thromboxane-a2 and Edema

Topics: Aldosterone; Angiotensin II; Anti-Inflammatory Agents; Arachidonic Acids; Bartter Syndrome; Bradykinin; Dopamine; Edema; Humans; Hyperaldosteronism; Hypertension; Hypotension, Orthostatic; Kallikreins; Kidney; Kinins; Myocardial Infarction; Natriuresis; Prostaglandins; Receptors, Dopamine; Renin; Thromboxane A2; Vasodilation

Thromboxane A2 (TXA2) can induce the platelet aggregation and lead to thrombosis. This will cause the low-reflow phenomenon after ischemic stroke and aggravate the damage of brain issues. Therefore, it is potential to develop the drugs inhibiting TXA2 pathway to treat cerebral ischemia.. This study aims to prove the protective effect of N2 (4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoic acid) on focal cerebral ischemia and reperfusion injury through platelet aggregation inhibition.. Middle cerebral artery occlusion/reperfusion (MCAO/R) is used as the animal model. Neurological deficit score, Morris water maze, postural reflex test, Limb-use asymmetry test, infarct volume, and water content were performed to evaluate the protective effect of N2 in MCAO/R rats. 9, 11-dieoxy-11α, 9α-methanoepoxyprostaglandin F2α (U46619) or adenosine diphosphate (ADP) was used as the inducer of platelet aggregation.. N2 can improve the motor function, learning and memory ability in MCAO/R rats while reducing the infarct volume. N2 can inhibit TXA2 formation but promote PGI2, and can inhibit platelet aggregation induced by U46619 and ADP. Further, N2 inhibits thrombosis with a minor adverse effect of bleeding than Clopidogrel. In conclusion, N2 can produce the protective effect on MCAO/R brain injury through inhibiting TXA2 formation, platelet aggregation and thrombosis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arteriovenous Shunt, Surgical; Blood Coagulation; Brain; Brain Ischemia; Edema; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Imidazoles; Male; Maze Learning; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Stroke; Thrombosis; Thromboxane A2; Vanillic Acid

Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/Neo)) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/Neo) mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1(Neo/Neo) mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.

Topics: Animals; Arachidonic Acid; Aspirin; Blood Platelets; Cyclooxygenase 1; Edema; Estradiol; Female; Humans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovary; Parturition; Pre-Eclampsia; Pregnancy; Progesterone; Prostaglandin-Endoperoxide Synthases; Receptors, Oxytocin; Thromboxane A2; Uterus

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI2 and PGE1 on vascular tone and gas exchange to that of infused prostanoids (PGI2, PGE1) and inhaled NO. An increase of pulmonary artery pressure (Ppa) from 8 to approximately 34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A2 (TxA2) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique). When standardized to reduce the Pps by approximately 10 mmHg, inhaled NO (200 ppm), aerosolized PGI2 (4 ng x kg(-1) x min(-1)) and nebulized PGE1 (8 ng x kg(-1) x min(-1)) all reduced both pre- and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V'/Q' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI2 > PGE1. In contrast, lowering of Ppa by intravascular administration of PGI2 and PGE1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng x kg(-1) x min(-1) of PGI2 or PGE1) did not provoke vascular leakage or affect the physiological V'/Q' matching. We conclude that aerosolization of prostaglandins I2 and E1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Alprostadil; Animals; Edema; Epoprostenol; Hypertension, Pulmonary; In Vitro Techniques; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Gas Exchange; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Ventilation-Perfusion Ratio

The effects of protopine on human platelet aggregation and arachidonic acid (AA) metabolism via cyclooxygenase (COX) and lipoxygenase (LOP) enzymes were examined. Platelet aggregation induced by various platelet agonists (AA, ADP, collagen and PAF) was strongly inhibited by protopine in a concentration-related manner. The IC50 values (microM) of protopine (mean +/- SEM) against: AA; 12 +/- 2: ADP; 9 +/- 2: collagen; 16 +/- 2 and PAF; 11 +/- 1, were much less than those observed for aspirin. In addition, protopine selectively inhibited the synthesis of thromboxane A2 (TXA2) via COX pathway and had no effect on the LOP pathway in platelets. In vivo, pretreatment with protopine (50-100 mg kg-1) protected rabbits from the lethal effects of AA (2 mg kg-1) or PAF (11 micrograms kg-1) in dose-dependent fashion. Protopine (50-100 mg kg-1) also inhibited carrageenan-induced rat paw oedema with a potency of three-fold as compared to aspirin. These results are suggestive that protopine acts as a potent inhibitor of thromboxane synthesis and PAF with anti-inflammatory properties.

Topics: Adenosine Diphosphate; Alkaloids; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Benzophenanthridines; Berberine Alkaloids; Blood Platelets; Carrageenan; Edema; Fibrinolytic Agents; Histamine H1 Antagonists; Male; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Rabbits; Rats; Rats, Sprague-Dawley; Thromboxane A2

1. The objectives of the present experiments were to assess the role of ETA receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of platelet-activating factor (PAF) and thromboxane A2 (TxA2) in these actions of ET-1 in rats. 2. Intravenous bolus injection of ET-1 (0.1-2 nmol kg-1) into anaesthetized rats induced ST segment elevation of the electrocardiogram in a dose-dependent manner without causing arrhythmias. ST segment elevation developed within 20-90 s and persisted for at least 10-20 min following administration of ET-1. 3. Pretreatment of the animals with the selective endothelin ETA receptor antagonist, FR 139317 (2.5 mg kg-1, i.v.) inhibited by 86% the ST segment elevation elicited by ET-1 (1 nmol kg-1). Pretreatment with intravenous administration of BM 13505 (1 mg kg-1), a TxA2 receptor antagonist, OKY-046 (10 mg kg-1), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1) markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg-1 bolus plus 2 mg kg-1 h-1) did not significantly affect ET-1-induced ST segment elevation. 4. Bolus injection of ET-1 (1 nmol kg-1, i.v.) to conscious rats resulted in a prolonged pressor effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia. ET-l enhanced albumin leakage by 87 and 120% in the left ventricle and right atrium, respectively, as measured by the extravasation of Evans blue dye.5. The selective ETA receptor antagonist, FR 139317 (2.5 mg kg-1) significantly blunted the pressor action of ET-1 and the accompanying bradycardia without affecting the depressor response. Furthermore,FR 139317 almost completely abolished the permeability effect of ET-l in both vascular beds studied.6. Pretreatment of the animals with BM 13505 (1 mg kg-1), OKY-046 (10mg kg-1), WEB 2086(1 mg kg-1) or BN 52021 (10mg kg-1) significantly reduced ET-1 (1 nmol kg-1)-induced albumin extravasation both in the left ventricle and right atrium. The PAF receptor antagonists, WEB 2086 and BN 52021 were equally potent inhibitors in the left ventricle, whereas BN 52021 appeared to be a more potent inhibitor than WEB 2086 in the right atrium. Pretreatment with indomethacin (3 mg kg-1 plus 2 mg kg-1 h-1) did not modify the permeability response to ET-1. None of these compounds af

Topics: Anesthesia; Animals; Blood Pressure; Capillary Permeability; Edema; Electrocardiography; Endothelin Receptor Antagonists; Endothelins; Heart Rate; In Vitro Techniques; Male; Myocardial Ischemia; Platelet Activating Factor; Platelet Membrane Glycoproteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Endothelin; Receptors, G-Protein-Coupled; Receptors, Thromboxane; Thromboxane A2

Prostaglandin D2 (PGD2) and thromboxane A2 (TXA2) have been suggested to play important roles in the pathogenesis of bronchial asthma. In the present study, effects of i.v.-administration of PGD2 on bronchial hyperresponsiveness in guinea pigs were investigated by the measurement of dynamic compliance and dynamic respiratory resistance with formulae which can exclude the effects of changes of the airway wall thickness. With these formulae, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of PGD2 induced airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was enhanced with the administration of PGD2. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of PGD2 administration.

Topics: Airway Resistance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Edema; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Thromboxane A2

Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Edema; Heart Diseases; Infusions, Intravenous; Injections, Intravenous; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Neutrophils; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane A2; Thromboxane B2

An increased accumulation of tissue thromboxane A2 occurred shortly after spinal cord injury. Prostacyclin formation was not affected. The magnitude of the increase in thromboxane and the extent of post-traumatic vascular damage as determined by extravasation of 125I-labeled human serum albumin were both dependent on the degree of injury. These findings raise the possibility that activation of arachidonic acid metabolism with a preponderance in thromboxane formation may contribute to microvascular injury in experimental spinal cord contusion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Vessels; Edema; Epoprostenol; Rats; Rats, Inbred Strains; Spinal Cord; Spinal Cord Injuries; Thromboxane A2; Thromboxane B2