6-ketoprostaglandin-f1-alpha and isbogrel

In rabbit platelet-rich plasma, a specific TXA2 synthase inhibitor, CV-4151 (isbogrel) alone modestly inhibited the platelet aggregation induced by arachidonic acid (AA); even at 10(-4) M the inhibition was less than 50% (IC40 value: 8.1 x 10(-5) M). Aspirin-treated rat aortic rings alone inhibited the AA-induced platelet aggregation by 7%. However, CV-4151 exhibited a potent antiplatelet action in the presence of the aortic rings and its IC40 value was 8.3 x 10(-8) M. Thus, the aortic rings caused 1000-fold enhancement of the antiplatelet action of CV-4151. Next, we investigated the effect of CV-4151 on the production of two highly biologically active prostanoids, TXA2 and PGI2, and the contribution of these prostanoids to the antiplatelet action of CV-4151. TXA2 and PGI2 were measured by a radioimmunoassay of their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Under the experimental conditions, CV-4151 simultaneously inhibited TXA2 generation and enhanced PGI2 generation. There was a positive linear relationship (r = 0.975, p < 0.01) between % inhibition of platelet aggregation and PGI2 generation and a significant negative linear relationship (r = 0.994, p < 0.001) between % inhibition of platelet aggregation and TXA2 generation. CV-4151 exhibits a potent antiplatelet action in the presence of PGI2 synthase, which is the in vivo situation, by simultaneously inhibiting TXA2 generation and enhancing PGI2 generation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arachidonic Acid; Aspirin; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Monounsaturated; In Vitro Techniques; Intramolecular Oxidoreductases; Isomerases; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase

To clarify the role of thromboxane (TX) A2 in arterial thrombus formation, we examined the antithrombotic effects of both a TXA2 synthetase inhibitor (CV-4151) and a TXA2 receptor antagonist (AA-2414) on the rabbit common carotid artery thrombosis which was induced by injury of the endothelium by treatment with 0.25% pronase solution. CV-4151 (1,10 mg/kg, p.o.) and AA-2414 (10 mg/kg, p.o.) significantly inhibited thrombus formation. Furthermore, the combined use of CV-4151 and AA-2414 (0.1 mg/kg, p.o. each) significantly inhibited thrombus formation, though these drugs at the same doses had no effect when administered singly. The plasma level of 11-dehydro TXB2 increased significantly during thrombus formation, and CV-4151 (10 mg/kg) markedly inhibited this increase. There was a significant correlation between the in vivo antithrombotic effects of these drugs and their ex vivo inhibitory effects on arachidonic acid-induced platelet aggregation. The antithrombotic effect of CV-4151 also correlated significantly with its ability to inhibit the production of serum TXA2. These results show that TXA2 may play an important role in the thrombus formation in arterial thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Benzoquinones; Carotid Artery Thrombosis; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Monounsaturated; Heptanoic Acids; Male; Platelet Aggregation; Pyridines; Quinones; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Ten weeks old male Sprague-Dawley rats were used. One mg/kg of a calfskin type III collagen was injected into a tail vein under pentobarbital anesthesia, and the electrocardiogram (ECG) was recorded via leads I, II and III for 10 min. Abnormal ECG patterns, i.e., ST-T changes and incidence of arrhythmia, were shown after collagen injection, and some rats suffered cardiac arrest. Oral administration of (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), a thromboxane synthetase inhibitor, at the dose of 10 mg/kg two hr before the collagen injection made the ST-T changes small, and it reduced the incidence of cardiac arrest. The effect of CV-4151 was greater than that of 30 mg/kg of ticlopidine with the same type of treatment. Neither CV-4151 nor ticlopidine had any affect on collagen-induced decreases in the blood platelet count. However, plasma thromboxane (TX) B2 level in the CV-4151-treated group was very low in comparison with those in both the control and ticlopidine-treated groups at 10 min after the collagen injection. These findings indicate that TXA2 may contribute, at least partly, to the collagen-induced ECG changes and indicate that CV-4151 might be a favorable agent for the prevention of TXA2-mediated cardiac ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Collagen; Coronary Disease; Electrocardiography; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Pyridines; Rats; Rats, Inbred Strains; Thiophenes; Thromboxane B2; Ticlopidine