Effect of phorbol myristate acetate on cerebral blood flow in normal and neutrophil-depleted rats.
OBJECTIVE
Recent evidence suggests a possible role for leukocytes in ischemic brain injury. This study examined the effect of activation of endogenous circulating leukocytes on cerebral blood flow in normal and neutrophil-depleted rats.


METHODS
Leukocytes were activated by rapid injection of either 50 micrograms/kg phorbol 12-myristate 13-acetate, a protein kinase C activator, or an equimolar amount of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine, into the right carotid artery. Control rats received an equal volume of dimethyl sulfoxide in saline vehicle. H2-clearance cerebral blood flow was measured in each of the three groups and in vinblastine-treated, neutrophil-depleted rats after carotid artery injection of phorbol.


RESULTS
Phorbol 12-myristate 13-acetate dramatically decreased circulating leukocyte and platelet counts from 5 to 120 minutes after infusion and decreased regional cerebral blood flow in the ipsilateral parietal cortex from a baseline of 119 +/- 14 mL.min-1.100 g-1 (mean +/- SEM) to 49 +/- 5 mL.min-1.100 g-1 at 30 minutes (P < .05). Decreased flow persisted for the 2-hour study. Neither N-formyl-methionyl-leucyl-phenylalanine or vehicle had an effect on cerebral blood flow. In the neutrophil-depleted rats the initial decrease in cerebral blood flow at 30 and 60 minutes after infusion of phorbol was observed, but cerebral blood flow was restored to 70% to 80% of its baseline value (P > .05 versus baseline) by 90 to 120 minutes.


CONCLUSIONS
The early phorbol 12-myristate 13-acetate-induced decrease in cerebral blood flow may be due to the effects of protein kinase C activation on vascular smooth muscle or on platelet aggregation, whereas the persistent decrease in cerebral blood flow appears to be mediated in part by neutrophil activation.
Uhl
M W
MW
Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pa.
Kochanek
P M
PM
Schiding
J K
JK
Nemoto
E M
EM
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010976:Platelet Count; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors
D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate