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HIGHLIGHTED TOPICS
Regulation of the Cerebral Circulation

Role of 20-HETE in the pial arteriolar constrictor response to decreased hematocrit after exchange transfusion of cell-free polymeric hemoglobin

¹Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore; ²Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland; and ³Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 22 July 2005 ; accepted in final form 13 September 2005

The cerebrovascular response to decreases in hematocrit and viscosity depends on accompanying changes in arterial O₂ content. This study examines whether 1) the arteriolar dilation seen after exchange transfusion with a 5% albumin solution can be reduced by the K_ATP channel antagonist glibenclamide (known to inhibit hypoxic dilation), and 2) the arteriolar constriction seen after exchange transfusion with a cell-free hemoglobin polymer to improve O₂-carrying capacity can be blocked by inhibitors of the synthesis or vasoconstrictor actions of 20-HETE. In anesthetized rats, decreasing hematocrit by one-third with albumin exchange transfusion dilated pial arterioles (14 ± 2%; SD), whereas superfusion of the surface of the brain with 10 µM glibenclamide blocked this response (–10 ± 7%). Exchange transfusion with polymeric hemoglobin decreased the diameter of pial arterioles by 20 ± 3% without altering arterial pressure. This constrictor response was attenuated by superfusing the surface of the brain with a 20-HETE antagonist, WIT-002 (10 µM; –5 ± 1%), and was blocked by two chemically dissimilar selective inhibitors of the synthesis of 20-HETE, DDMS (50 µM; 0 ± 4%) and HET-0016 (1 µM; +6 ± 4%). The constrictor response to hemoglobin transfusion was not blocked by an inhibitor of nitric oxide (NO) synthase, and the inhibition of the constrictor response by DDMS was not altered by coadministration of the NO synthase inhibitor. We conclude 1) that activation of K_ATP channels contributes to pial arteriolar dilation during anemia, whereas 2) constriction to polymeric hemoglobin transfusion at reduced hematocrit represents a regulatory response that limits increased O₂ transport and that is mediated by increased formation of 20-HETE, rather than by NO scavenging.

anemia; blood substitute; cytochrome P-450; nitric oxide; oxygen carrier; ATP-sensitive potassium channel

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