dinoprost and ozagrel

Stretch-induced contraction of rabbit pulmonary artery depends on endothelium-derived vasoactive prostanoids. We investigated which prostanoid(s) was responsible for the stretch-induced contraction of the artery, and whether integrin was involved in this mechanotransduction process. Stretch increased productions of untransformed prostaglandin H(2), prostaglandin E(2), prostaglandin F(2alpha), and thromboxane A(2) in the pulmonary artery with intact endothelium. A blocking peptide for integrins (RGD peptide) significantly inhibited productions of thromboxane A(2) and prostaglandin F(2alpha), but the peptide did not affect productions of untransformed prostaglandin H(2) and prostaglandin E(2), as well as contraction in response to stretch. SQ29,548, a prostaglandin H(2)/thromboxane A(2) receptor antagonist, inhibited the contractile response to not only stretch but also exogenous prostaglandin H(2). Acetylcholine (up to 30 microM) also contracted the artery in an endothelium-dependent manner. Ozagrel (10 nM-1 microM), an inhibitor of thromboxane synthase, abolished the production of thromboxane A(2), in response to both stretch and acetylcholine, whereas the inhibitor mostly inhibited acetylcholine-induced contraction, but it did not suppress stretch-induced contraction. The results suggested that prostaglandin H(2) and thromboxane A(2), either released from endothelium by mechanical stretch or by acetylcholine, produced contraction of rabbit pulmonary artery in a RGD-independent manner.

Topics: Acetylcholine; Animals; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Dinoprostone; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Isometric Contraction; Methacrylates; Oligopeptides; Prostaglandin Antagonists; Prostaglandin H2; Pulmonary Artery; Rabbits; Receptors, Thromboxane A2, Prostaglandin H2; Stress, Mechanical; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasodilator Agents

We evaluated the capacity of anti-aggregating agents to influence thromboxane A(2) and prostacyclin formation, arachidonic acid-endoperoxide redirection, platelet aggregation and vessel tone, in isolated rabbit aorta incubated with homologous platelets. Picotamide (N,N'bis(3-pyridinylmethyl)-4-methoxy-isophthalamide), the only dual thromboxane A(2)-synthase inhibitor/receptor antagonist in clinical use, inhibited arachidonic acid-induced platelet aggregation with low potency, increased 180-fold by aorta presence. It inhibited thromboxane A(2) formation in platelets and, in aorta presence, increased prostacyclin formation. Ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid), a pure thromboxane A(2)-synthase inhibitor, behaved similarly to picotamide, although the aorta caused a higher (600-fold) shift. The potency of the antagonist SQ 29,548 (1S-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid) was unaffected by aorta. In coincubation experiments, arachidonic acid-challenge increased thromboxane A(2)-dependent vessel tone; picotamide increased prostacyclin and reduced thromboxane A(2) formation and vasoconstriction. Ozagrel mimicked picotamide; aspirin (acetylsalicylic acid) reduced aorta contractility, thromboxane A(2) and prostacyclin formation. SQ 29,548 reduced vasoconstriction without affecting eicosanoids. We demonstrate the importance of redirection of eicosanoids in the mechanism of action of thromboxane A(2) inhibitors/antagonists within platelet-vascular wall interactions. These findings bear relevance in the development of novel anti-thrombotic drugs.

Topics: Animals; Aorta, Thoracic; Arachidonic Acid; Aspirin; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Communication; Dinoprost; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Male; Methacrylates; Muscle Tonus; Muscle, Smooth, Vascular; Phthalic Acids; Platelet Activation; Platelet Aggregation Inhibitors; Rabbits; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

We have previously shown that superoxide anion (O2-) stimulates the release of vasoconstrictor prostanoids and induces a prolonged rise in coronary perfusion pressure (CPP) that persists even after removal of O2-. In this study, we tested the hypothesis that the increased CPP is mediated by activation of TxA2/ PGH2 (TP) receptors and protein kinase C (PKC)-dependent mechanisms. In Langendorff perfused rat hearts, O2- was applied for 15 min and then washed out over a period of 20 min. Application of O2- increased the release of vasoconstrictive (TxA2 and PGF2alpha) and decreased vasodilating (PGI2 and PGE2) prostanoids. Although indomethacin (10 microM), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2- perfusion, the increase was not completely blocked. OKY 046Na (10 microM), a thromboxane synthase inhibitor, had no effect on O2--induced increases in CPP, whereas ONO 3708 (10 microM), a TP receptor antagonist, suppressed this effect. PKC activity was also elevated by more than 50% by O2- perfusion. CPP typically increased throughout the O2- wash-out. This post-O2- vasoconstriction was not inhibited by indomethacin, nitroglycerin or nitrendipine. In contrast, ONO 3708 (10 microM) and two PKC inhibitors, staurosporine (10 nM) and calphostin C (100 nM), completely blocked the rise in CPP, and even elicited vasodilation. PDBu enhanced the post-O2- vasoconstriction. We conclude that O2--induced coronary vasoconstriction is initially mediated by TP receptors, but activation of PKC sustains the response.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium Channel Blockers; Cardiovascular Agents; Coronary Disease; Dinoprost; Enzyme Inhibitors; In Vitro Techniques; Indomethacin; Male; Methacrylates; Naphthalenes; Perfusion; Prostaglandins; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Staurosporine; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

8-Epi-prostaglandin F2alpha (8-epi-PGF2alpha) is an F2-isoprostane formed mainly via noncyclooxygenase pathways in vivo. We investigated whether 8-epi-PGF2alpha has any effect on airflow obstruction and plasma exudation in vivo. Airflow obstruction was quantified by measuring lung resistance (RL) in anesthetized and ventilated guinea pigs, and plasma exudation was quantified by the Evans Blue dye method (20 mg/kg intravenously). Intratracheal instillation of 8-epi-PGF2alpha (1 nmol or 10 nmol) caused dose-related increases in RL. Furthermore, the higher dose of 8-epi-PGF2alpha produced Evans Blue dye extravasation in main bronchi and intrapulmonary airways. A prostanoid TP-receptor antagonist, BAY u3405 (1 mg/kg intravenously), abolished the airway effects of 8-epi-PGF2alpha (10 nmol). A thromboxane A2 (TxA2) synthase inhibitor, OKY-406 (30 mg/kg intravenously), significantly attenuated these effects of 8-epi-PGF2alpha (10 nmol). The level of TxB2, a stable TxA2 metabolite, increased in bronchoalveolar lavage fluid (BALF) after 8-epi-PGF2alpha instillation. We conclude that 8-epi-PGF2alpha causes airflow obstruction and plasma exudation in vivo. This effect may be mediated primarily via prostanoid TP-receptors, and a secondary generation of TxA2 may be involved in part of the airway responses in 8-epi-PGF2alpha in the guinea pig.

Topics: Airway Obstruction; Animals; Bronchoalveolar Lavage Fluid; Carbazoles; Dinoprost; Guinea Pigs; Histamine Antagonists; Male; Methacrylates; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2; Thromboxane B2; Vasoconstrictor Agents

The purpose of this study was to explore whether cyclooxygenase products derived from endothelium or vascular muscle participate in the response of guinea-pig uterine arterial rings to prostaglandin F2 alpha (PGF2 alpha). Contraction to PGF2 alpha (0.1-30 microM) occurred with and without endothelium at similar potency and efficacy (pEC50 (-log EC50) values respectively 5.87 +/- 0.06 and 5.97 +/- 0.07; maximal response respectively 78.1 +/- 1.3% and 76.9 +/- 1.5% of contraction induced by 126 mM KCl). Indomethacin (3-30 microM) suppressed the maximum response to PGF2 alpha and induced a rightward shift of concentration-response curves, regardless of the presence of endothelium. pIC50 values for indomethacin were 4.67 and 4.74 for vessels with and without endothelium, respectively. In contrast, the thromboxane synthesis inhibitor OKY-046 (10 and 100 microM) did not affect the response to PGF2 alpha. We conclude that the PGF2 alpha-induced contraction in guinea-pig uterine artery is mediated, at least in part, through constrictor non-thromboxane prostanoid(s) of vascular muscle origin.

Topics: Animals; Arteries; Cyclooxygenase Inhibitors; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Female; Guinea Pigs; Indomethacin; Methacrylates; Muscle, Smooth, Vascular; Thromboxane-A Synthase; Uterine Contraction; Uterus

Quick stretch at a rate of 10 cm/sec with the amount of 30% of the slack length ( = 100%) produced a contraction in dog cerebral artery. The stretch-induced contraction was potentiated by 2-3 times in the presence of hemolysate (0.2 mg oxyHb/ml) only when the endothelium was intact. The stretch-induced contraction was also augmented by vasoconstrictor prostaglandins (PGs) such as PGF2 alpha or a stable thromboxane A2 (TXA2) analogue, U46619 (9, 11-dideoxy-11 alpha, 9 alpha-epoxymethano prostaglandin F2 alpha). ONO-3708 (7-[2 alpha, 4 alpha-(dimethylmethano-6 beta-(2-cyclopentyl-2 beta-hydroxyacetamido)-1 alpha-cyclohexyl]-5(z) heptenoic acid), a specific receptor antagonist for thromboxane A2 (TXA2)/prostaglandin (PG) endoperoxide, inhibited the potentiated stretch-induced contraction in the presence of hemolysate by about 50%. The compound completely inhibited the increase of stretch-induced contraction by PGF2 alpha or U46619. A cyclooxygenase inhibitor, acetylsalicylate, or a TXA2 synthetase inhibitor, OKY-046 ((E)-3-[4-(1-imidazolyl methyl)phenyl]-2-propenate) did not affect the potentiated stretch-induced contraction. The amount of PGF2 alpha released from the cerebral artery was not increased by hemolysate. These findings suggest that the potentiation of the stretch-induced contraction by hemolysate/oxyhemoglobin is not attributable to cyclooxygenase metabolites such as vasoconstrictor PGs. ONO-3708 seems to inhibit the potentiated stretch-induced contraction by hemolysate/oxyhemoglobin via mechanisms other than antagonism for cyclooxygenase products.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aspirin; Cerebral Arteries; Cyclooxygenase Inhibitors; Dinoprost; Dogs; Endothelium, Vascular; Enzyme Inhibitors; Female; Male; Methacrylates; Muscle Contraction; Muscle, Smooth, Vascular; Oxyhemoglobins; Oxytocics; Reflex, Stretch; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

We examined the responses to intraluminally applied acetylcholine (ACh) in isolated and perfused canine basilar arteries by the stainless-steel cannula-inserting method. In control vessels with intact endothelium, ACh produced a slight vasodilatation followed by a long-lasting vasoconstriction in the absence of induced tone. Propranolol, a beta-adrenoceptor blocker, had no effect on the response to ACh. After endothelial removal with intraluminal saponin, the constrictor component of the response to ACh was significantly enhanced, and the constrictions to prostaglandin F2 alpha (PGF2 alpha) and potassium chloride (KCl) were significantly potentiated. After exposure to extraluminal oxyhemoglobin, the ACh-induced constriction was significantly augmented, whereas the dilator component of the response to calcium ionophore A23187 was significantly attenuated. The enhanced constriction to ACh after endothelial removal was significantly blocked by OKY-046 (a thromboxane synthetase inhibitor) and nimodipine (a dihydropyridine calcium antagonist), but was slightly though not significantly suppressed by AA-861 (a lipoxygenase inhibitor). The response to PGF2 alpha was not altered by OKY-046 or AA-861. These results suggest that the potentiation of ACh-induced constriction after endothelial removal may be mediated in part by thromboxane A2 (TXA2), linked with extracellular calcium entry in smooth muscle cells (SMC). This mechanism might be involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH).

Topics: Acetylcholine; Animals; Basilar Artery; Benzoquinones; Catheterization, Peripheral; Dinoprost; Dogs; Drug Synergism; Endothelium, Vascular; Enzyme Inhibitors; Female; Injections, Intra-Arterial; Lipoxygenase Inhibitors; Male; Methacrylates; Oxyhemoglobins; Perfusion; Potassium Chloride; Propranolol; Saponins; Thromboxane-A Synthase; Vasoconstriction; Vasodilation; Vasodilator Agents

1. We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5 mg kg-1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30 mg kg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2 alpha (PGF2 alpha; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2. Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI-192,605 and OKY-046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4. 3. Instilled PGF2 alpha into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2 alpha produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2 alpha, instillation of U-46619 produced a biphasic increase in RL and extravasation of Evans Blue dye. The potency of PGF2a, in inducing these airway responses was about 1000 times less than U-46619. ICI-192,605 abolished both the immediate and the delayed increase in RL after PGF2a, and also blocked PGF2a,-induced extravasation of Evans Blue dye. However, OKY-046 had no inhibitory effects on these responses.4. We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP-receptors. On the other hand,instilled PGF2a, while inducing similar responses, does so primarily by direct activation of TP receptors,rather than via TxA2 generation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Obstruction; Airway Resistance; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Capillary Permeability; Dinoprost; Dioxanes; Evans Blue; Exudates and Transudates; Guinea Pigs; In Vitro Techniques; Leukotriene D4; Male; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

In monkey coronary artery strips contracted with prostaglandin (PG) F2 alpha or K+, exchange of entire N2 for O2 in the gas aerating the bathing media produced a contraction. Endothelium denudation did not alter the response. Aspirin, indomethacin, and ONO 3708, a PG receptor antagonist, markedly inhibited the hypoxia-induced contraction, whereas superoxide dismutase and OKY 046, a thromboxane (Tx) A2 synthesis inhibitor, were ineffective. Diltiazem depressed the contraction. Hypoxia increased the release of PGE2 but not 6-keto-PGF1 alpha and TxB2. Contractions induced by hypoxia of human coronary artery strips were also independent of the endothelium but were suppressed by indomethacin and diltiazem. On the other hand, dog coronary artery contractions induced by hypoxia were attenuated by endothelium denudation but were not influenced by indomethacin. It may be concluded that the hypoxia-induced contraction of monkey and human epicardial coronary arteries is associated with vasoconstrictor PGs released from subendothelial tissues; however, TxA2 and superoxide anion are not involved. The dog coronary artery contraction appears to be elicited by substance(s), other than cyclooxygenase products, released from the endothelium.

Topics: Animals; Aspirin; Coronary Vessels; Dinoprost; Dogs; Endothelium, Vascular; Female; Humans; Hypoxia; In Vitro Techniques; Indomethacin; Isometric Contraction; Macaca; Male; Methacrylates; Muscle Relaxation; Muscle, Smooth, Vascular; Papaverine; Prostaglandins; Species Specificity; Superoxide Dismutase; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effects of subarachnoid hemorrhage (SAH) on intracranial prostaglandins (PGs) were studied in canines. Subarachnoid hemorrhage was produced by the "two hemorrhage" method. Basilar artery caliber and regional cerebral blood flow (rCBF) in the occipital cortex were reduced by 42% and 43% during delayed vasospasm, respectively. Once delayed vasospasm had developed, intravenous infusion of OKY-046, a selective inhibitor of thromboxane (TX) A2 synthetase, induced no significant change in angiographic vasospasm but caused a significant increase in rCBF. In delayed vasospasm, cortical levels of PGF2 alpha were significantly decreased, whereas plasma levels of PGF2 alpha and TXB2 in the transverse sinus were significantly increased. The intravenous infusion of OKY-046 in delayed vasospasm induced a significant increase in cortical PGF2 alpha and PGE in the occipital cortex, and caused a significant increase in plasma 6-keto-PGF1 alpha and a significant decrease in plasma TXB2 in the transverse sinus. In delayed vasospasm, decreased cortical levels of PGF2 alpha may reflect a decrease in rCBF and increased plasma PGF2 alpha and TXB2 levels may reflect enhancement of intravascular coagulation. These PGs have very strong and various biological activities. The results suggest that SAH induces complicated changes of intracranial PGs and OKY-046 can improve these pathological changes.

Topics: Animals; Basilar Artery; Brain; Cerebrovascular Circulation; Dinoprost; Dogs; Infusions, Intravenous; Ischemic Attack, Transient; Methacrylates; Prostaglandins E; Subarachnoid Hemorrhage; Thromboxane-A Synthase

The influence of eicosanoids on the proliferation of hepatoma (HTC) cells was studied in culture and in tumor-bearing rats. The cells in culture demonstrated a capacity to metabolize arachidonic acid to eicosanoids including thomboxane B2 and the prostaglandins E2 and F2 alpha a. An effect of these eicosanoids on cell proliferation was suggested by the decreased cell division seen with an inhibitor of cyclooxygenase, flurbiprofen. A biphasic effect on the proliferation of HTC cells was observed with increasing concentrations of prostaglandin F2 alpha. These studies were extended to tumor-bearing rats where inhibitory effects on the early stages of tumor growth were seen with flurbiprofen. Bleeding times were decreased in tumor-bearing rats but were restored to control values by treatment with flurbiprofen and an inhibitor of thromboxane synthetase, OKY 046. These drugs and a thromboxane/endoperoxide receptor antagonist, SQ 29, 548, were not observed to have statistically significant effects on isotope-labeled water distribution but they had substantial effects on the maintenance of body weight by tumor-bearing rats. The data suggested that the cachexia of tumor-bearing animals may be mediated at least in part by the action of eicosanoids.

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Bridged Bicyclo Compounds, Heterocyclic; Cell Division; Chromatography, Thin Layer; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Eicosanoids; Fatty Acids, Unsaturated; Flurbiprofen; Hydrazines; Liver Neoplasms, Experimental; Male; Methacrylates; Rats; Thromboxane B2; Thromboxane-A Synthase; Tumor Cells, Cultured

In order to examine the functional changes in the vascular smooth muscle, the effects of a thromboxane A2 synthetase inhibitor (OKY-046) and a calcium channel blocker (diltiazem) on vessels following subarachnoid hemorrhage, and the contractile activity of cerebral vessels with various vasoactive agents, were investigated by studying isometric tension recordings in rings of cat basilar artery. The maximum contractile activities of the vessels in response to noradrenalin and adrenaline during the course of subarachnoid hemorrhage were significantly less than those in the control group. On the other hand, the maximum contractile activity of the vessels in response to prostaglandin F2 alpha on the seventh day following subarachnoid hemorrhage was significantly augmented compared with that in the control group. A significant decline in the relaxation of responsiveness to diltiazem during the course of subarachnoid hemorrhage was observed compared with that of diltiazem in the control group. This responsiveness to vasoactive agents was not influenced by the application of OKY-046. The present study reveals functional changes in vascular smooth muscle exposed to subarachnoid hemorrhage in response to vasoactive agents and a calcium entry blocker. Thromboxane A2 may not be a significantly influential factor in the present results. It is suggested that cerebral vasospasm may well be related to functional changes of the arterial wall, which appear to be associated with derangement of the mechanisms of smooth muscle constriction and dilatation based on organic changes.

Topics: Animals; Basilar Artery; Cats; Diltiazem; Dinoprost; Disease Models, Animal; Epinephrine; Methacrylates; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Serotonin; Subarachnoid Hemorrhage; Thromboxane-A Synthase

The effect of OKY-046 (ONO, Japan), a selective TX inhibitor, was studied for its effect on uterine and platelet activity. On day 21 of pregnancy, rats were injected with either 0, 1, or 5 mg/kg OKY-046 via the tail vein. One hour following injections, in vitro activity of uteri and platelets was assessed. A decrease (P less than .01) in uterine TXB2 production (measured by RIA) occurred with increasing OKY-046 dose (104 +/- 31 vs 44 +/- 6 vs 24 +/- 2 ng TXB2/g tissue/45 min). OKY-046 treatment had no effect on other prostanoids. Contractile activity was not affected by OKY-046. The amount of TXB2 produced in platelets from OKY-046 (5 mg/Kg) treated rats was 45.5% less than that from controls (P less than .001). Likewise, arachidonate-induced aggregation of platelets from OKY-046 treated rats was 46.1% less (P less than .05) than that of controls. In summary, in vivo administration of OKY-046 selectively reduced uterine TXB2 without altering other prostanoids, or affecting uterine contractions. In contrast, both platelet TXB2 production and platelet function (aggregation) was decreased.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Blood Platelets; Dinoprost; Dinoprostone; Female; Imidazoles; Methacrylates; Pregnancy; Pregnancy, Animal; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes; Uterus

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.

Topics: Animals; Arachidonic Acids; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Guinea Pigs; Indomethacin; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lung; Male; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins F; SRS-A; Thromboxane B2

We studied the effect of leukotriene B4 aerosols on airway responsiveness to inhaled acetylcholine aerosols and on the cellular components and cyclooxygenase metabolites in bronchoalveolar lavage fluid in dogs. Inhalation of leukotriene B4 aerosols had no effect on resting total pulmonary resistance but increased airway responsiveness, an effect that was maximum in 3 h and that returned to control levels within 1 wk. Three hours after leukotriene B4, the number of neutrophils and the concentration of thromboxane B2 recovered in lavage fluid increased markedly. Pretreatment with the thromboxane synthase inhibitor OKY-046 prevented the increases in airway responsiveness and in thromboxane B2 but did not alter neutrophil chemotaxis. Thus we speculate that leukotriene B4 causes neutrophil chemotaxis and release of thromboxane B2, which increases airway responsiveness.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Aerosols; Airway Resistance; Animals; Chemotaxis, Leukocyte; Dinoprost; Dinoprostone; Dogs; Leukotriene B4; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Prostaglandins F; Pulmonary Alveoli; Respiratory System; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dental Pulp; Dinoprost; Dinoprostone; Epoprostenol; In Vitro Techniques; Indomethacin; Kinetics; Methacrylates; Prostaglandins E; Prostaglandins F; Rats; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Tranylcypromine