iloprost and dazoxiben

The role of vascular cyclooxygenase pathway on tissue-type plasminogen activator (t-PA) release after venous occlusion was studied in anesthetized rats. After the inferior vena cava was clamped for 30 min, fibrinolytic activity increased from 143.7 +/- 14.5 to 209.5 +/- 10.3 mm2 (mean +/- SE, P < 0.002). This increase was prevented by aspirin at high (100 mg/kg i.v.) but not at low doses (1 mg/kg i.v.). Dazoxiben (10 mg/kg i.v.), an inhibitor of thromboxane synthase, was ineffective on the fibrinolytic response. Both the basal levels of 6-ketoprostaglandin F1 alpha and its increase after venous occlusion were suppressed by 100 mg/kg aspirin administration (from 0.64 +/- 0.2 to 0.05 +/- 0.002 ng/ml before occlusion, P < 0.001; and from 1.08 +/- 0.2 to 0.06 +/- 0.002 ng/kg after occlusion, P < 0.001), whereas they were both unaffected by aspirin at low doses (from 0.53 +/- 0.06 before to 1.20 +/- 0.08 ng/ml after stasis). Moreover, iloprost, a stable analogue of prostacyclin, reversed the aspirin inhibitory effects on fibrinolytic activity by restoring t-PA vascular release after venous stasis. Our results provide experimental evidence that an intact cyclooxygenase pathway in vascular wall is required for the fibrinolytic activity increase after venous occlusion in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Pressure; Dose-Response Relationship, Drug; Fibrinolysis; Iloprost; Imidazoles; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Tissue Plasminogen Activator; Vena Cava, Inferior

Hydrogen peroxide (H2O2) and methyl mercury induced the liberation of arachidonate and its metabolites from human washed platelets. [14C]Eicosanoids were extracted from the supernatants of [14C] arachidonate-prelabelled platelets and analysed by thin layer chromatography and radioscanning. Thromboxane B2 (TXB2), 12(S)-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) were found as stable metabolites, together with unreacted arachidonate. In the presence of dazoxiben, a shift in eicosanoid metabolism was observed towards prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha), while in the presence of indomethacin there was a shift towards 12-HETE and unmetabolized arachidonate. The concentration pattern of those metabolites resembled that found with the physiological agonist, thrombin. H2O2 and methyl mercury also induced platelet shape change, aggregation and secretion. The EC50 values for the induction of shape change and aggregation were 27 and 850 mumol/l for H2O2 and 0.33 and 2.7 mumol/l for methyl mercury, respectively. The [3H]serotonin release required higher stimulus concentrations and amounted to 45% with 2 mumol/l H2O2 and to 16% with 3 mumol/l methyl mercury. These effects on platelet function were absent in platelets exposed to acetylsalicylic acid and prevented by indomethacin, the prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptor antagonist, daltroban, and the functional antagonist, iloprost. In contrast, none of these drugs suppressed the formation of [14C]eicosanoids, indicating that the platelet activation by H2O2 and methyl mercury essentially requires previous PGH2/TXA2 formation. As expected, the thromboxane synthase inhibitor, dazoxiben, did not prevent, but instead potentiated the activation by H2O2 and methyl mercury through accumulated PGH2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arachidonic Acids; Aspirin; Blood Platelets; Dose-Response Relationship, Drug; Eicosanoids; Epoprostenol; Humans; Hydrogen Peroxide; Iloprost; Imidazoles; Indomethacin; Methylmercury Compounds; Platelet Aggregation; Serotonin; Thrombin

The thromboxane (TX) synthetase inhibitor dazoxiben (80 micrograms/kg X min) and the prostacyclin analogue iloprost (0.6 micrograms/kg X min) were investigated in a cat model of acute myocardial ischaemia (MI) plus reperfusion. The agents were i.v. infused starting 30 min after LAD occlusion until the end of the observation period (5h). Dazoxiben significantly reduced the MI-induced increase in TXB2 and platelet ATP secretion. Dazoxiben did not influence the MI-induced depression in platelet count (PC), the fall in CK-specific activity or the ECG alterations associated with reperfusion whereas iloprost resulted in a nearly complete recovery of these parameters. These data suggest an efficacy of PGI2 administration but not of TX synthetase inhibition in preserving the myocardium from reperfusion injury. These data indicate that reperfusion-induced tissue damage appears not to be a thromboxane-dependent phenomenon.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Cardiovascular Agents; Cats; Collagen; Disease Models, Animal; Epoprostenol; Iloprost; Imidazoles; Infusions, Parenteral; Myocardial Infarction; Oxidoreductases; Platelet Count; Thromboxane-A Synthase