Effects of phorbol esters on pial arteriolar diameter and brain production of prostanoids in piglets

D. W. Busija, Charles Leffler

Research output: Contribution to journalArticle

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Abstract

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-PGF(1∞) PGF(2∞) 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 4α-phorbol 12,13-didecanoate (4α-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 μm. 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 μm (mean±SEM), and diameter was 140±17 μm at 10-8 M PDB, 120±18 μm at 10-7 M PDB (p<0.05), and 108±14 μm 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), PGF(2α) increased from 3,362±1,107 to 8,270±1,708 pg/ml (n=6), and 6-keto-PGF(1α) increased from 1,637±412 to 3,451±727 pg/ml (n=5). 4α-Phorbol 12,13-didecanoate and dimethyl sulfoxide did not increase prostanoid levels at any dose. Inhibition of prostanoid synthesis by indomethacin pretreatment (5 mg/kg i.v.) (n=5) or topical quinacrine (10-3 M) (n=5) blocked increases in prostanoid production during application of PDB but did not alter arteriolar responses. We conclude that PDB is a potent constrictor of pial arterioles and inducer of prostanoid production by cerebral vessels and/or tissues in piglets.

Original languageEnglish (US)
Pages (from-to)1253-1258
Number of pages6
JournalCirculation research
Volume69
Issue number5
DOIs
StatePublished - Jan 1 1991

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Phorbol 12,13-Dibutyrate
Phorbol Esters
Prostaglandins
Cerebrospinal Fluid
Brain
Prostaglandins F
Arterioles
Dimethyl Sulfoxide
Dinoprostone
Protein Kinase C
Quinacrine
Thromboxane B2
Indomethacin
Radioimmunoassay
Swine

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Effects of phorbol esters on pial arteriolar diameter and brain production of prostanoids in piglets. / Busija, D. W.; Leffler, Charles.

In: Circulation research, Vol. 69, No. 5, 01.01.1991, p. 1253-1258.

Research output: Contribution to journalArticle

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N2 - 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-PGF(1∞) PGF(2∞) 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 4α-phorbol 12,13-didecanoate (4α-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 μm. 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 μm (mean±SEM), and diameter was 140±17 μm at 10-8 M PDB, 120±18 μm at 10-7 M PDB (p<0.05), and 108±14 μm 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), PGF(2α) increased from 3,362±1,107 to 8,270±1,708 pg/ml (n=6), and 6-keto-PGF(1α) increased from 1,637±412 to 3,451±727 pg/ml (n=5). 4α-Phorbol 12,13-didecanoate and dimethyl sulfoxide did not increase prostanoid levels at any dose. Inhibition of prostanoid synthesis by indomethacin pretreatment (5 mg/kg i.v.) (n=5) or topical quinacrine (10-3 M) (n=5) blocked increases in prostanoid production during application of PDB but did not alter arteriolar responses. We conclude that PDB is a potent constrictor of pial arterioles and inducer of prostanoid production by cerebral vessels and/or tissues in piglets.

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