Effects of protein kinase C inhibitors on thromboxane production by thrombin-stimulated platelets.
The purpose of these studies was to identify a possible role for protein kinase C in thromboxane production. The effects of four putative protein kinase C inhibitors were studied with platelet stimulation by thrombin (0.5-150 nM), Thrombin Quick I (1.5-500 nM) or a thrombin receptor (protease activated receptor-1) agonist peptide (TRAP) (5-120 microM). Thromboxane production was increased by the bisindolylmaleimide derivative, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimi de (GF 109203X), unchanged by the inhibitors 12-(2-cyanoethyl)-6,7, 12,13-tetrahydro-13-methyl-5-oxo-5H-indolo (2,3-a) pyrrolo (3, 4-c)-carbazole (Gö 6976) and 5,21:12,17-dimetheno-18H-dibenzo[i, o]pyrrolo[3,4-l][1,8]diazacyclohexadecine-18,20(19H)-dione, 8-[(dimethylamino)methyl]-6,7,8,9,10,11-hexahydro-, monomethanesulfonate (379196), the latter of which is protein kinase C beta-selective, and decreased by 1-[6-[(3-acetyl-2,4, 6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2, 2-dimethyl-2H-1-benzopyran-8-yl]-3-phenyl-2-propen-1-one (rottlerin), an inhibitor selective for protein kinase C delta. These results indicate complex regulation of thromboxane synthesis in human platelets including a probable role for protein kinase C delta. The results taken together further suggest that GF 109203X may suppress negative feedback resulting from an unidentified kinase and that the classical protein kinase C isoforms alpha and beta do not have a significant role in regulating thromboxane production by platelets.
Samokhin
G P
GP
Section of Allergy, Asthma and Immunology, Department of Medicine, East Carolina University, Greenville, NC 27858-4354, USA.
Jirousek
M R
MR
Ways
D K
DK
Henriksen
R A
RA
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008301:Maleimides / Q000494:pharmacology; D015539:Platelet Activation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013917:Thrombin / Q000378:metabolism; D013931:Thromboxanes / Q000096:biosynthesis* / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D013931:Thromboxanes; C081021:Go 6976; C085746:rottlerin; D011493:Protein Kinase C; D013917:Thrombin; C070515:bisindolylmaleimide I