缺氧时TXA_2和PGI_2对心肌血流量变化的调节作用

目的本文旨在探讨TXA2和PGI2在缺氧时对心肌血流量的调节作用。方法大鼠随机分为平原组和急性缺氧组,用99mTc标记蟾蜍红细胞测定心肌血流量,用放免法分别测量血栓素A2、前列环素的含量。结果急性缺氧导致左、右心室心肌血流量、血浆TXB2含量、TXB2/6-keto-PGF1浕比值明显增高（P〈0.05）,左、右心室心肌血管阻力明显下降（P〈0.05）,6-keto-PGF1浕无明显变化？崧邸〖毙匀？氧时,左、右心室心肌血流量增加,TXA2和PGI2参与了急性缺氧时心肌血流量的调节,以TXA2的缩血管作用为主。     

New trends in thromboxane and prostacyclin modulators

Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two labile products formed from arachidonic acid by the way of cyclooxygenase. An overproduction of thromboxane A2 has been detected in a series of diseases whereby this prostanoid is assumed to contribute to the underlying pathomechanisms by its potent stimulation of platelet aggregation and smooth muscle contraction. This increased TXA2 biosynthesis is frequently accompanied by a stimulation of prostacyclin formation which is one of the most potent inhibitors of platelet aggregation and smooth muscle contraction. Therefore, TXA2 / prostaglandin endoperoxide H2 receptor antagonists, thromboxane synthase inhibitors and drugs which combine both activities have been developed with the aim to suppress the formation and/or the action of thromboxane A2. Since prostacyclin has been demonstrated to counterbalance the pathological effects of TXA2, several PGI2 agonists have also been developed. This review will highlight the evolution and some of the latest findings in the field of prostacyclin and thromboxane A2 modulators mainly those which are under clinical evaluation or marketed.     

蛇毒抗栓酶对冠心病、高血压病患者血浆血栓素和前列环素的影响

用蛇毒抗栓酶以自身对照方法治疗17例急性心肌梗塞、38例心绞痛和19例高血压病患者,分别测定不同治疗时间患者血浆TXB_2、6—酮—PGF_1α浓度。结果表明:用药后各组TXB_2和T/K比值均见下降,6—酮—PGF_1α逐渐升高。提示蛇毒抗栓酶有影响前列腺素代谢,调节TXA_2与PGI_2平衡的作用,该药抑制血小板聚集的作用与此有关。     

The effect of prolonged treatment with sulphinpyrazone on thromboxane A2 and prostacyclin in man.

We studied the effect of 3 weeks' treatment with 4 x 200 mg of sulphinpyrazone daily (six healthy volunteers) on proaggregatory thromboxane A2 (TxA2) and antiaggregatory prostacyclin (PGI2). Platelet TxA2 production was evaluated by measuring its stable metabolite, immunoreactive thromboxane B2, from serum, and vessel wall PGI2 production by measuring its stable metabolite, immunoreactive 6-keto-prostaglandin F1 alpha in plasma. The TxA2 production (initially 209.0 +/- 27.1 ng/ml, mean +/- s.e. mean) decreased to about 30% from the second day of the treatment onwards, and it recovered in three days after the discontinuation of the treatment. PGI2 (initially 33.6 +/- 3.6 pg/ml) did not change. The shift of the balance between TxA2 and PGI2 to the dominance of antiaggregatory PGI2 during sulphinpyrazone treatment may be involved with the efficacy of the drug in the secondary prevention of myocardial infarction.     

Advance in understanding the biosynthesis of prostacyclin and thromboxane A2 in the endoplasmic reticulum membrane via the cyclooxygenase pathway

Recent advances in topological and structural characterization of the prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)) synthases have led to the understanding of the biosynthesis of PGI(2) and TXA(2) at a structural level. This mini-review focuses on the molecular mechanism of the isomerization of the prostaglandin H(2) to PGI(2)and TXA(2) by their synthases in the endoplasmic reticulum (ER) membrane coordinated with cyclooxygenase-1 or -2. This review summarizes the evidences in which the biosynthesis of PGI(2)and TXA(2) are influenced/modulated by the membrane anchor residues of the synthases and the ER membrane itself, and provides the structural basis for engineering the synthases for the next generation of gene therapy and drug designs targeting the specific synthases.     

Delta-opioid receptor activation mimics ischemic preconditioning in the canine heart

The role of delta-opioid receptors in mediating ischemic preconditioning (IPC) in rats, rabbits, and pigs has been well-established; however, no studies have been performed in dogs. Therefore, the purpose of the present study was to determine if activation of delta-opioid receptors can mimic the cardioprotective effects of IPC in the canine heart and to determine if a nonselective opioid receptor antagonist could block IPC. All dogs were subjected to 60 minutes of left anterior descending (LAD) coronary artery occlusion and 3 hours of reperfusion. Ischemic preconditioning was produced by one 5-minute period of ischemia 10 minutes before LAD coronary artery occlusion. Infarct size (IS) expressed as a percent of the area at risk (AAR; IS/AAR) was determined by triphenyltetrazolium staining. Two selective delta-opioid receptor (DOR) agonists, TAN-67 and BW373U86, were administered by intracoronary infusion for 30 minutes before LAD occlusion and the opioid receptor antagonist naloxone was administered 30 minutes before IPC. Both TAN-67 and BW373U86 produced significant reductions in IS/AAR similar to that of IPC (control: 28+/-2.1; TAN: 12.3+/-2.2; IPC: 9.3+/-3.0: BW: 11.7+/-2.6). Naloxone attenuated the effect of IPC (control: 28+/-2.1; naloxone: 18.2+/-4.5). These results suggest that opioid receptors are important in IPC in dogs, and stimulation of delta-opioid receptors with selective agonists can mimic the cardioprotective effects of IPC and may have therapeutic potential.     

Roles of brain prostaglandin E2 and thromboxane A2 in the activation of the central sympatho-adrenomedullary outflow in rats

This study addressed the question whether proximal and distal guinea pig tracheal segments respond differently to contractile agents. Using a perfused trachea set-up, histamine, KCl or the cyclo-oxygenase inhibitor, indomethacin, could be administered selectively to the mucosa (at the inside) or the serosa (at the outside) of the tracheal segments. Proximal parts contracted significantly more (40-60%) than distal parts when 1 mM histamine was administered to the mucosal or serosal side or when KCl (50 mM) was added to the serosal side. When histamine was administered to the mucosal side of epithelium-denuded segments, the contractions were twice as high in proximal than in distal parts (3057 vs. 1526 mg). Inhibition of tracheal cyclo-oxygenase with indomethacin at the mucosal side increased proximal and distal reactivity to mucosally administered histamine to the same extent. Serosal administration of indomethacin, however, increased histamine reactivity only in proximal segments (from 2690 to 5180 mg). In the latter segments, subsequent administration of histamine to the serosal side further increased the contraction, while serosal histamine in the absence of serosal indomethacin produced a relaxation (net difference of 4672 mg). In conclusion, the higher intrinsic contractility of proximal tracheal segments is counteracted by serosal cyclo-oxygenase products.     

Imbalanced synthesis of cyclooxygenase-derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome

BACKGROUND AND PURPOSE: Thoracic aortic dissection is a life-threatening complication of Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1. We have demonstrated that nitric oxide-mediated endothelial-dependent relaxation is impaired in the thoracic aorta in Marfan syndrome. In the present study, we determined whether the cyclooxygenase (COX)-pathway is involved in the compromised aortic vasomotor function. EXPERIMENTAL APPROACH: Thoracic aortae from mice at 3, 6 and 9 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), 'Marfan', n=35), were compared with those from age-matched controls (n=35). KEY RESULTS: Isometric force measurement revealed that preincubation with indomethacin, a non-specific COX inhibitor, but not valeryl salicylate, a specific COX-1 inhibitor, improved the phenylephrine-induced contractions (at 6 months, EC(50) and E(max) were increased 4.5-fold and by 45%, respectively) in Marfan aortae. Sensitivity to acetylcholine-induced relaxation was improved 10-fold. Blockade of the thromboxane-endoperoxide receptor by SQ-29548 did not affect phenylephrine-mediated contractions in Marfan aortae, although they did respond to the thromboxane analogue, U46619. From 6 months on, phenylephrine-induced secretion of prostacyclin and thromboxane A(2) in Marfan aortae was 200% and 40%, respectively, of those in controls. Reduced COX-1 expression was detected in Marfan aortae at 3 and 9 months, whilst COX-2 expression was increased from 3 months on. CONCLUSIONS AND IMPLICATIONS: The compromised vasomotor function in Marfan thoracic aortae is associated with an imbalanced synthesis of thromboxane A(2) and prostacyclin resulting from the differential protein expression of COX-1 and COX-2.     

New developments on thromboxane and prostacyclin modulators part II: prostacyclin modulators

Prostacyclin (PGI(2)) is a potent endogenous inhibitor of platelet function and possesses a strong vasodilator effect. Furthermore, prostacyclin is currently presented as the physiologic antagonist of thromboxane A(2)(TXA(2)), which exhibits pro-aggregatory and vasoconstrictor properties. So, the balance between PGI(2) and TXA(2) production is crucial for the cardiovascular system. Indeed, an imbalance in the production or effect of these products is deleterious for the circulatory system and can lead to characterized vascular diseases such as hypertension, stroke, atherosclerosis or myocardial infarction. Although the biological effects of PGI(2) are considered to be clinically useful, its use as therapeutic agent is largely limited by both its chemical and metabolic instability. Actually, several prostacyclin agonists have been synthesized and pharmacologically evaluated. Among these, some have been clinically evaluated as therapeutic agents in several vascular diseases. This review focuses on the latest chemical and pharmacological developments in the field of the prostacyclin agonists.     

Drug interactions with the in vivo synthesis of thromboxane and prostacyclin

The biosynthesis and metabolic degradation of thromboxane and prostacyclin are briefly described with particular emphasis on the peculiarities of the enzymes involved. This is of great importance for the understanding of this system and for proper interpretation of experimental data. The requirements for adequate methodology in studies designed to assess the in vivo synthesis of those prostanoids are discussed. The characteristics of the thromboxane-prostacyclin system in normals are presented in detail with particular emphasis on those facets of importance for interpretation of literature data, like the diurnal variation, the large interindividual variation etc. The present status of knowledge about the involvement of this system in various cardiovascular diseases as well as the interaction of drugs of various types with the in vivo synthesis of those prostanoids is reviewed in detail.     

低分子肝素对肾病综合征大鼠血栓素A2及前列环素表达的影响

目的探讨低分子肝素(LMWH)对肾病综合征(NS)大鼠肾脏保护作用的可能机制。方法将雄性SD大鼠随机分为正常对照组、肾病综合征模型组、肾病综合征模型加低分子肝素治疗组,分别于2、3、4周留取24 h尿,测定尿蛋白,并离心沉淀备测血栓素A2(TXA2)和前列环素(PGI2),同时腹主动脉取血测定血清白蛋白。结果肾病综合征大鼠尿中TXA2明显增加,随病变发展逐渐升高。而PGI2没有明显变化。LMWH治疗后尿中PGI2浓度升高,24 h尿蛋白减少,血清白蛋白升高。结论LMWH可增加NS大鼠尿中PGI2浓度,纠正TXA2/PGI2比值失衡,是其保护肾脏的可能机制之一。     

川芎嗪对慢性低氧和高二氧化碳致大鼠肺动脉高压及TXA2和PGI2的影响

目的 研究川芎嗪对慢性低O2和高CO2致大鼠肺动脉高压及TXA2和PGI2的影响。方法 30只SD大鼠分为正常对照组（A组）,4wk低O2高CO2组（B组）,4wk低O2高CO2＋川芎嗪组（C组）,观察川芎嗪对慢性低O2高CO2大鼠肺动脉平均压（mPAP)、颈动脉平均压（mCAP)、肺动脉显微和超微结构、血浆TXB2及6-keto-PGF1α浓度的影响。结果（1）B组mPAP明显高于A组（P＜0．01）,C组mPAP明显低于B组（P＜0．01）,三组间mCAP无明显差异（P＞0．05）;（2）光镜下,肺细小动肺管壁面积／管总面积比值（WA／TA）、肺细小动脉中膜平滑肌细胞密度（SMC）B组较A组明显增高（P均＜0.01),C组WA／TA、SMC较B组明显降低（P均＜0.01),电镜下,B组肺细小动脉中膜平滑肌细胞增生,面积增大,染色质增多,外膜胶原纤维密集,C组大集肺细小动脉中膜平滑肌细胞和外膜胶原纤维增生较B组明显减轻;（3）B组TXB2较A组明显增高（P＜0.01),C组TXB2较B组明显降低（P＜0.01),6-keto-PGF1α三组间无显性差异（P＞0.05),B组TXB2／6－keto-PGF1α比值较A组明显增高（P＜0.01),C组TXB2／6－keto-PGF1α比值较B组明显降低（P＜0.01)。结论 川芎嗪抑制TXA2合成可能为其抑制慢性低O2和高CO2性肺动脉高压及肺血管结构重建的作用机制之一。     

5-Hydroxytryptamine stimulates the release of prostacyclin but not thromboxane A2 from isolated rat dental pulp

The effect of 5-hydroxytryptamine (5-HT) on the release of prostacyclin and thromboxane (TX) A2 from isolated rat dental pulp was evaluated. 5-HT (1-1,000 microM) caused a dose-dependent and marked stimulation of the release of prostacyclin but not TXA2. Of the 5-HT-related indolealkylamines tested, only tryptamine had a similar stimulatory effect while tryptophan and 5-hydroxytryptophan had no effect. Neither histamine (100 microM) nor bradykinin (100 microM) had such an effect. Our results suggest the possible involvement of 5-HT receptors in 5-HT-induced stimulation of prostacyclin production in rat dental pulp.     

当归注射液对冠心病患者血浆前列环素、血栓素 A_2 及血小板聚集的影响

２４例冠心病患者静脉滴注当归注射液治疗后，血浆６－酮－前列腺素Ｆ１α（６－Ｋ）、６－Ｋ／血栓素Ｂ２（ＴＸＢ２）和ＴＸＢ２、血小板最大聚集率均分别显著高于和低于治疗前水平。结果表明，当归注射液有调节前列环素－血栓素Ａ２平衡和抑制血小板聚集的作用。     

Effects of nonsteroidal anti-inflammatory drugs on prostacyclin and thromboxane in the kidney

Dose-response curves were obtained relating the effects of increasing amounts of aspirin, a nonselective cyclooxygenase (COX) inhibitor, and celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, on the concentrations of prostacyclin and thromboxane in renal cortex and medulla of rabbits. The concentrations of the two agonists (aspirin and celecoxib) which elicit a half-maximal response on the prostanoid concentration (EC(50)) were compared. Additionally, controls for prostacyclin and thromboxane were related to values for the experimental groups. The EC(50) values for celecoxib were considerably lower than those for aspirin, indicating that celecoxib was more effective in suppressing prostanoid production. There were also significant differences between the majority of experimental groups and their respective controls, further evidence for the greater inhibitory activity of celecoxib on prostacyclin. Celecoxib lowered the ratio prostacyclin/thromboxane in the renal medulla; mercuric chloride further diminished the concentration of prostacyclin in the renal medulla. The results confirm that in the normal rabbit kidney, both nonselective and specific COX inhibitors interfere with renal prostanoid synthesis, but that a selective COX-2 inhibitor is more effective.     

Effects of S-adenosyl-L-methionine on platelet thromboxane and vascular prostacyclin

We therefore designed the present study to evaluate the effect of S-adenosyl-L-methionine (SAMe) on the synthesis of platelet thromboxane and vascular prostacyclin. The experimental materials were human blood and aortic rings from untreated Wistar rats; and platelets and aortic rings from Wistar rats treated for 7 days with SAMe at 5 or 10 mg/kg/day s.c. The administration of 10 mg/Kg/day of SAMe to rats significantly increased vascular production of 6-keto-PGF_1α. In vitro vascular production of 6-keto-PGF_1α increased in a concentration-dependent manner when SAMe was incubated in the range of 10⁻⁷ to 10⁻⁴ M. The greatest increase was 167 ± 15%, obtained in samples incubated with 5 × 10⁻⁵M SAMe. In aortic rings, lipid peroxidase production was inhibited in a concentration-dependent manner in the SAMe range of 10⁻⁷ to 10⁻⁵ M. Maximum inhibition (75.3 ± 6.2%) was obtained with SAMe at 1.5 × 10⁻⁵M. Vascular 6-keto-PGF_1α production showed a significant inverse linear correlation with vascular lipid peroxide production (Y = −0.04 × + 18.1, r = 0.7309, P < 0.0001).     

Effects of the new thromboxane A2 antagonist vapiprost on isolated canine blood vessels.

Effects of the new thromboxane A2 antagonist vapiprost (SN-309, GR-32191B, CAS 85505-64-2) on isolated canine blood vessels were investigated. U46619 ((15S)-hydroxy-11a, 9a-(epoxymethano) prosta-5Z, 13E-dienoic acid) 10(-10)-10(-6) mol/l, a thromboxane A2 analogue, produced concentration-dependent contractions of oblong or ring preparations isolated from basilar, coronary, mesenteric and femoral arteries. Vapiprost 10(-8) and 10(-7) mol/l significantly and concentration-dependently shifted the concentration-contraction curves for U46619 of these arteries to the right. The pA2 values were 8.80 +/- 0.09 in basilar arteries, 8.67 +/- 0.12 in coronary arteries, 8.86 +/- 0.05 in mesenteric arteries and 9.01 +/- 0.07 in femoral arteries. On the other hand, oblong or ring preparations of basilar, coronary, mesenteric and femoral arteries showed sustained contractile responses to KCl 3 x 10(-2) mol/l, U46619 10(-7) mol/l or prostaglandin (PG) F2 alpha 10(-5) mol/l. Norepinephrine (NE) 3 x 10(-5) mol/l also produced sustained contractions in mesenteric and femoral arterial preparations, but not in basilar and coronary arterial preparations. Vapiprost 10(-10)-3 x 10(-6) mol/l relaxed these four arterial preparations constricted with U46619 10(-7) mol/l and PGF 2 alpha 10(-5) mol/l in a concentration-dependent fashion, but hardly affected them constricted with KCl 3 x 10(-2) mol/l. NE 3 x 10(-5) mol/l-induced contractures of mesenteric and femoral arterial preparations were not influenced by any concentrations of vapiprost. Results indicate that vapiprost has an antagonistic action on a so-called TP-receptor and/or a vasoconstrictive prostaglandin(s)-receptor and thus produces vasorelaxation.