calcimycin and 3-5-dimethyl-2-(3-pyridyl)thiazolidin-4-one

We analyzed the effect of the PAF receptor antagonist (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) on the release of leukotriene B4 and IL-8 from human leukocytes. Peripheral blood from healthy donors was separated in two different fractions: polymorphonuclear leukocytes (PMN) and a lymphocyte, monocyte and basophil granulocyte cell fraction (LMB). After incubation of the cell population with different concentrations of SM-12502 the cells were subsequently stimulated with either the Ca ionophore A23187, the bacterial derived peptide fMLP, or with an activator of heterotrimetric G-proteins, the sodium fluoride (NaF, in the presence of Al3+). The PAF receptor antagonist led to a concentration and time dependent inhibition of LTB4 formation and IL-8 release from PMN and LMB. Our data clearly indicate an inhibitory effect of the PAF receptor antagonist SM-12502 on the formation of mediators of the lipoxygenase pathway and on the release of IL-8.

Topics: Aluminum; Basophils; Calcimycin; Calcium; Depression, Chemical; Gene Expression Regulation; GTP-Binding Proteins; Humans; Interleukin-8; Ionophores; Leukocytes, Mononuclear; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Sodium Fluoride; Thiazoles; Thiazolidines

We analyzed the effect of the PAF receptor antagonist (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) on human platelet aggregation as well as mediator release. After incubation of human platelet with different concentrations of SM-12502 the cells were subsequently stimulated with either the Ca ionophore A23187, with human thrombin, or with an activator of heterotrimeric G-proteins, sodium fluoride (NaF, in the presence of Al3+). Preincubation of platelets with the PAF receptor antagonist led to an inhibition of 12-lipoxygenase derived 12(S)-HETE and cyclooxygenase derived 12(S)-HHT. Pretreatment of platelets with the PAF receptor antagonist SM-12502 prior to activation with the Ca ionophore A23187 or PAF also inhibited platelet aggregation. Our data clearly indicate an inhibitory effect of the new PAF receptor antagonist SM-12502 on the formation of platelet derived inflammatory mediators of the lipoxygenase pathway as well as of the cyclooxygenase pathway, and furtherone, treatment with the PAF receptor antagonist diminished platelet aggregation after subsequent specific and unspecific activation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Aluminum; Arachidonate 12-Lipoxygenase; Calcimycin; Calcium; Fatty Acids, Unsaturated; Gene Expression Regulation; GTP-Binding Proteins; Humans; Ionophores; Platelet Activating Factor; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Prostaglandin-Endoperoxide Synthases; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Sodium Fluoride; Thiazoles; Thiazolidines; Thrombin