Stable Analogue Of Thromboxane A2 Research Articles

Indomethacin in vivo increases the sensitivity to Listeria infection in mice. A possible role for macrophage thromboxane A2 synthesis.

This paper demonstrates that in the presence of indomethacin, a cyclooxygenase inhibitor, 100% of the mice died when infected with live Listeria, whereas none of the animals died in the absence of the drug. The death of the animals correlated with the numbers of bacteria found extraperitoneally in the spleen and not with the Ia expression of the peritoneal macrophages. Increases in the spleen bacterial numbers between mice treated with either indomethacin or a specific thromboxane synthase inhibitor, OKY1581, and those not receiving either drug, were found as early as 2-4 h after infection. The differences in the initial increased bacterial spleen counts in the presence of indomethacin were reversed by administration of a stable thromboxane A2 analog or another potent vasoconstrictor, phenylephrine. Because thromboxane A2 does not regulate macrophage or T cell functions directly (Tripp, C.S., A. Wyche, E.R. Unanue, and P. Needleman, 1986, J. Immunol., In press; and Ceuppens, J.S., S. Vertessen, H. Deckmyn, and J. Vermylen, 1985, Cell Immunol., 90:458-463), but is probably generated at the site of an infection (Tripp, C.S., K.M. Leahy, and P. Needleman, 1985, J. Clin. Invest., 76:898-901), these data suggest an important role for the vasoconstrictive properties of thromboxane A2 in the regulation of immunity to Listeria infection.

Effects of administered thromboxanes on the intact, normal rat kidney.

The effects of administered thromboxanes on the intact, normal rat kidney were studied. Euvolemic male rats received intraarterial infusions of thromboxane B2 (TXB2) and the stable thromboxane A2 analog (U46619) and the effects on renal function were investigated, using glomerular micropuncture and whole-kidney clearance techniques. Both TXB2 and U46619 were renal vasoconstrictors and lowered GFR by reducing renal plasma flow rate; U46619 was much more potent that TXB2. Neither agent caused any marked change in the glomerular capillary ultrafiltration coefficient (Kf). Thus in the rat, the thromboxanes reduce filtration rate by increasing renal vascular resistance and without exerting a marked influence on Kf.

P-215 - Effects of prostacyclin(PGI2), a stable analogue of thromboxane A2(STA2) and indomethacin on myocardial ischemia in isolated perfused rat heart, as studied with 31P-NMR

P-215 - Effects of prostacyclin(PGI2), a stable analogue of thromboxane A2(STA2) and indomethacin on myocardial ischemia in isolated perfused rat heart, as studied with 31P-NMR

Effect of repeated antigen exposure on antigen-and mediator-induced bronchospasm in sheep.

We studied the effects of repeated exposures of antigen on airway reactivity to mediators of anaphylaxis and immediate response to the antigen. Seven antigen-sensitive sheep were exposed to aerosols of Ascaris suum antigen 5 times biweekly; a control group of seven sheep underwent the same exposure regimen with saline vehicle. Sheep were assigned to experimental (Ascaris) or control groups so the distribution of animals with regard to bronchial reactivity to mediators was about the same. Airway reactivity was assessed by determining the effects of aerosolized histamine (10-1,000 micrograms), prostaglandin F2 alpha (PGF2 alpha, 10-300 micrograms), and a stable analogue of thromboxane A2 (U-46619, 1-100 micrograms) on lung resistance (RL) and dynamic lung compliance (Cdyn). Before treatment, experimental and control groups showed similar changes in RL and Cdyn, with analogue greater than histamine greater than PGF2 alpha. At the highest dose of each agonist, mean increases in RL were 50, 123, and 29%, respectively, and mean decreases in Cdyn were 21, 45, and 12%. During the first 15-min exposures to antigen aerosol, mean RL had increased by 125% and Cdyn decreased by 38% of base-line values; hyperinflation following the exposures reduced the changes to 56 and 31%, respectively. Changes in RL and Cdyn during the final antigen exposures and following postexposure hyperinflation were reduced significantly (P less than 0.05) compared with the initial exposures. Baseline RL and Cdyn before and after the exposures to antigen or saline were not significantly different. Airway reactivity to histamine, PGF2 alpha, or analogue was not significantly altered in these atropinized animals over the range of doses studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine-induced spasm not significantly modulated by prostanoids in a swine model of coronary artery spasm

The role of prostanoids in a swine model of coronary artery spasm was examined. Eighteen miniature pigs underwent endothelial denudation of the left coronary artery (left circumflex branch in 14 pigs and left anterior descending branch in 4 pigs) followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the vasoconstrictive effect of thromboxane A2 and the preventive effects of indomethacin and prostacyclin against histamine-induced coronary artery spasm were examined. Intracoronary administration of thiothromboxane A2, 200 micrograms, a stable thromboxane A2 analog, failed to provoke coronary artery spasm (seven of seven cases) but nonselectively constricted the coronary artery by 33%. Intravenous administration of indomethacin, 2 mg/kg, or continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm (four of four and eight of eight cases, respectively), yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine model, prostanoids may not play a primary role in the occurrence of coronary artery spasm.

Ｅｌａｓｔａｓｅの血小板凝集および血小板アラキドン酸代謝に及ぼす影響について

We studied ex vivo and in vitro effects of elastase on platelet aggregation and its arachidonic acid (AA) metabolism in normal aubjects. Aggregation of platelets in citrated plasma (PRP aggregation) and of washed platelets were nephelometrically studied and whole blood aggregation by the impedance method was also determined. Elastase showed the significant inhibitory effects on PRP aggregation induced by collagen (0.5μg/ml) and AA (increase in its threshold concentration) as well as on whole blood aggregation by collagen (2.0μg/ml) after its oral administration of 10, 800 units per day for a week in 8 volunteers. Plasma prostacyclin-regenerating activities were not affected throughout. In in vitro experiments, elastase inhibited washed platelet aggregation induced by AA, collagen and thrombin, and PRP aggregation induced by ADP, epinephrine and STA2 (a stable analog of thromboxane A2) was also inhibited. Elastase decreased TX B2 production by platelets incubated with collagen or thrombin as measured by a radioimmunoassay, but failed to inhibit its production by exogenous AA.Thus, it was demonstrated that elastase inhibited platelet aggregation in certain conditions ex vivo as well as in vitro and its mechanism seemed to be due to some inhibitory effects on the platelet membrane rather than through the inhibition of cyclo-oxygenase activities.

Protection of ischemic cat myocardium by CGS-13080, a selective potent thromboxane A2 synthesis inhibitor.

A specific inhibitor of thromboxane A2 (TxA2) synthesis, CGS-13080, was studied during acute myocardial ischemia (MI) in cats. To define more clearly the mechanism of action of CGS-13080, we also studied it effects on isolated cat coronary arteries, in vitro aggregation of cat platelets, and production of thromboxane B2 (TxB2) from cat platelet-rich plasma (PRP). MI cats that received the vehicle for CGS-13080 exhibited a significant increase in plasma concentration of TxB2. This was accompanied by increases in the ST segment of the electrocardiogram, specific activity of plasma creatine kinase (CK), and loss of CK activity and amino-nitrogen from the ischemic myocardium. In contrast, TxB2 concentrations, plasma and tissue CK activities, and myocardial amino-nitrogen concentration of MI cats treated with CGS-13080 were not significantly different from those in sham MI cats that had received the drug. In vitro, CGS-13080 did not inhibit contraction of cat coronary arteries produced by a stable TxA2 analog and did not inhibit aggregation of cat PRP indiced by arachidonic acid (AA). However, production of TxB2 by cat platelets treated with AA was completely inhibited by this agent. Thus, specific inhibition of TxA2 synthesis without thromboxane receptor antagonism can exert a protective effect on the myocardium during ischemia in cats.

Platelet Aggregation and Exposure of Fibrinogen Receptors by Prostaglandin Endoperoxide Analogues

Two stable analogues of prostaglandin endoperoxides—9.11-azo-prostanoid III (9-11-azo PGH2) and 9,11-methanoepoxy PGH2 (U46619 compound)—caused aggregation of washed human platelets and release of α-granule contents. Platelet aggregation induced by these compounds was potentiated by the addition of purified human fibrinogen in a dose-dependent manner. Incubation of prostaglandin endoperoxide analogues with washed platelets in a nonstirred system exposed fibrinogen receptors. Enzymes that remove adenosine diphosphate (ADP) [apyrase and creatine phosphate in the presence of creatine Phosphokinase (CP/CPK)], adenosine triphosphate (ATP), a competitive antagonist of ADP, and 5' parafluorosulfonylbenzoyl adenosine (FSBA), an affinity label for ADP binding sites, all blocked platelet aggregation and binding of 125I-fibrinogen to platelets stimulated by prostaglandin endoperoxide analogues. In contrast, these compounds did not prevent platelet shape change induced by prostaglandin endoperoxide analogues. Apyrase, CP/CPK. ATP, and FSBA reversed platelet aggregation stimulated by ADP or prostaglandin endoperoxide analogues. Carbocyclic thromboxane-A2 (CTA2), a stable analogue of thromboxane-A2, blocked shape change and platelet aggregation and caused disaggregation of platelets stimulated by prostaglandin endoperoxide analogues. However, CTA2 did not inhibit ADP-induced platelet shape change and aggregation, and it did not disaggregate platelets that were previously aggregated by ADP. The mechanism of platelet aggregation induced by analogues of prostaglandin endoperoxides appears to involve (A) initial release of ADP and fibrinogen, (B) ADP-induced exposure of platelet membrane fibrinogen receptors, and (C) fibrinogen binding to the exposed receptors resulting in platelet aggregation. The occupation of prostaglandin endoperoxide receptors is required during all stages of this process.

Dissociation of vasoconstrictor and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analog of thromboxane A2.

Carbocyclic thromboxane A2 [2 beta (Z),3 alpha- (1E,3R*)-3-(3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid], a stable analog of thromboxane A2, has been tested for its physiologic properties. Carbocyclic thromboxane A2 is a potent coronary vasoconstrictor, stimulating cornonary vascular smooth muscle at concentrations as low as 29 pM. At 1-5 micro M it is also an inhibitor of arachidonic-acid- and endoperoxide-induced aggregation of platelets. At 200 nM it stimulated the release of lysosomal hydrolases from large granule fractions of liver homogenate. It inhibited thromboxane synthesis in platelets, although it did not inhibit synthesis of prostacyclin in ram seminal vesicles. Thus, carbocyclic thromboxane A2, a molecule closely related to thromboxane A2, separates coronary vasoconstrictor from platelet-aggregating activity. The constrictor activity predominates in vivo; carbocyclic thromboxane A2 induces coronary vasoconstriction leading to myocardial ischemia and sudden death in rabbits in the absence of pulmonary or coronary thrombosis.