baseline intrauterine oxygenation state, thereby indicating that the effect of 17-ODYA was selective for increased oxygenation. In cerebral arteries isolated from fetal sheep, increasing oxygenation increased 20-HETE production. We conclude that cytochrome P-450 omega-hydroxylase activity makes an important contribution to cerebral vasoconstriction associated with the onset of ventilation at birth.
Ohata
Hiroto
H
Dept. of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 600 North Wolfe St./Blalock 1404, Baltimore, MD 21287-4961, USA.
Gebremedhin
Debebe
D
Narayanan
Jayashree
J
Harder
David R
DR
Koehler
Raymond C
RC
D000818:Animals; D001160:Arterioles / Q000196:embryology / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D016857:Hypocapnia / Q000196:embryology / Q000201:enzymology; D008168:Lung / Q000196:embryology*; D018715:Microscopy, Video; D010100:Oxygen / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D011247:Pregnancy; D012123:Pulmonary Ventilation; D012121:Respiration, Artificial; D012756:Sheep; D014661:Vasoconstriction / Q000187:drug effects
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C047008:17-octadecynoic acid; D042926:Cytochrome P-450 CYP4A; D010100:Oxygen