Aspirin is an important antithrombotic agent. However, its clinical benefit is impaired by aspirin resistance. The term of "aspirin resistance" usually refers to laboratory resistance. It can be identified by measuring thromboxane A2 or thromboxane-dependent platelet function. Clinical trials have shown that laboratory aspirin resistance is correlated with vascular events.
Aspirin ; therapeutic use ; Drug Resistance ; Humans ; Thromboxane A2 ; blood

OBJECTIVE: There is no proven regimen to reduce the severity of stroke in patients with acute cerebral infarction presenting beyond the thrombolytic time window. Ozagrel sodium, a selective thromboxane A2 synthetase inhibitor, has been known to suppress the development of infarction. The antiplatelet effect is improved when aspirin is used together with a thromboxane synthetase inhibitor. METHODS: Patients with non-cardiogenic acute ischemic stroke who were not eligible for thrombolysis were randomly assigned to two groups; one group received ozagrel sodium plus 100 mg of aspirin (group 1, n=43) and the other 100 mg of aspirin alone (group 2, n=43). Demographic data, cardiovascular risk factors, initial stroke severity [National Institute of Health Stroke Scale (NIHSS) and motor strength scale] and stroke subtypes were analyzed in each group. Clinical outcomes were analyzed by NIHSS and motor strength scale at 14 days after the onset of stroke. RESULTS: There were no significant differences in the mean age, gender proportion, the prevalence of cardiovascular risk factors, stroke subtypes, and baseline neurological severity between the two groups. However, the clinical outcome for group 1 was much better at 14 days after the onset of stroke compared to group 2 (NIHSS score, p=0.007, Motor strength scale score, p<0.001). There was one case of hemorrhagic transformation in group 1, but there was no statistically significant difference in bleeding tendency between two groups. CONCLUSION: In this preliminary study, thromboxane A2 synthetase inhibitor plus a low dose of aspirin seems to be safe and has a favorable outcome compared to aspirin alone in patients with acute ischemic stroke who presented beyond the thrombolytic time window.
Aspirin ; Cerebral Infarction ; Hemorrhage ; Humans ; Infarction ; Methacrylates ; Prevalence ; Risk Factors ; Sodium ; Stroke ; Thromboxane A2 ; Thromboxane-A Synthase ; Tissue Plasminogen Activator

OBJECTIVETo investigate the roles of thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)) in development of oligohydramnios.

METHODSThe concentration of TXB(2) and 6-keto-PGF1 in umbilical cord blood collected from 30 normal parturients (control) and 30 parturients with oligohydramnios was detected by radioimmunoassay to calculate the TXA(2)/PGI(2) ratio. Immunohistochemistry was performed to detect the contents of TXA(2)R in vascular endothelial cell in the placental villi.

RESULTSCompared with the control group, the concentration of umbilical cord blood TXB(2) in oligohydramnios group was significantly increased (P<0.01), but the elevation of 6-keto-PGF(2) concentration was not statistically significant (P>0.05). The oligohydramnios group showed significantly higher positivity rates of TXB2 and 6-keto-PGF1 in than the control group (P<0.01), and the positivity rate of TXA(2)R in the vascular endothelial cells in the placental villi was also significantly higher in the oligohydramnios group (22/30, 77.3% vs 11/30, 36.7%, P<0.05). Most of the TXA(2)R-positive cases in the oligohydramnios group showed strong positivities of TXA(2)R.

CONCLUSIONAbnormal elevation of TXA(2) concentration in the umbilical cord blood and the TXA(2)/PGI(2) imbalance are responsible for the development of oligohydramnios.

Adult ; Alprostadil ; analogs & derivatives ; blood ; Epoprostenol ; blood ; Female ; Fetal Blood ; chemistry ; Humans ; Oligohydramnios ; metabolism ; Placenta ; chemistry ; Pregnancy ; Radioimmunoassay ; Receptors, Thromboxane A2, Prostaglandin H2 ; chemistry ; Thromboxane A2 ; blood

OBJECTIVE: High thromboxane level evidence supports pivotal involvement of TxA2 in pathophysiology of pregnancy induced hypertension and provides a strong rationale for pursuing TxA2-blocking strategies in drug development. METHODS: The stable metabolites of TXA2 (Thromboxane B2) in maternal blood of 12 patients with mild preeclampsia, 4 patients with severe preeclampsia and 14 normal parturients were measured by competitive enzyme immunoassay. RESULTS: TxB2 concentrations were not increased in mild preeclampsia (101 +/- 12 pg/mL, n=12) as compared with normal pregnancy (150 +/- 15 pg/mL, n=14), but they were significantly increased in severe preeclampsia (454 +/- 102 pg/mL, p<0.0001, n=4). CONCLUSION: Maternal plasma thromboxane is increased only in severe preeclampsia. Thus, increased thromboxane A2 biosynthesis correlates with disease severity and may have a pathogenetic role in pregnancy-induced hypertension. These findings provide a rationale for the use of aspirin in the treatment as well as in the prevention of this disorder.
Aspirin ; Female ; Humans ; Hypertension, Pregnancy-Induced* ; Immunoenzyme Techniques ; Plasma ; Pre-Eclampsia ; Pregnancy ; Thromboxane A2

Acute hypoxia induces contraction of pulmonary artery (PA) to protect ventilation/perfusion mismatch in lungs. As for the cellular mechanism of hypoxic pulmonary vasoconstriction (HPV), hypoxic inhibition of voltage-gated K+ channel (Kv) in PA smooth muscle cell (PASMC) has been suggested. In addition, our recent study showed that thromboxane A2 (TXA2) and hypoxia-activated nonselective cation channel (I(NSC)) is also essential for HPV. However, it is not well understood whether HPV is maintained in the animals exposed to ambient hypoxia for two days (2d-H). Specifically, the associated electrophysiological changes in PASMCs have not been studied. Here we investigate the effects of 2d-H on HPV in isolated ventilated/perfused lungs (V/P lungs) from rats. HPV was almost abolished without structural remodeling of PA in 2d-H rats, and the lost HPV was not recovered by Kv inhibitor, 4-aminopyridine. Patch clamp study showed that the hypoxic inhibition of Kv current in PASMC was similar between 2d-H and control. In contrast, hypoxia and TXA2-activated I(NSC) was not observed in PASMCs of 2d-H. From above results, it is suggested that the decreased I(NSC) might be the primary functional cause of HPV disappearance in the relatively early period (2 d) of hypoxia.
4-Aminopyridine ; Animals ; Anoxia* ; Lung ; Muscle Cells* ; Myocytes, Smooth Muscle ; Pulmonary Artery ; Rats* ; Thromboxane A2 ; Vasoconstriction*

BACKGROUND: Thromboxane A2 and endothelin-1 are the potent vasoconstrictors affecting pulmonary pathophysiology in response to whole body inflammatin following CPB. Aprotinin, as an antiiflammatory agent, may decrease the release of such vasoactive substance from pulmonary tissues, preventing pulmonary hypertension after cardiopulmonary bypass. MATERIAL AND METHOD: Ten mongrel dogs(Bwt. ac. 20kg) were subjected to cardioupulmonary bypass for 2 hours and postbypass pulmonary vascular resistance(0, 1, 2, 3 hours) were compared with prebypass level. The dogs were divided into 2 groups; control group(n-5) and aprotinin group(n=5). In the aprotinin group, aprotinin was administered as follows; 50,000 KIU/kg mixed in pump priming solution, 50,000 KIU/kg prebypass intravenous infusion over 30 minutes, 10,000 KIU/kg/hour postbypass continuous infusion. Prebypass and postbypass 0, 1, 2, 3 hour pulmonary vascular resistance were measured. At prebypass and postbypass 0, 90, 180 minutes, blood samples were obtained from pulmonary arterial and left atrial catherers for the assay of plasma thromboxane B2 a stable metabolite of thromboxane A2, and endothelin-1 concentrations. RESULT: The ratios of pustbypass over prebypass pulmonary vascular at postbypass 0, 1, 2, 3 hours were 1.28+/-0.20, 1.82+/-0.23, 1.90+/-0.19, 2.14+/-0.18 in control group, 1.58+/-0.18, 1.73+/-0.01, 1.66+/-0.10, 1.50+/-0.08 in aprotinin group ; the ratios gradually increased in control group while decreased or fluctuated after postbypass 1 hour in aprotinin group. There was statistically significant difference between control group and aprotinin group at postbypass 3 hours(P=0.014). Pulmonary arterial plasma concentration of thromboxane B2(pg/ml) at prebypass, postbypass 0, 90, 180 minutes were 346.4+/-61.9, 529.3+/-197.6, 578.3+/-255.8, 493.3+/-171.3 in control group, 323.8+/-118.0, 422.6+/-75.6, 412.3+/-59.9, 394.5+/-154.0 in aprotinin group. Left atrial concentrations were 339.3+/-89.2, 667.0+/-65.7, 731.2+/-192.7, 607.5+/-165.9 in control group, 330.0+/-111.2, 468.4+/-190.3, 425.4+/-193.6, 4.7.3+/-142.8 in aprotinin group. These results showed decrement of pulmonary thromboxane A2 generation in aprotinin group. Pulmonary arterial concentrations of endothelin-1(fmol/ml) at the same time sequence were 7.84+/-0.31, 13.2+/-0.51, 15.0+/-1.22, 16.3+/-1.73 in control group, 7.76+/-0.12, 15.3+/-0.71, 22.6+/-6.62, 14.9+/-1.11 in aprotinin group. Left atrial concentrations were 7.61+/-17.2, 57.1+/-28.4, 18.9+/-18.2, 31.5+/-20.5 in control group, 5.61+/-7.61, 37.0+/-26.2, 28.6+/-21.7, 37.8+/-30.6 in aprotinin group. These results showed that aprotinin had no effect on plasma endothelin-1 concentration after cardiopulmonary bypass. CONCLUSIONS: Administration of aprotinin during cardiopulmonary bypass could attenuate the increase in pulmonary vascular resistance after bypass. Inhibition of pulmonary thromboxane A2 generation was thought to be one of the mechanism of this effect. Aprotinin had no effect on postbypass endothelin-1 concentration.
Animals ; Aprotinin* ; Cardiopulmonary Bypass ; Dogs ; Endothelin-1* ; Endothelins ; Extracorporeal Circulation* ; Hypertension, Pulmonary ; Infusions, Intravenous ; Plasma* ; Thromboxane A2 ; Thromboxane B2* ; Vascular Resistance ; Vasoconstrictor Agents

Cyclosporine A(CsA) induced nephrotoxicity is a common clinical problem in the patients who underwent organ transplantation and subsequent immunosuppressive therapy. The precise pathophysiology of CsA induced nephrotoxicity still remains uncertain though many hypothesized mechanisms were reported. Therefore, no effective strategy is currently available to counter the nephrotoxic effects of CsA while cyclosporine G or cyclosporine microemulsion was tried to reduce the toxic effects. Recently, CsA was reported to induce lipid peroxidation in renal cortical mitochondria, which may cause mitochondrial damage. To examine the hypothesis of lipid peroxidation in the pathogenesis of acute CsA induced nephrotoxicity, antioxidant vitamin E was co-administerated in the CsA induced acute nephrotoxicity. Sprague Dawley male rats weighing from 250 to 400 gm were heminephrectomized 7 days prior to the experiments. The rats were divided into 3 groups and each group consisted of 7 rats. In group I(control group), the rats were given sterilized olive oil intraperitoneally, in group II(CsA group), CsA 50 mg/kg of body weight/day intraperitoneally, and in group III(CsA with vitamin E), CsA 50 mg/kg of body weight/day intraperitoneally with vitamin E 10 mg/kg of body weight/day intramuscularly for 7 days respectively. From the 6th day, all experimental animals were placed in a metabolic cage collecting urine for the measurement of 24-hours urine thromboxane B2, the metabolite of thromboxane A2. On the 7th day, at the sacrifice of the experimental animals, blood samplings for the measurement of blood CsA level and serum creatinine and left nephrectomy for morphological study were performed. Comparison of mean serum creatinine levels between 2 study groups revealed 171.7+/-164.2 micro Mol/L in group II and 53.4+/-13.9 micro Mol/L in group III(p<0.05). Mean 24-hour urine thromboxane B2 levels were 39.0+/-6.9 ng/24 hours in group I, 74.8+/-22.6 ng/24 hours in group II, and 34.5+/-8.0 ng/24 hours in group III. Urine thromboxane B2 was significantly(p=.0026) lower in group III. The differences of morphological changes in group II and III can be summarized as a diminution of PAS(+) granules under the light microscope and a diminution of the numbers of secondary lysosomes in the proximal tubular epithelial cell under the electron microscope. In conclusion, this animal study provides an evidence that CsA-induced acute nephrotoxicity is related with lipid peroxidation and the antioxidant, vitamin E was considered to ameliorate CsA-induced acute nephrotoxicity in rats.
Animals ; Creatinine ; Cyclosporine* ; Epithelial Cells ; Humans ; Lipid Peroxidation ; Lysosomes ; Male ; Mitochondria ; Nephrectomy ; Olea ; Olive Oil ; Organ Transplantation ; Rats* ; Thromboxane A2 ; Thromboxane B2 ; Transplants ; Vitamin E* ; Vitamins*

In order to find out the relationship between arachidonic acid(AA) metabolites and the development of vasospasm following a subarachnoid hemorrhage(SAH), we evaluated the cerebrospinal fluid(CSF) levels of the two main AA metabolites, prostacyclin(PGI2) and thromboxane A2(TXAZ) by measuring their stable degredation products 6-keto-prostaglandin F1alpha(PGF1) and thromboxane B2(TXB2) using radioimmunoassay methods in 32 patients after an aneurysmal rupture and in 11 patients without an aneurysmal rupture as a control group. We compared the data between aneurysmal ruptured patients and control group patients. We also divided the data of the aneurysmal ruptured patients into 3 groups checking them between 1-4, 5-11, and 12-28 days after the SAH, and compared the data among the groups, then the data was also compared between non-vasospasm and clinical or severe angiographic vasospasm groups of patients. The results showed that the AA metabolism was enhanced after the SAH, The TXB2 increased the greatest amount in 1-4 days after the SAH and significantly decreased statistically 12 days after the SAH(p<0.002). This study also showed that the TXB2 level was significantly higher statistically in 1 to 4 days in the clinical or angiogrophically severe vasospasm group than in the non-vasospasm group of patients(p<0.032). PGF1 did not show any statistically significant changes according to the number of SAH days or a difference between the vasospasm and non-vasospasm groups. This result suggests if the AA metabolites are involved in the pathogenesis of cerebral vasospasm, and the lumbar CSF levels of AA metabolites in aneurysmal patients reflect the arterial synthesis of PGI2 and platelet origin of TXA2, the elevation of TXA2 or other vasoconstrictor prostaglandins is more likely to play a major role in the pathogenesis of vasospasm than PGI2 deficiency. The measurements of the CSF TXB2 in 1 to 4 days after a SAH may have an expectant value in the development of clinical or severe angiographic vasospasm(exclude the accompanying intraventricular hemorrhage patients).
Aneurysm* ; Arachidonic Acid ; Blood Platelets ; Cerebrospinal Fluid* ; Epoprostenol ; Hemorrhage ; Humans ; Metabolism ; Prostaglandins I ; Radioimmunoassay ; Rupture ; Subarachnoid Hemorrhage* ; Thromboxane A2 ; Thromboxane B2* ; Vasospasm, Intracranial

OBJECTIVETo investigate the dynamic changes of plasma levels of prostacycline (PGI2) and thromboxane A2 (TXA2) and their relationship with the severity of hepatic injury in rats with nonalcoholic fatty liver disease (NAFLD).

METHODSWe established a NAFLD model, with a fat-rich diet consisting of 10% lard oil + 2% cholesterol, which was given to Sprague-Dawley rats (n=48) for a period of 8, 12, 16 and 24 weeks. The other rats were fed standard diets and were used as normal controls (n=24). At sacrifice, liver pathology scores were evaluated and plasma levels of PGI2, its stable metabolic product 6-keto-PGF1 alpha and TXA2, and TXB2 were determined by radioimmunoassay.

RESULTSSimple fatty livers were observed in the model group at 8 weeks. From 12 weeks to 24 weeks, the livers gradually progressed from simple steatohepatitis to liver fibrosis. Plasma levels of TXB2 in the model group increased higher than in the control group after 8 weeks [(52.4+/-3.15) ng/L vs (41.1+/-1.45) ng/L] and continued to increase over time, with the highest levels at 24 weeks [(117.7+/-7.47) ng/L]. A strong positive correlation (r=0.537) was seen between plasma TXB2 levels and the severity of liver injury. Plasma 6-keto-PGF1 alpha concentrations decreased in the model group in comparison with the control group after 8 weeks [(31.1+/-1.62) ng/L vs (36.5+/-1.68) ng/L] and continued to decrease over time, with the lowest concentrations at 24 weeks [(3.4+/-2.43) ng/L t=3.77]. A negative correlation was shown between the 6-keto-PGF1 alpha level and the severity of the liver injury.

CONCLUSIONA rat model of NAFLD was established successfully by feeding a fat-rich diet for 24 weeks. In this model, the imbalance of plasma PGI2 and TXA2 levels (increased TXB2 and decreased 6-keto-PGF1 alpha levels) may play a role in the pathogenesis of experimental NAFLD.

6-Ketoprostaglandin F1 alpha ; blood ; Animals ; Epoprostenol ; blood ; Fatty Liver ; blood ; Liver ; pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Thromboxane A2 ; blood ; Thromboxane B2 ; blood

It is well known that cigarette smoke can cause erectile dysfunction by affecting the penile vascular system. However, the exact effects of nicotine on the corpus cavernosum remains poorly understood. Nicotine has been reported to cause relaxation of the corpus cavernosum; it has also been reported to cause both contraction and relaxation. Therefore, high concentrations of nicotine were studied in strips from the rabbit corpus cavernosum to better understand its effects. The proximal penile corpus cavernosal strips from male rabbits weighing approximately 4 kg were used in organ bath studies. Nicotine in high concentrations (10(-5)~10(-4) M) produced dose-dependent contractions of the corpus cavernosal strips. The incubation with 10(-5) M hexamethonium (nicotinic receptor antagonist) significantly inhibited the magnitude of the nicotine associated contractions. The nicotine-induced contractions were not only significantly inhibited by pretreatment with 10(-5) M indomethacin (nonspecific cyclooxygenase inhibitor) and with 10(-6) M NS-398 (selective cyclooxygenase inhibitor), but also with 10(-6) M Y-27632 (Rho kinase inhibitor). Ozagrel (thromboxane A2 synthase inhibitor) and SQ-29548 (highly selective TP receptor antagonist) pretreatments significantly reduced the nicotine-induced contractile amplitude of the strips. High concentrations of nicotine caused contraction of isolated rabbit corpus cavernosal strips. This contraction appeared to be mediated by activation of nicotinic receptors. Rho-kinase and cyclooxygenase pathways, especially cyclooxygenase-2 and thromboxane A2, might play a pivotal role in the mechanism associated with nicotine-induced contraction of the rabbit corpus cavernosum.
Baths ; Cyclooxygenase 2 ; Erectile Dysfunction ; Hexamethonium ; Humans ; Indomethacin ; Male ; Nicotine* ; Phosphotransferases ; Prostaglandin-Endoperoxide Synthases ; Rabbits ; Receptors, Nicotinic ; Receptors, Thromboxane ; Relaxation ; rho-Associated Kinases ; Smoke ; Thromboxane A2 ; Tobacco Products