sq-29548 and dazoxiben

The effects of constrictor prostanoid (CP) pathway inhibitors on vascular reactivity to vasopressin (VP) and phenylephrine (PE) were examined in thoracic aortas of male, female, and ovariectomized (OVX) female Sprague-Dawley rats. Maximal contractile response of control (Cont) aortas to VP was markedly higher in females (3,885 +/- 332 mg/mg ring wt) than in males (810 +/- 148 mg). Indomethacin (Indo; 10 microM) attenuated maximal response to VP in females (3,043 +/- 277 mg) but not in males. SQ-29,548 (SQ; 1 microM) attenuated maximal response to VP in females (3,042 +/- 290 mg) to a similar extent as Indo. Dazoxiben (Daz; 10 microM) alone had no effect, but Daz + SQ attenuated maximal contractile response to VP to a similar extent as SQ alone. Removal of the endothelium in female aortas attenuated contractile responses to VP in Cont aortas. OVX attenuated maximal contractile response to VP in Cont aortas (2,093 +/- 329 mg) and abolished the attenuating effects of Indo. Indo, SQ, and Daz exerted identical effects on contractile responses of male, female, and OVX female aortas to PE. These findings establish the following in the rat aorta: 1) CP, probably thromboxane and/or endoperoxide, is responsible for approximately 25-30% of contractile responses of females, but not males, to VP and PE; 2) CP production by the female aorta is primarily endothelial in origin; and 3) ovarian steroids modulate production and/or actions of CP in female aortas.

Topics: Animals; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Estrogens; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Indomethacin; Male; Ovariectomy; Phenylephrine; Progesterone; Prostaglandins; Rats; Rats, Sprague-Dawley; Sex Characteristics; Thromboxanes; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Arachidonic acid (AA) is a potent inducer of platelet aggregation in vitro; this activity is due to its conversion to biologically active metabolites, prostaglandin (PG) endoperoxides and thromboxane A2 (TxA2). PG endoperoxides and TxA, are thought to act on the same receptor; however, at least two isoforms of this receptor have been identified. The aim of our work was to clarify whether endoperoxides and TxA2 activate the same or different receptor subtypes to induce aggregation and calcium movements in human platelets. AA-induced aggregation and calcium rises were still detectable in platelets preincubated with thromboxane synthase inhibitors, which suppress TxA2 formation and induce PGH2 accumulation, suggesting that PG endoperoxides can activate platelets. Exogenously added PGH2 was able to induce aggregation and calcium rises. Pretreatment of platelets with GR32191B or platelet activating factor, which desensitize one of the two receptor subtypes identified in platelets, did not prevent calcium rises induced by endogenously generated or by exogenouly added PGH2, indicating that TxA2 and PG endoperoxides share the same receptor subtype(s) to activate platelets. HEK-293 cells overexpressing either of the two thromboxane receptor isoforms cloned to date (TPalpha and TPbeta) and identified in human platelets, stimulated with PGH2, or with the stable endoperoxide analog U46619, formed inositol phosphates. These data show that endoperoxides and TXA2 mediate their effects on platelets acting on both, and the same, receptor isoform(s).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aspirin; Biphenyl Compounds; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Calcium Signaling; Cells, Cultured; Enzyme Inhibitors; Fatty Acids, Unsaturated; Heptanoic Acids; Humans; Hydrazines; Imidazoles; Inositol Phosphates; Kidney; Methacrylates; Phenylacetates; Platelet Activating Factor; Platelet Activation; Prostaglandin H2; Prostaglandins H; Protein Isoforms; Receptors, Thromboxane; Recombinant Fusion Proteins; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The present experiments were designed to determine the role of endothelium-derived contracting factor(s) in the contractions of the rat aorta to endothelin-1 (ET-1) and endothelin-3 (ET-3). Rings, with and without endothelium, of aortas of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were suspended in organ chambers for isometric tension recording in the presence of NG-nitro-L-arginine [NLA; inhibitor of nitric oxide synthase (NOS)]. The removal of endothelium decreased the contractions evoked by both ETs in the aorta of the SHRs but not of the WKY rats. Indomethacin (inhibitor of cyclooxygenase), dazoxiben (inhibitor of thromboxane synthase), and SQ 29,548 (antagonist of thromboxane A2 receptors) reduced the contractions to ETs in rings with, but not without, endothelium in the SHRs, whereas their effect was not endothelium dependent in the WKY rats. The presence of endothelium increased the basal and ET-stimulated release of thromboxane B2 in the aorta of the SHRs but not of WKY rats. These findings suggest that endothelium-derived thromboxane A2 contributes to contractions evoked by ET-1 and ET-3 in the aorta of the SHRs but not of the WKY rats.

Topics: Amino Acid Oxidoreductases; Animals; Aorta, Thoracic; Arginine; Bridged Bicyclo Compounds, Heterocyclic; Endothelins; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; In Vitro Techniques; Indomethacin; Isometric Contraction; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane-A Synthase

The aim was to study the effects of endothelin-1 on human placental veins and the role of cyclooxygenase products as mediators of these effects.. Rings of placental veins with and without endothelium were suspended in organ chambers filled with physiologic salt solution. After a period of stabilization at optimal basal tension, isometric tensions in the control group were recorded at increasing concentrations of endothelin-1 (10(-10) to 10(-7) mol/L). Rings in the experimental groups were treated with either indomethacin (cyclooxygenase inhibitor, 10(-5) mol/L), dazoxiben (thromboxane synthetase inhibitor, 10(-4) mol/L), or SQ29548 (thromboxane receptor antagonist, 10(-6) mol/L) before addition of endothelin-1. To demonstrate the presence of functional thromboxane receptors in the rings, contractile responses to U-46619 (10(-9) to 10(-6) mol/L), a thromboxane A2 analog were measured. The effectiveness of SQ29548 blockade was tested in rings treated with SQ29548 (10(-6) mol/L) before addition of U-46619. The concentration-response curves of the treated and control groups were compared with the Student paired t test.. Endothelin-1 in doses of 10(-10) to 10(-7) mol/L caused concentration-dependent contraction of placental veins. Indomethacin significantly reduced the response of veins with endothelium to low endothelin-1 concentrations (10(-9.5) to 10(-9) mol/L), (p < 0.05). However, it had no effect at higher endothelin-1 concentrations or in vessels without endothelium. The presence of functional thromboxane A2 receptors was confirmed by the vasoconstrictor effect of U-46619 and its blockade by treatment with SQ29548. Neither SQ29548 nor the thromboxane A2 synthesis inhibitor dazoxiben significantly influenced the response to endothelin-1.. These results demonstrated that endothelin-1 is a potent vasoconstrictor in the human placental vein. Although functional thromboxane A2 receptors exist in this vessel, endothelin-1's action is independent of thromboxane A2. Prostaglandins may mediate part of the endothelin-1-induced placental vasoconstriction. However, endothelin-1 acts primarily by a direct effect on vascular smooth muscle cells.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Bridged Bicyclo Compounds, Heterocyclic; Endothelins; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Humans; Hydrazines; Imidazoles; In Vitro Techniques; Indomethacin; Placenta; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents; Veins

The role of products of cyclooxygenase was investigated in the responses of isolated airways to H2O2. Strips of guinea pig trachea, in some of which the epithelium had been removed mechanically, were suspended in organ chambers, and isometric tension was recorded. Under basal conditions, H2O2 induced indomethacin-sensitive contractions, which were larger in preparations without than in those with epithelium; the difference was abolished by inhibitors of thromboxane synthase or thromboxane A2 receptors. During contractions to acetylcholine, low concentrations of H2O2 induced relaxation in preparations with but had no significant effect in those without epithelium. At higher concentrations of H2O2, the epithelium-dependent relaxation was attenuated but an epithelium-independent relaxation appeared. The epithelium-dependent but not the epithelium-independent responses to H2O2 were blocked by indomethacin. Under basal conditions, prostaglandin E2 (PGE2; < or = 10(-7) M), U-46619, prostaglandin PGF2 alpha (PGF2 alpha), prostaglandin PGD2 (PGD2), and prostacyclin (PGI2) caused contractions. During contractions to acetylcholine, PGE2 induced larger relaxations in preparations with than in those without epithelium. Radioimmunoassay revealed that lower concentrations of H2O2 predominantly increased the release of PGE2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha); in preparations without epithelium, the release of thromboxane B2 was augmented also. At higher concentrations of H2O2, the release of PGE2, PGF2 alpha, PGD2, 6-keto-PGF1 alpha, and thromboxane B2 increased in preparations with and without epithelium. These findings demonstrate that the responses of the guinea pig trachea to H2O2 are mediated mainly by products of cyclooxygenase and that the effects of H2O2 are modulated by the epithelium.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Bridged Bicyclo Compounds, Heterocyclic; Epithelium; Fatty Acids, Unsaturated; Guinea Pigs; Hydrazines; Hydrogen Peroxide; Imidazoles; In Vitro Techniques; Indomethacin; Isometric Contraction; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin Endoperoxides, Synthetic; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Radioimmunoassay; Receptors, Thromboxane; Thromboxane-A Synthase; Trachea; Vasoconstrictor Agents

The aim of the present study was twofold: 1) to assess whether inhibition of thromboxane A2 (TxA2) synthase exerts more potent antiplatelet effects when applied concomitantly with TxA2 and prostaglandin (PG)H2 receptor blockade and 2) whether these effects are mediated through redirection of PG endoperoxides toward the synthesis of antiplatelet PGs, such as PGI2 and PGE2. Thus, cyclic flow variations (CFVs), due to recurrent platelet aggregation, were initiated in the stenotic, endothelially injured carotid arteries of 39 rabbits. After 30 min of CFVs, the animals received: 1) SQ29548 (up to 0.6 mg/kg bolus + 0.2 mg kg-1 hr-1, n = 13), a TxA2/PGH2 receptor antagonist; 2) dazoxiben (up to 15 mg/kg bolus + 5 mg kg-1 hr-1, n = 13), a TxA2 synthase inhibitor and 3) picotamide (up to 20 mg/kg bolus + 20 mg kg-1 hr-1, n = 13), a drug with simultaneous TxA2 synthase and receptor blocking properties. CFVs were abolished in 6, 7, and 12 animals treated with SQ29548, dazoxiben, and picotamide, respectively (P < .01 for picotamide versus SQ29548 and dazoxiben). The animals in which CFVs were not abolished by SQ29548 or dazoxiben received the other drug at the same dose. CFVs were abolished by dazoxiben in five of seven rabbits that initially did not respond to SQ29548 and by SQ29548 in five of six animals that did not respond to dazoxiben. All animals that responded to the combination of SQ29548 and dazoxiben, as well as those that responded to picotamide, received increasing intravenous infusions of epinephrine to restore CFVs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Epinephrine; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Phthalic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane-A Synthase

The aim of this study was to assess whether prostaglandin endoperoxides, which continue to be formed in the setting of thromboxane A2 synthase inhibition, might influence the fate of ischemic myocardium in a model of coronary occlusion and reperfusion.. It was recently demonstrated that thromboxane A2 synthase inhibitors reduce ischemic myocardial injury through a redirection of prostaglandin (PG) endoperoxides toward the synthesis of "cardioprotective" prostaglandins, such as PGI2, PGE2 and PGD2. However, part of these prostaglandin endoperoxides may also stimulate a receptor, shared with thromboxane A2, mediating platelet aggregation and vasoconstriction.. New Zealand White rabbits were subjected to 30 min of coronary occlusion, followed by 5.5 h of reperfusion. Fifteen minutes before reperfusion, the animals were randomized to receive 1) saline solution (control animals, n = 8); 2) SQ 29548, a potent and selective thromboxane A2/PGH2 receptor antagonist (n = 8); 3) dazoxiben, a selective thromboxane A2 synthase inhibitor (n = 8); 4) R 68070 (Ridogrel), a drug with dual thromboxane A2 synthase-inhibiting and thromboxane A2/PGH2 receptor-blocking properties (n = 8); or 5) aspirin + R 68070 (n = 8).. Dazoxiben and R 68070, but not SQ 29548, significantly reduced thromboxane B2 formation and increased plasma levels of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha. Ex vivo platelet aggregation induced by U46619 (a thromboxane A2 mimetic) was inhibited by SQ 29548 and R 68070 but not by dazoxiben. In control animals, infarct size determined at the end of the experiment by triphenyltetrazolium chloride staining averaged 57.7 +/- 3.2% of the area at risk of infarction. The administration of SQ 29548 did not significantly reduce infarct size compared with that in control animals, whereas dazoxiben and R 68070 significantly reduced infarct size to 36.7 +/- 2.8% and 16.6 +/- 3.6% of area at risk of infarction, respectively (p < 0.001 vs. control values). In rabbits treated with R 68070, infarct size was also significantly smaller than that of dazoxiben-treated rabbits (p < 0.01). This protective effect of R 68070 was completely abolished when the drug was administered with aspirin, infarct size in this group averaging 59.7 +/- 1.6% (p = NS vs. control values). No differences in regional myocardial blood flow, systemic blood pressure, heart rate or extent of area at risk were observed among groups.. Thus, prostaglandin endoperoxides play an important role in modulating the cardioprotective effects of thromboxane A2 synthase inhibitors. The simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/PGH2 receptors by R 68070 identify a pharmacologic interaction of potential therapeutic importance.

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Pyridines; Rabbits; Receptors, Thromboxane; Thromboxane-A Synthase

1. Canine jugular and femoral veins were studied to determine the possible importance of thromboxane (TXA2) and prostaglandin endoperoxides (prostaglandin H2, PGH2) in mediating bradykinin(BK)-induced contraction. 2. Isolated vein rings incubated in modified Krebs solution contracted to TXA2/PGH2 analogs SQ26655 and U44069 with potency of contraction exceeding that for BK. The potency ranking for both veins was SQ26655 greater than U44069 greater than BK greater than PGF2 alpha greater than TXB2 much greater than PGD2. 3. The cyclo-oxygenase inhibitors indomethacin (3 x 10(-7) M) and flufenamic acid (10(-5) M) reduced BK contractions without affecting those induced by noradrenaline (NA). 4. TXA2/PGH2 receptor antagonists SQ29548 (10(-8) M) and BM13177 (10(-6) M) strongly inhibited BK-induced tension. The action of antagonists was reversible with negligible influence on NA-elicited contraction. Selective removal of endothelium had no effect on BK-induced contraction or the action of the antagonists. 5. The thromboxane synthase inhibitors dazoxiben (10(-4) M) and CGS 12970 (10(-5) M) had no significant inhibitory effect on BK-induced tension. 6. These results suggest that in canine jugular and femoral vein, the action of BK is largely dependent upon stimulation of the cyclo-oxygenase pathway to produce PGH2 and possibly TXA2, which can activate a smooth muscle TXA2/PGH2 receptor to elicit vasoconstriction.

Topics: Animals; Bradykinin; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandin-Endoperoxide Synthases; Prostaglandins H; Pyridines; Receptors, Prostaglandin; Sulfonamides; Thromboxane-A Synthase; Thromboxanes; Veins

The purpose of this study was to test the hypothesis that combined thromboxane A2 synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2 receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2 synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2 synthetase inhibitor and thromboxane A2-prostaglandin H2 receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070. Complete abolition of cyclic flow variations was achieved in 71% of dogs in Group I, 82% in Group II, 100% in Group III (p = 0.06 compared with Group I) and 50% in Group IV (p = 0.03 compared with Group III). Epinephrine was infused into dogs with abolished cyclic flow variations: all dogs in Group I had cyclic flow variations restored, 44% in Group II (p = 0.01 compared with Group I) and 64% in Group III (p = 0.04 compared with Group I). The plasma epinephrine levels required to restore cyclic flow variations were 2.2 +/- 0.5 ng/ml (control 0.04 +/- 0.01) in Group I, 8.7 +/- 4.5 ng/ml (control 0.05 +/- 0.02) in Group II and 7.4 +/- 2.6 ng/ml (control 0.07 +/- 0.02) in Group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Epinephrine; Epoprostenol; Ergolines; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Thrombosis; Cricetinae; Dogs; Fatty Acids, Unsaturated; Fibrinolysis; Hydrazines; Imidazoles; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxane-A Synthase; Tissue Plasminogen Activator

Bacterial sepsis often precedes the development of the adult respiratory distress syndrome (ARDS) and bacterial endotoxin (LPS) produces a syndrome similar to ARDS when infused into experimental animals. We determined in isolated, buffer-perfused rabbit lungs, free of plasma and circulating blood cells that LPS synergized with platelet activating factor (PAF) to injure the lung. In lungs perfused for 2 h with LPS-free buffer (less than 100 pg/ml), stimulation with 1, 10, or 100 nM PAF produced transient pulmonary hypertension and minimal edema. Lungs perfused for 2 h with buffer containing 100 ng/ml of Escherichia coli 0111:B4 LPS had slight elevation of pulmonary artery pressure (PAP) and did not develop edema. In contrast, lungs exposed to 100 ng/ml of LPS for 2 h had marked increases in PAP and developed significant edema when stimulated with PAF. LPS treatment increased capillary filtration coefficient, suggesting that capillary leak contributed to pulmonary edema. LPS-primed, PAF-stimulated lungs had enhanced production of thromboxane B2 (TXB) and 6-keto-prostaglandin F1 alpha (6KPF). Indomethacin completely inhibited PAF-stimulated production of TXB and 6KPF in control and LPS-primed preparations, did not inhibit the rise in PAP produced by PAF in control lungs, but blocked the exaggerated rise in PAP and edema seen in LPS-primed, PAF-stimulated lungs. The thromboxane synthetase inhibitor dazoxiben, and the thromboxane receptor antagonist, SQ 29,548, similarly inhibited LPS-primed pulmonary hypertension and edema after PAF-stimulation. These studies indicate that LPS primes the lung for enhanced injury in response to the physiologic mediator PAF by amplifying the synthesis and release of thromboxane in lung tissue.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Drug Synergism; Endotoxins; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; In Vitro Techniques; Indomethacin; Lipopolysaccharides; Lung; Perfusion; Platelet Activating Factor; Pulmonary Edema; Rabbits; Thromboxanes; Tumor Necrosis Factor-alpha

Human and experimental colitis are associated with release of both vasoconstrictor and vasodilator eicosanoids. To determine the pattern of colonic blood flow in vivo and the role of prostaglandins and thromboxanes, immune complex-mediated colitis and delayed hypersensitivity-mediated colitis were induced in rabbits. Organ blood flow was determined in conscious animals by radiolabeled microspheres before and after cyclooxygenase or thromboxane synthetase inhibition. Colonic blood flow was twofold higher in colitis than in control animals. Thromboxane synthetase inhibition with dazoxiben caused a slight further increase of colon perfusion in animals with colitis, but thromboxane receptor blockade had no effect. Prostaglandin inhibition with indomethacin and ibuprofen did not affect blood flow in controls, but in animals with colitis these drugs markedly reduced colonic blood flow to the level of control animals. The data demonstrate that vasodilatory prostaglandins enhance colonic blood flow in acute colon inflammation.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Colitis; Colon; Dinitrochlorobenzene; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; Immune Complex Diseases; Male; Prostaglandins; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Regional Blood Flow; Thromboxane-A Synthase

The antiaggregatory and antisecretory effects of two newly developed thromboxane receptor antagonists, BM-13,177 and SQ-29,548, were studied in an in vivo model of platelet activation. Arterial platelet count and whole blood ATP concentrations were measured continuously on-line in the arterial blood of anesthetized rabbits. Injections of collagen decreased peripheral platelet count by 25% of initial value. ATP concentrations increased 50 to 100 nM during collagen challenge. SQ-29,548 and BM-13,177 dose-dependently reduced platelet loss to about 50% of that observed in vehicle treated animals. Injection of arachidonic acid (AA) or 9,11-methanoepoxy-PGH2 resulted in sudden death of the animals associated with a 67 to 69% decrease in platelet count and a marked release of ATP. Pretreatment with SQ-29,548 or BM-13,177 increased survival rates from 0 to 100%, and reduced or totally inhibited ATP secretion and decreases in platelet count. In contrast, the thromboxane synthetase inhibitor, dazoxiben, was effective in inhibiting AA induced sudden death, but was without any effect when 9,11-methanoepoxy-PGH2 was used as the challenging agent. We conclude that SQ-29,548 and BM-13,177 are effective in antagonizing the effects of subsequent conversion to thromboxane A2. BM-13,177 and SQ-29,548 are generally considered as specific antagonists of endoperoxide/thromboxane receptors on platelets and smooth muscles in vitro. Preliminary clinical studies with BM-13,177 showed a marked inhibition of ex vivo platelet aggregation in human volunteers and patients (18, 19). These reports encourage further study of thromboxane receptor antagonists as effective anti-thrombotic drugs in the experimental and clinical setting.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Collagen; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hydrazines; Imidazoles; Kinetics; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane-A Synthase; Thromboxanes

The TxA2 synthetase inhibitor, dazoxiben, and the TxA2 antagonist, +/- SQ 29,548, were examined for effects on release and vasoactivity of TxA2 and prostacyclin. Isolated perfused guinea pig lungs were used as the enzyme source from which TxA2 and prostacyclin were released in response to injections of arachidonic acid or bradykinin. Both dazoxiben and +/- SQ 29, 548 inhibited contraction of the superfused rat aorta and bovine coronary artery after arachidonic acid injection through the lung. +/- SQ 29,548 abolished contractions of the rat aorta, but significant aorta contracting activity persisted during dazoxiben treatment. Dazoxiben significantly inhibited arachidonate-induced release of TxA2 (immunoreactive TxB2) into the superfusate, but TxA2 release was significantly potentiated by +/- SQ 29,548. Thus, in the presence of enhanced TxA2 concentrations, +/- SQ 29,548 effectively antagonized the vasospastic effect of TxA2. Dazoxiben diverted a significantly greater amount of arachidonic acid into prostacyclin synthesis (immunoreactive 6-keto-PGF1 alpha), changing original coronary vasoconstriction into relaxation. +/- SQ 29,548 did not significantly modify lung prostacyclin synthesis. Moreover, with +/- SQ 29,548, the absence of TxA2-mediated coronary contraction unmasked active relaxation of the superfused bovine coronary artery, coincident with thromboxane and prostacyclin release. Dazoxiben consistently inhibited TxA2 synthesis and enhanced prostacyclin synthesis. +/- SQ 29,548 augmented TxB2 release in response to arachidonate, but not bradykinin, and did not significantly alter 6-keto-PGF1 alpha release in response to either arachidonate or bradykinin. In terms of vasoactivity measured in vitro, +/- SQ 29,548 and dazoxiben produced similar anti-vasospastic effects, although this was accomplished by completely different mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Bradykinin; Bridged Bicyclo Compounds, Heterocyclic; Cattle; Epoprostenol; Fatty Acids, Unsaturated; Guinea Pigs; Hydrazines; Imidazoles; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oxidoreductases; Rats; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes