ozagrel and Pulmonary-Edema

This study was carried out to understand the onset mechanism of adrenaline (ADR)-induced pulmonary edema (PE) and the effect of drugs related to the arachidonate cascade in a rabbit model. ADR was administered intravenously by a bolus injection to the rabbits at 50, 75 and 100 microg/kg. To evaluate the severity of PE, the lung-water ratio (LWR) was calculated as a ratio of the difference between wet and dry lung weight to dry lung weight. The PE incidence and LWR exhibited a dose-dependent increase, and LWR correlated with the left atrial pressure (LAP). The involvement of the arachidonate cascade was evaluated by the co-administration of flurbiprofen, a cyclooxygenase inhibitor; ozagrel, a thromboxane synthase inhibitor; and OP-2507 (15-cis-(4-n-propylcyclohexyl)-6,17,18, 19,20-pentanor-9-deoxy-6,9-alpha-nitriloprostaglandin F1 methyl ester), a prostaglandin I2 analogue. Co-treatment of the rabbits with ADR and flurbiprofen resulted in an increase in LAP and the incidence of PE, whereas co-administration of ozagrel did not exhibit any significant changes in the measured parameters. Conversely, OP-2507 reduced the LAP, PE incidence and LWR when co-administered with ADR. Rabbits co-treated with OP-2507 displayed an improved cardiac function. The results of these studies demonstrated the effectiveness of OP-2507 in protecting the lung and cardiac function from the ADR-induced PE.

Topics: Animals; Cyclooxygenase Inhibitors; Epinephrine; Epoprostenol; Flurbiprofen; Methacrylates; Models, Animal; Pulmonary Edema; Rabbits; Thromboxane-A Synthase

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate 5-Lipoxygenase; Cardiac Output; Dogs; Extravascular Lung Water; Leukocyte Count; Leukotriene B4; Male; Methacrylates; Oxygen; Pulmonary Edema; Tetradecanoylphorbol Acetate; Thromboxane-A Synthase; Thromboxanes

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Diethylcarbamazine; Disease Models, Animal; Dogs; Ethchlorvynol; Indomethacin; Leukotrienes; Lung; Male; Methacrylates; Neutrophils; Pulmonary Edema; Respiratory Distress Syndrome; Tetradecanoylphorbol Acetate; Thromboxanes

The systemic circulation to the lung is thought to be an important microvascular exchange region which may contribute to pulmonary edema resulting from airway injury. In a chronic sheep model, we have evaluated the flow through the bronchial artery after airway injury caused by the aspiration of 2.5 ml/kg of 0.1 N hydrochloric acid with and without inhibition of thromboxane synthetase and cyclooxygenase. Cyclooxygenase inhibition with ibuprofen resulted in no rise in bronchial artery blood flow associated with airway acid aspiration (9.8 +/- 1.72 ml/min to 63.7 +/- 8.9 ml/min in the control group versus 11.3 +/- 2.5 ml/min to 10.3 +/- 3.4 ml/min in the ibuprofen group). No difference in bronchial artery blood flow was noted between control acid aspiration and acid aspiration with thromboxane synthetase inhibition. Significant early reduction in lung lymph flow was noted in the cyclooxygenase inhibition group compared to control. These data suggest that inhibition of the cyclooxygenase pathway of eicosanoid production may lessen the injury caused by airway acid aspiration. The decrease in airway blood flow with associated reduction in lymph flow suggests that airway blood flow may be important in the generation of pulmonary edema in this model.

Topics: Animals; Bronchial Arteries; Cyclooxygenase Inhibitors; Eicosanoids; Hydrochloric Acid; Ibuprofen; Inhalation; Lymph; Methacrylates; Pneumonia, Aspiration; Pulmonary Circulation; Pulmonary Edema; Sheep; Thromboxane-A Synthase

Phorbol myristate acetate (PMA), which produces an experimental model of acute lung injury similar to the adult respiratory distress syndrome, was studied in isolated dog lung lobes perfused at constant pressure in Zone 3 conditions. The effect of 25 to 50 micrograms PMA on pulmonary vascular permeability and resistance was observed in 4 groups of lungs: Group 1, perfused with a plasma/dextran solution; Group 2, perfused with blood; Group 3, blood-perfused and pretreated with verapamil (a calcium channel blocker); and Group 4, blood-perfused and pretreated with OKY-046 (a thromboxane synthetase inhibitor). Permeability changes were assessed by determining capillary filtration coefficient (Kf), isogravimetric capillary pressure (Pci), and in blood-perfused lungs, the protein reflection coefficient (sigma d). An increase in Kf, a decrease in Pci, and a decrease in sigma d, all indicative of an increase in vascular permeability, occurred 1 h after PMA in blood-perfused but not in plasma/dextran-perfused lungs. An increase in pulmonary vascular resistance occurred in both blood- and plasma/dextran-perfused lungs. Verapamil (2 X 10(-5) M) and OKY-046 (7 X 10(-4) M) pretreatment in blood-perfused lungs essentially blocked the PMA-induced change in permeability and significantly attenuated the increased vascular resistance. Total leukocyte and platelet counts fell in all blood-perfused lungs, whether pretreated or not. We conclude that cellular components of blood (platelets and/or leukocytes) are required to produce the permeability injury but not the pulmonary vasoconstriction and that the injury can be attenuated by either a calcium channel blocker or a specific thromboxane synthetase inhibitor. The left ventricular volume change caused by increasing right ventricular volume was measured at normal and elevated pericardial pressures.

Topics: Acrylates; Animals; Capillary Permeability; Dogs; Leukocyte Count; Lung; Methacrylates; Perfusion; Phorbols; Platelet Count; Pulmonary Edema; Respiratory Distress Syndrome; Tetradecanoylphorbol Acetate; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Verapamil

Topics: Acrylates; Animals; Cell Membrane Permeability; Drug Evaluation, Preclinical; Drug Interactions; Lung; Methacrylates; Pulmonary Edema; Tetradecanoylphorbol Acetate; Thromboxane-A Synthase; Verapamil

We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Blood Gas Analysis; Body Fluids; Consciousness; Endotoxins; Escherichia coli; Hemodynamics; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Leukocyte Count; Lung; Methacrylates; Oxidoreductases; Platelet Count; Pulmonary Edema; Sheep; Thromboxane B2; Thromboxane-A Synthase