Effects of protein kinase C inhibitors on thromboxane production by thrombin-stimulated platelets

• Published in: European journal of pharmacology 1999-12, Vol.386 (2), p.297-303
• Main Authors: Samokhin, Gennady P, Jirousek, Michael R, Ways, D.Kirk, Henriksen, Ruth Ann
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Benzopyrans - pharmacology; Biological and medical sciences; Blood coagulation. Blood cells; Blood Platelets - drug effects; Blood Platelets - metabolism; Carbazoles - pharmacology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; human; Humans; In Vitro Techniques; Indoles - pharmacology; Isoenzymes - antagonists & inhibitors; Maleimides - pharmacology; Molecular and cellular biology; Platelet; Platelet Activation; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein kinase inhibitor; Thrombin; Thrombin - metabolism; Thromboxane; Thromboxanes - biosynthesis; Thromboxanes - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00737-2

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 μM). Thromboxane production was increased by the bisindolylmaleimide derivative, 2-[1-(3-dimethylaminopropyl)-1 H-indol-3-yl]-3-(1 H-indol-3-yl)-maleimide (GF 109203X), unchanged by the inhibitors 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5 H-indolo (2,3- a) pyrrolo (3,4- c)-carbazole (Gö 6976) and 5,21:12,17-dimetheno-18 H-dibenzo[ i, o]pyrrolo[3,4- l][1,8]diazacyclohexadecine-18,20(19 H)-dione, 8-[(dimethylamino)methyl]-6,7,8,9,10,11-hexahydro-, monomethanesulfonate (379196), the latter of which is protein kinase C β-selective, and decreased by 1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethyl-2 H-1-benzopyran-8-yl]-3-phenyl-2-propen-1-one (rottlerin), an inhibitor selective for protein kinase C δ. These results indicate complex regulation of thromboxane synthesis in human platelets including a probable role for protein kinase C δ. 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 α and β do not have a significant role in regulating thromboxane production by platelets.