15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Arterial-Occlusive-Diseases

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To determine whether the reactivity of pulmonary vessels to endothelins (ET) was altered in POPV and to explore potential mechanisms, we ligated the left main pulmonary artery of 18 rats. Four weeks later, using a lung explant technique, we compared POPV lungs with controls for contractile responses of intrapulmonary vessels to ET-1 and ET-3 and for relaxant responses to ET-1 and sodium nitroprusside (SNP) after precontraction with U-46619. Morphometric measurements were made on vessels studied pharmacologically. Competition receptor binding studies with 125I-labeled ET-1 and unlabeled ET-1 and BQ-123 were performed using membrane proteins of pulmonary vessels. We found, in arteries, that contractile responses to ET-1 and ET-3 were significantly increased and that relaxant responses to ET-1 but not to SNP were reduced; in veins, only relaxation to SNP was increased. Morphometry showed that arteries and veins in POPV had reduced diameters without altered muscle thickness. Receptor binding studies showed that the proportion of ETA receptors in arteries was significantly increased in POPV (66%) vs. controls (54%). We conclude that, in POPV, the increase in reactivity to ET-1 and ET-3 is primarily related to an augmented proportion of ETA receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterial Occlusive Diseases; Binding, Competitive; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelium, Vascular; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Organ Culture Techniques; Peptides, Cyclic; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Sprague-Dawley; Receptors, Endothelin

We have developed a photochemical model to induce thrombotic occlusion of the guinea-pig femoral artery. Using this model, we investigated the effect of cholesterol feeding on arterial occlusion time in the guinea-pig. Animals were divided into two groups, one on standard diet and the other on standard diet containing 0.5% cholesterol for 3 weeks. The time for femoral artery occlusion was significantly shorter (p < 0.05) in cholesterol fed animals as compared to the control group. In vitro collagen-, U-46619- (a thromboxane A2 adenosine diphosphate analogue) and (ADP)-induced platelet aggregation responses in whole blood in cholesterol-fed animals were increased 13-, 10- and 4-fold, respectively. U-46619- and collagen-induced washed platelet aggregation responses were also significantly enhanced by cholesterol feeding (p < 0.01). Further, TXA2 generation by collagen-stimulated washed platelets in cholesterol-fed animals increased similar to the platelet aggregation responses. However, platelet-activating factor (PAF)-induced platelet aggregation in whole blood was relatively unaffected by cholesterol feeding. 11-dehydro TXB2 levels in plasma were increased significantly by cholesterol feeding. Our observations suggest that increased plasma TXA2 level and platelet aggregation response to TXA2 and stimulated TXA2 synthesis in platelets play a role in enhanced arterial occlusion in cholesterol fed guinea-pigs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arterial Occlusive Diseases; Cholesterol, Dietary; Collagen; Femoral Artery; Guinea Pigs; Male; Photochemistry; Platelet Activating Factor; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thrombosis; Thromboxane A2; Time Factors

The purpose of this study was to examine whether the blockade of thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptor by the selective TxA2/PGH2 receptor antagonist KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) is effective in enhancing tissue-type plasminogen activator (tPA)-induced thrombolysis and preventing reocclusion in a model of femoral artery thrombosis in anesthetized dogs. The thrombus was formed by inserting a copper coil into the femoral artery. Sodium heparin (100 U/kg i.v.) was administered shortly after the formation of thrombus. All dogs received i.v. tPA at a dose of 20 micrograms/kg/min starting 60 min after the formation of the occlusive thrombus for up to 60 min if necessary, to achieve reperfusion. After 30 min of thrombotic occlusion, the animals received vehicle (Group I, controls, n = 9) or KW-3635 (Group II, 0.3 mg/kg bolus i.v. + 0.3 mg/kg/h infusion, n = 9; Group III, 1 mg/kg bolus i.v. + 1 mg/kg/h infusion, n = 9) and the infusion of either vehicle or KW-3635 was continued thereafter throughout the experiment. The time to reperfusion in Group I was 37.3 +/- 5.2 min, while those in Group II and Group III were 25.3 +/- 6.2 min (p greater than 0.05) and 17.3 +/- 3.1 min (p less than 0.05), respectively. Reocclusion occurred within 4 h in 100% of Group I, whereas the incidence of reocclusion was reduced to 67% in Group II and to 0% in Group III. These data suggest that endogenous TxA2 generation is involved in lysis and rethrombosis during thrombolytic therapy by tPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterial Occlusive Diseases; Benzimidazoles; Benzoxepins; Dogs; Female; Femoral Artery; Fibrinolytic Agents; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Recurrence; Thrombosis; Thromboxane A2; Tissue Plasminogen Activator