The release of thromboxane A2 and prostacyclin following experimental acute pulmonary embolism

Reeves, William C.; Demers, Laurence M.; Wood, M. C.; Skarlatos, Sonia I.; Copenhaver, Gary L.; Whitesell, Larry F.; Luderer, John R.

doi:10.1016/0262-1746(83)90104-x

Cited by 62 publications

(23 citation statements)

References 12 publications

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“…1) could exert a beneficial effect in the setting of nonthrombotic, fixed pulmonary vascular occlusion. Prior experimental models of PE that have either measured or pharmacologically altered prostaglandin concentrations included autologous clot infusion (9,26,30,39). These animal models have found short-lived increase in plasma thromboxane concentrations (30,39) and conflicting results as to whether pretreatment with COX-1/2 inhibition is beneficial (26,30) or detrimental (9) to gas exchange and pulmonary vascular resistance (9).…”

Section: Discussionmentioning

confidence: 99%

“…In humans with PE, blood concentrations of thromboxane have been found to be elevated for up to 7 days after onset of symptoms (10). Both the mechanical vascular occlusion and release of vasoconstrictive agents from massive PE appear to produce a synergistic effect that causes acute pulmonary hypertension, worsened gas exchange, impaired right ventricular (RV) function that can culminate in acute cor pulmonale, circulatory shock, and even death (26,30,39).…”

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confidence: 99%

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Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat

Jones

Watts

Debelak

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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2002.-Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B2 (TxB2) in bronchoalveolar lavage fluid and increased urinary dinor TxB2. Furegrelate and ketorolac treatments reduced TxB2 and dinor TxB2 to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB 2. Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE. thromboembolism/treatment; cyclooxygenase; thromboxane; leukotriene; ketorolac; heart failure; Langendorff; animal model PULMONARY EMBOLISM (PE) continues to be a major cause of morbidity and mortality in the United States. In one large autopsy-based study, massive PE was the second leading cause of sudden death in adults aged Ͻ65 yr (4). The primary treatment strategy for massive PE is the recanalization of occluded pulmonary vasculature by fibrinolytic agents (11), catheter fragmentation (32), or surgical removal of clot (16). However, up to one-half of patients with massive PE have contraindications to fibrinolysis (15), and few hospitals have facilities for invasive treatment of PE. Even under optimal conditions (e.g., immediate bolus infusion of a fibrinolytic agent), these interventions require Ͼ2 h to effect a significant reduction in pulmonary vascular resistance (20). PE may also cause pulmonary vasoconstriction through the liberation of vasoconstrictive agents, including PGF 2␣ and thromboxane (Tx) A 2 and B 2 (10). PE can cause hypoxemia and increased pulmonary arterial pressure in previously healthy patients (19). Both hypoxemia and increased shear forces in the pulmonary vascular bed have been found to increase expression of the cyclooxygenase (COX)-2 gene (3). In humans with PE, blood concentrations of thromboxane have been found to be elevated for up to 7 days after onset of symptoms (10). Both the mechanical vascular occlusion and release of vasoconstrictive agents from massive PE appear to produce a synergistic effect that causes acute pulmonary hypertension, worsened gas exchange, impaired right ventricular (RV) function that can culminate in acute cor pulmonale, circulatory shock, and even death (26,30,39).In the ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat

Jones

Watts

Debelak

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…TXA 2 liberation occurs in the very first minutes after embolism, and its degree of production correlates with the risk of mortality in experimentally induced pulmonary embolism (Utsonomiya et al, 1982;Reeves et al, 1983). TXA 2 dominates early vasomotor response, accounting for the early hemodynamic impairment, whereas prostacyclin is more active in later course (Reeves et al, 1983;Smulders, 2000).…”

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confidence: 99%

Effect of BM-573 [N-Terbutyl-N′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist, in a Porcine Model of Acute Pulmonary Embolism

Ghuysen

Lambermont

Dogné

et al. 2004

J Pharmacol Exp Ther

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The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-NЈ-[2-(4Ј-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a dual thromboxane A 2 synthase inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo (placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 (BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element windkessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, thromboxane A 2 , and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11␣,9␣-epoxymethanoprostaglandin F 2␣ ) or by arachidonic acid, and thromboxane A 2 overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level.

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“…Gei and Hankins (20) proposed a pathophysiological course. Three distinct responses (22) and lead to pulmonary hypertension, intrapulmonary shunting, bronchoconstriction, and severe hypoxia (21) Exactly which components of amniotic fluid actually cause this effect is unknown (10). The conventional explanation states that particulate matter such as fetal squamous cells, lanugo, and meconium contained in the amniotic fluid produce pulmonary vascular obstructions that lead to pulmonary hypertension, right-and left-sided heart failure, hypotension, and death.…”

Section: Pathophisiologymentioning

confidence: 99%

Amniotic Fluid Embolism

Toy

2009

ELECTRON J GEN MED

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The release of thromboxane A2 and prostacyclin following experimental acute pulmonary embolism

Cited by 62 publications

References 12 publications

Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat

Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat

Effect of BM-573 [N-Terbutyl-N′-[2-(4′-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist, in a Porcine Model of Acute Pulmonary Embolism

Amniotic Fluid Embolism

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