thromboxane-b2 and piriprost

Because alveolar hypoxia (HYP) triggers pulmonary mast cell degranulation with elaboration of vasoactive mediators such as leukotrienes, we investigated the effects of aerosolized cromolyn sodium (CS), a mast cell stabilizing agent, and U-60,257(U) (a leukotriene blocker) on the circulation, lung mechanics and thromboxane (TXB2) levels in 11 lambs during acute exposure to HYP. Studies were performed in awake, chronically instrumented animals, once after placebo (saline) and again after CS (100 mg; n = 5) or U (90 mg; n = 6). Pulmonary arterial pressure increased 42% during HYP after saline, and 32% and 19% after CS and U, respectively. Pulmonary vascular resistance did not change during HYP after CS or U. Systemic arterial pressure was unchanged after saline and CS but decreased after U; systemic vascular resistance dropped after both CS and U. No changes were seen in tidal volume, lung compliance or airway resistance during HYP after saline or either drug, but minute ventilation increased during HYP in all studies. TXB2 increased during HYP after saline in both studies and was not altered by CS. In contrast, after U, TXB2 decreased. Thus, U more effectively blunted the pulmonary vascular response to HYP than CS and resulted in mild systemic hypotension. The drop in TXB2 after U suggests leukotriene-induced thromboxane synthesis contributes to regulation of pulmonary, and possibly, systemic vasoactivity.

Topics: Animals; Blood Pressure; Cromolyn Sodium; Epoprostenol; Hypoxia; Lung; Pulmonary Circulation; Sheep; Thromboxane B2; Vasoconstriction

To investigate the relative irritant potencies of inhaled aldehydes, guinea pigs were exposed to formaldehyde or acrolein and specific total pulmonary resistance and bronchial reactivity to intravenous acetylcholine were assessed. The mechanisms associated with these responses were investigated by analyzing morphologic and biochemical changes in airway epithelial cells after in vivo and in vitro exposures. Immediately after exposure to formaldehyde or acrolein, specific resistance increased transiently and returned to control values within 30 to 60 minutes. Bronchial hyperreactivity, assessed by the acetylcholine dose necessary to double resistance, increased and became maximal two to six hours after exposure to at least 9 parts per million2 (ppm) formaldehyde or at least 1 ppm acrolein for two hours. The effect of exposure to 3 ppm formaldehyde for two hours was less than the effect of exposure to 1 ppm formaldehyde for eight hours; thus, extended exposures produced a disproportionate heightening of bronchial reactivity. Bronchial hyperreactivity often persisted for longer than 24 hours. Increases in three bronchoconstrictive eicosanoids, prostaglandin F2 alpha, thromboxane B2, and leukotriene C4, occurred immediately after exposure, whereas an influx of neutrophils into lavage fluid occurred 24 hours later. Histological examination of the tracheal epithelium and lamina propria also demonstrated a lack of inflammatory cell infiltration. Treatment with leukotriene synthesis inhibitors and receptor antagonists inhibited acrolein-induced hyperreactivity, supporting a causal role for these compounds in this response. Acrolein also stimulated eicosanoid release from bovine epithelial cells in culture. However, the profile of metabolites formed differed from that found in lavage fluid after in vivo exposure. Similarly, human airway epithelial cells did not produce cysteinyl leukotriene or thromboxane B2. However, cysteinyl leukotrienes were mitogenic for human airway epithelial cells in a concentration-dependent manner and exhibited a structure-activity relationship; leukotriene C4 was more potent than its sequential metabolites D4 and E4. The potency of leukotriene C4 was striking, stimulating colony-forming efficiency in concentrations as low as 0.01 pM. Together, these findings suggest that environmentally relevant concentrations of aldehydes can induce bronchial hyperreactivity in guinea pigs through a mechanism involving injury to cells present in the air

Topics: Acetylcholine; Acrolein; Air Pollutants; Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Epithelium; Epoprostenol; Formaldehyde; Guinea Pigs; Hyperplasia; Inflammation; Leukocyte Count; Leukotriene B4; Lipoxygenase Inhibitors; Neutrophils; Phenothiazines; Phenylbutyrates; Prostaglandins F; SRS-A; Thromboxane B2; Time Factors

To determine the role of eicosanoids in hypoxic pulmonary vasoconstriction, we studied 42 isolated, blood-perfused lamb lungs during normoxia and hypoxia. We used the lung micropuncture technique to measure microvascular pressures in 20- to 80-micron diameter arterioles and venules and estimated segmental vascular resistance. In separate experiments, lungs were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), Dazmegrel (a thromboxane synthetase inhibitor), SQ 29548 (a thromboxane receptor blocker), FPL 57231 (a leukotriene receptor blocker), or U 60257 (a 5'lipoxygenase inhibitor). In control untreated lungs both pulmonary arteries and veins constricted during hypoxia. Addition of indomethacin, Dazmegrel, or SQ 29548 to the perfusate resulted in abolition of venous constriction during hypoxia but enhancement of arterial constriction. FPL 57231 or U 60257 resulted in complete abolition of the pulmonary hypoxic vasoconstrictor response. Our results indicate that during hypoxia, leukotrienes mediate arterial and venous constriction with thromboxane A2 being necessary for venous constriction. We conclude that the interaction between 5'lipoxygenase and cyclooxygenase products of arachidonic acid results in the characteristic pulmonary hypoxic vasoconstrictor response in isolated, perfused lamb lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Chromones; Epoprostenol; Hypoxia; Imidazoles; In Vitro Techniques; Indomethacin; Lipoxygenase; Lung; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Circulation; Receptors, Leukotriene; Receptors, Prostaglandin; Sheep; SRS-A; Thromboxane B2; Thromboxanes; Vasoconstriction

We examined the effects of arachidonic acid (AA) on pulmonary hemodynamics and fluid balance in Ringer- and blood-perfused guinea pig lungs during constant-flow conditions. Mean pulmonary arterial (Ppa), venous (Pv), and capillary pressures (Pcap, estimated by the double-occlusion method) were measured, and arterial (Ra) and venous resistances (Rv) were calculated. Bolus AA injection (500 micrograms) caused transient increases (peak response 1 min post-AA) in Ppa, Pcap, and Rv without affecting Ra in both Ringer- and blood-perfused lungs. The response was sustained in blood-perfused lungs. AA had no effect on the capillary filtration coefficient in either Ringer- or blood-perfused lungs. AA stimulated the release of thromboxane B2 and 6-ketoprostaglandin F1 alpha in both Ringer- and blood-perfused lungs, but the responses were sustained only in the blood-perfused lungs. Meclofenamate (1.5 X 10(-4) M), a cyclooxygenase inhibitor, abolished the AA-induced pulmonary hemodynamic responses in both Ringer- and blood-perfused lungs, whereas U-60257 (10 microM), a lipoxygenase inhibitor, attenuated the response only in the blood-perfused lungs. In conclusion, AA does not alter pulmonary vascular permeability to water in either Ringer- or blood-perfused lungs. AA mediates pulmonary venoconstriction and thus contributes to the rise in Pcap. The venoconstriction results from the generation of cyclooxygenase-derived metabolites from lung parenchymal cells and blood-formed elements. Lipoxygenase metabolites may also contribute to the vasoconstriction in the blood-perfused lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Epoprostenol; Female; Guinea Pigs; In Vitro Techniques; Lung; Meclofenamic Acid; Microcirculation; Osmolar Concentration; Perfusion; Pulmonary Circulation; Thromboxane B2; Vascular Resistance

Reactive oxygen metabolites cause pulmonary vasoconstriction and activate arachidonic acid metabolism. We proposed that hydrogen peroxide, generated enzymatically in an insolated rat lung model, would cause vasoconstriction which was independent of circulating cells, but dependent on activation of the arachidonic acid cascade. Although hydrogen peroxide caused an increase in lung effluent thromboxane B2 concentration, indomethacin did not inhibit hydrogen peroxide induced vasoconstriction. In order to test the hypothesis that hydrogen peroxide activates the 5-lipoxygenase pathway, lung effluents were analyzed for 5-hydroxy-eicosatetranoic acid (5-HETE) using a sensitive, highly specific mass spectrometer technique. Glucose oxidase increased the 5-HEFE effluent concentrations and this was prevented by U60,257. We therefore conclude that hydrogen peroxide stimulates the 5-lipoxygenase pathway and that substances derived from this pathway are at least in part responsible for the hydrogen peroxide induced vasoconstriction in isolated rat lungs.

Topics: Animals; Epoprostenol; Glucose Oxidase; Hydrogen Peroxide; Indomethacin; Male; Perfusion; Pulmonary Circulation; Pulmonary Wedge Pressure; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2; Vasoconstriction

6,9-deepoxy- 6,9-(phenylimino)-delta 6,8-Prostaglandin I1 (U-60,257), a prostaglandin analogue known to inhibit leukotriene formation in a number of cell systems, potentiates mast cell release of prostaglandin D2 from human dispersed lung cells activated with ionophore A23187. Over the same concentration range of 30-300 microM there was a related inhibition of ionophore-induced generation of thromboxane B2 (r = 0.93, P less than 0.01). As both prostaglandin D2 and thromboxane A2 are potent bronchoconstrictors, these observations may be relevant to the potential of this drug in the treatment of asthma.

Topics: Calcimycin; Dinoprost; Epoprostenol; Humans; In Vitro Techniques; Lung; Mast Cells; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Thromboxane B2; Thromboxanes

Topics: Animals; Basophils; Epoprostenol; Glutathione Transferase; Kinetics; Leukemia, Experimental; Monocytes; Prostaglandins; Rats; SRS-A; Thromboxane B2

Addition of the calcium inophore, A 23187, and cysteine to isolated mononuclear cells from rat peritoneal washings causes a marked increase in the formation of thromboxane B2 (TxB2) along with the formation of leukotrienes C and D (LT's). The formation of LT's in this system was inhibited by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1, U-60,257, or its methyl ester, U-56,467, (ID50 4.6 and 0.31 microM, respectively). There was no inhibition of TxB2 formation. By contrast, two structurally-related compounds, PGI2 and its stable analog, 6-beta-PGI1, did not affect the formation of either LT's or TxB2. The inhibition of LT formation by U-60,257 was rapidly reversed after removal of this compound from the cells. U-60,257 did not inhibit the cyclooxygenase of human polymorphonuclear leukocytes. Nor did it inhibit formation of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in human platelets. On the other hand, U-60,257 inhibited glutathione S-transferase activity of rat basophil leukemia cells (ID50, 37 microM), suggesting that this compound may inhibit the last step in LTC biosynthesis. In addition to inhibiting LT synthesis, U-60,257 also appears to be a competitive inhibitor of the action of LT on the guinea pig ileum, although this inhibition requires a higher drug concentration than those ordinarily encountered during assay for LT's in U-60,257-treated incubations.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Epoprostenol; In Vitro Techniques; Monocytes; Neutrophils; Prostaglandins; Rats; SRS-A; Thromboxane B2; Time Factors