Effects of Phorbol Esters on Pial Arteriolar Diameter and Brain Production of

We determined the effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C, on pial arteriolar diameter and cerebrospinal fluid (CSF) prostanoid levels in newborn pigs. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy. In addition, CSF was sampled from under the window, and prostanoid levels (prostaglandin [PG] E2, 6-keto-PGFI,, PGF2a, and thromboxane B2) were determined by radioimmunoassay. Diameter and CSF prostanoid levels were determined during application of artificial CSF containing no drugs and during application of 10-8, 10-7, and 10-6 M PDB. We also determined effects of 4a-phorbol 12,13-didecanoate (4a.PDD), a phorbol ester that does not activate protein kinase C, and dimethyl sulfoxide, the vehicle for the phorbol esters, on pial arteriolar diameter and CSF prostanoid levels. Initial diameters were 100-200 gm. At 10-8_10-6 M, PDB progressively constricted pial arterioles and increased CSF levels of prostanoids; the other phorbol ester and dimethyl sulfoxide had no such effects. Baseline arteriolar diameter was 147 ± 17,um (mean±SEM), and diameter was 140 ± 17,um at 10 ` M PDB, 120±18 gm at 10-7 M PDB (p<0.05), and 108 ± 14,um at 10-6 M PDB (p<0.05) (n=5). At 10-6 M PDB, CSF levels of PGE2 increased from 2,030±616 to 13,622±4,228 pg/ml (n=7)