thromboxane-a2 and Carotid-Artery-Thrombosis

Metabolism of arachidonic acid (AA) in blood platelets and in vascular endothelium does not lead to prostaglandins, but thromboxane A2 and prostacyclin are generated. These labile metabolites of AA antagonize each other: thromboxane A2 is a vasoconstrictor and proaggregatory agent, whereas prostacyclin dilates arteries, prevents platelets from aggregation, and dissipates the preformed platelet clumps. Prostacyclin is a powerful stimulator of adenylate cyclase in platelets and therefore its antiplatelet action is potentiated by phosphodiesterase inhibitors such as theophylline or dipyridamole. Cyclo-oxygenase of AA is inhibited by aspirin, thromboxane synthetase by analogues of prostaglandin endoperoxides, and prostacyclin synthetase by linear lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxydation in the body and the subsequent molecular damage to prostacyclin synthetase in the rheologically determined areas of arterial walls. Endothelium deprived of prostacyclin is the basis for microthrombi formation, and follows a sequence of events described by Rokitansky and later by Ross. Prostacyclin is also a circulating hormone which is generated by the lungs. Thereby a damage of this "endocrine gland" by respiratory disorders, air pollution, or tobacco smoking are likely to contribute to pathogenesis of atherosclerosis, myocardial infarction, and arterial thromboembolism. Pharmacological treatment and prevention of these diseases should logically include antioxydants, prostacyclin and its analogues, thromboxane synthetase inhibitors and perhaps cyclooxygenase inhibitors (aspirin ?). Prostacyclin was already infused intravenously to men and its powerful antiaggregatory and deaggregatory actions were demonstrated. These properties of prostacyclin along with its vasodilator and positive inotropic actions destine this hormone to be a new type of antithrombotic drug in acute myocardial infarction.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Aspirin; Blood Circulation; Blood Vessels; Carotid Artery Thrombosis; Cyclooxygenase Inhibitors; Dogs; Epoprostenol; Female; Humans; Infusions, Parenteral; Male; Mice; Myocardial Infarction; Platelet Aggregation; Prostaglandins; Rabbits; Rats; Structure-Activity Relationship; Thromboembolism; Thromboxane A2; Thromboxanes

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Platelets; Carotid Artery Thrombosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Membrane Proteins; Mice; Mice, Knockout; Platelet Activation; Platelet Aggregation Inhibitors; Prostaglandin D2; Receptors, G-Protein-Coupled; Receptors, Immunologic; Receptors, LDL; Receptors, Nicotinic; Receptors, Prostaglandin; Thromboxane A2

Botrocetin (bt)-facilitated binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex on platelets in suspension initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work has demonstrated that bt/VWF-mediated agglutination activates alphaIIbbeta3 and elicits ATP secretion in a thromboxane A2 (TxA2)-dependent manner. The signaling that results in TxA2 production was shown to be initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and PKC. Here, we demonstrate that the signaling elicited by GPIb-mediated agglutination that results in TxA2 production is dependent on Bruton tyrosine kinase (Btk). The results demonstrate that Btk is downstream of Lyn, Syk, SLP-76, and PI3K; upstream of ERK1/2, PLCgamma2, and PKC; and greatly enhances Akt phosphorylation. The relationship(s), if any, between ERK1/2, PLCgamma2, and PKC were not elucidated. The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries. These results demonstrate that the Btk family kinase, Tec, cannot provide the function(s) missing because of the absence of Btk and that Btk is essential for both bt/VWF-mediated agglutination-induced TxA2 production and GPIb-dependent stable arterial thrombus formation in vivo.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Carotid Artery Thrombosis; Crotalid Venoms; Male; MAP Kinase Signaling System; Mice; Mice, Inbred CBA; Mice, Knockout; Mice, Mutant Strains; Phospholipase C gamma; Phosphorylation; Platelet Aggregation; Platelet Glycoprotein GPIb-IX Complex; Protein-Tyrosine Kinases; Signal Transduction; Thrombosis; Thromboxane A2; von Willebrand Factor

The two objectives of this study were to assess the potential of BAY U 3405 to prevent arterial thrombosis in response to vessel wall injury and to determine the ability of BAY U 3405 to prevent thrombotic reocclusion after thrombolysis with anisoylated plasminogen streptokinase activator complex.. Dogs were instrumented with a carotid flow probe, stimulating electrode, and a stenosis. Current (150 microA) was applied to the intimal surface of the right carotid artery, and time to occlusive thrombus formation was noted. BAY U 3405 was administered, and the procedure for thrombus formation was repeated for the left carotid artery.. BAY U 3405 administration prevented occlusive arterial thrombosis formation. Ex vivo platelet aggregation was inhibited, bleeding time increased, and thrombus weight reduced after BAY U 3405 treatment. In a second group, thrombi were formed initially in both carotid arteries, BAY U 3405 was administered as before, and anisoylated plasminogen streptokinase activator complex was infused in the right carotid artery proximal to the occlusive thrombus. BAY U 3405 did not alter the incidence of rethrombosis compared with the lytic agent alone.. BAY U 3405 prevented primary arterial thrombosis, corresponding to inhibition of platelet aggregation, and increased bleeding times. BAY U 3405, however, did not prevent rethrombosis after successful thrombolysis with anisoylated plasminogen streptokinase activator complex, despite the fact that platelet reactivity was inhibited. The data are consistent with the concept that the residual thrombus represents a more effective thrombogenic stimulus as compared with arterial wall injury alone and that the mechanisms associated with primary versus secondary thrombus formation may require separate therapeutic approaches.

Topics: Animals; Carbazoles; Carotid Artery Thrombosis; Disease Models, Animal; Dogs; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2

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

Prostacyclin (PGI2) is a powerful inhibitor of platelet aggregation, but its role in the pathogenesis of arterial thrombosis is uncertain. We have studied the thrombogenic effect of inhibiting PGI2 production by aspirin (ASA) in carotid arteries of rabbits given 0, 3, 10, or 100 mg ASA/kg either 1, 3, 6, or 20 h beforehand. Platelet accumulation onto injured carotid arteries was enhanced with ASA in a dose of 10 mg/kg. A higher dose of ASA (100 mg/kg) had no further effect. The enhanced thrombogenic effect of ASA persisted for at least 20 h and was associated with a decrease in vessel wall PGI2 production. There was a strong inverse correlation (r = 0.55, P less than 0.01) between PGI2 production and platelet accumulation. The findings suggest that the margin of safety in obtaining an antithrombotic effect of ASA and producing a potential thrombotic effect in arteries may not be as large as predicted by studies using cultured endothelial cells or experimentally induced thrombosis in veins.

Topics: Animals; Aspirin; Blood Platelets; Carotid Arteries; Carotid Artery Injuries; Carotid Artery Thrombosis; Dose-Response Relationship, Drug; Epoprostenol; Microscopy, Electron; Platelet Aggregation; Rabbits; Thromboxane A2; Time Factors