thromboxane-a2 and nictindole

The mechanism of action of LTB4 has been investigated on the guinea-pig lung parenchymal strip. Mepacrine (20 microgram/ml), an inhibitor of phospholipase A2, abolished the action of LTB4 on parenchymal strips. Eicosatetraynoic acid (10 microgram/ml) and BW755C (40 microgram/ml) which are inhibitors of cyclooxygenase and lipoxygenase pathways, produced a marked inhibition of the lung strip contraction to LTB4. Similarly, aspirin (30 micrograms/ml) and flufenamate (1 microgram/ml) showed a strong inhibition of the contraction of parenchymal strips to LTB4; these results suggested that cyclooxygenase products mediate the action of LTB4. The response to LTB4 was unaffected by 15-hydroperoxyeicosatatraenoic acid (15-HPETE; 1 microgram/ml) while L8027 (25 ng/ml) reduced the contraction by 50%, suggesting that thromboxane A2 rather than prostacyclin was involved. Since parenchymal strips do not appear to be very sensitive to PGF2 alpha, PGE2 and the endoperoxides, and since effluents from LTB4-treated lungs produced contractions of lung strip and rabbit aorta which were reduced after 5 min. at 25 degrees, thromboxane A2 was postulated to mediate the lung effect of LTB4. The release of thromboxane B2 (TxB2) from lungs stimulated with LTB4 was confirmed by gas-chromatography-mass spectrometric (GC-MS) analyses.

Topics: Animals; Arachidonic Acids; Aspirin; Female; Flufenamic Acid; Guinea Pigs; Imidazoles; Indoles; Leukotriene B4; Leukotrienes; Lipid Peroxides; Lung; Male; Muscle Contraction; Peroxides; Prostaglandins; Pyridines; Quinacrine; Thromboxane A2; Thromboxane B2; Thromboxanes

N-Carboxy-3-morpholinosydnone imine ethyl ester (molsidomine) and its main metabolite 3-morpholinosydnone imine (SIN-1) were investigated in rabbit platelet-rich plasma (PRP) for antiaggregatory activity and inhibition of thromboxane A2 (TXA2) generation (arachidonic acid (AA)-induced) as well as in human PRP regarding prostaglandin endoperoxide analogue (U-46 619)- and AA-induced aggregation and TXB2 formation. The results were compared with the effects of nictindole. In rabbit PRP the inhibitory effects of molsidomine on aggregation and TXA2 generation were 20fold lower than that of SIN-1. The IC50-values of SIN-1, which is the pharmacologically active biotransformation product of molsidomine, were about 1 mumol/l in the experimental models used. The inhibitory effects of nictindole were about 50 times higher than those of SIN-1. In human PRP the inhibitory potency of SIN-1 decreased in the following sequence: U-46 619-induced aggregation (IC50 = 0.9 mumol/l) greater than AA-induced aggregation (IC50 = 1.4 mumol/l) greater than TXB2 formation (IC50 = 2.9 mumol/l). Molsidomine was nearly without effect in human PRP. Our own preliminary results and findings obtained by other authors seem to exclude a direct effect of SIN-1 on cyclooxygenase and thromboxane synthetase. The possible clinical significance of our findings in different types of angina pectoris and for myocardial infarction is discussed.

Topics: Animals; Arachidonic Acids; Blood Platelets; Drug Interactions; Female; Humans; Indoles; Male; Molsidomine; Oxadiazoles; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Rabbits; Sydnones; Thromboxane A2; Thromboxanes

Topics: Adenosine Diphosphate; Arachidonic Acids; Blood Platelets; Collagen; Epinephrine; Epoprostenol; Humans; In Vitro Techniques; Indoles; Oxidoreductases; Platelet Aggregation; Prostaglandins; Pyridines; Thrombin; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes

Topics: Adenosine Triphosphate; Animals; Arachidonic Acids; Bronchi; Female; Guinea Pigs; Imidazoles; In Vitro Techniques; Indoles; Male; Platelet Aggregation; Prostaglandins E; Pyridines; Thromboxane A2; Thromboxane B2; Thromboxanes