Search PubMed⌕ Search

Biomedical subjects

S Moncada

Publications and source records attributed to S Moncada.

At least 379 records · Page 21Linked to original sources
PubMed1984

The use of stable prostaglandins to investigate prostacyclin (PGI2)-binding sites and PGI2-sensitive adenylate cyclase in human platelet membranes.

Prostacyclin, (PGI2) is a potent but unstable inhibitor of platelet aggregation, probably acting through stimulation of adenylate cyclase. A stable analogue of prostacyclin with antiaggregatory properties, 5,6-dihydro-PGI2 (6 beta-PGI1), and PGE1 can compete for the binding sites labelled by 3H-PGI2 in human platelet membranes (the affinity being PGI2 greater than PGE1 greater than 6 beta-PGI1). Both 6 beta-PGI1 and PGE1, as well as PGI2, bind to two classes of binding sites. 6 beta-PGI1 and PGE1 activate adenylate cyclase to the same extent as PGI2, with a rank order of potency which parallels that observed in binding experiments. The stimulation of this enzyme is brought about by interaction of each of these prostanoids with two different classes of components. The comparison of binding and adenylate cyclase data suggests that the sites to which PGI2, 6 beta-PGI1 and PGE1 bind might be coupled to the activation of adenylate cyclase. Since 6 beta-PGI1 seems to act through the same molecular mechanisms as PGI2, because of its stability it is an useful tool to investigate the mode of action of prostacyclin in platelets.

Adenylyl Cyclases↗
PubMed1984

Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C.

The effects of three anti-inflammatory drugs, which interfere with arachidonic acid transformation by three different enzymes, have been compared by using a simple model of tissue damage and foreign body rejection. In groups of control rats, subcutaneously implanted polyester sponges were rejected after a mean of 12 days. Indomethacin, which selectively inhibits prostaglandin synthesis, did not significantly change time to rejection but BW755C (3-amino-1-[m-(trifluoromethyl) phenyl]-2-pyrazoline), which is a dual inhibitor of prostaglandin and leukotriene synthesis, prolonged time to rejection to a mean of 22 days. The anti-inflammatory steroid dexamethasone, which reduces arachidonic acid metabolism by stimulating the formation of a phospholipase inhibitor, prolonged time to sponge rejection as BW755C did. Treatment with BW755C or dexamethasone was also accompanied by a reduction in total leukocyte numbers in inflammatory exudates collected at 1-14 days, whereas indomethacin increased leukocyte migration on days 1 and 2 and had no effect at later times. These results suggest that the inhibition of the leukotriene-forming lipoxygenase suppresses leukocyte activation and that this leads to a reduced rate of tissue damage in experimental inflammation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Role of leukocytes in acute myocardial infarction in anesthetized dogs: relationship to myocardial salvage by anti-inflammatory drugs.

The invasion of leukocytes into and around a myocardial infarct was studied in chloralose-anesthetized dogs subjected to 1-hr occlusion of the left anterior descending coronary artery and reperfused for periods up to 5 hr. Polymorphonuclear leukocytes adhering to the endothelium of blood vessels within the ischemic area are evident at the end of the occlusion period. During reperfusion, the leukocytes migrate into the myocardium and large groups of cells can be observed "streaming" toward the irreversibly damaged area after 5 hr reperfusion. Infarcted tissue produces 10 times more 12-hydroxyeicosatetraenoic acid (a metabolite attributed to the invading leukocytes) from arachidonic acid than adjacent "normal" areas of the ventricle. BW755C (10 mg/kg-1 i.v.), which inhibits both the lipoxygenase and cyclooxygenase pathways of arachidonic metabolism, attenuates leukocyte infiltration into the infarcted myocardium, prevents 12-hydroxyeicosatetraenoic acid formation and significantly reduces infarct size (P less than .005). BW755C also significantly diminishes the incidence of cardiac arrhythmias during infarction. In animals where circulating white cells are reduced 60% by treatment with hydroxyurea (20 mg/kg-1 i.v./day for 5 days), there is also a smaller infarct (P less than .01). Indomethacin (5 mg/kg-1 i.v.) and dexamethasone (0.2 mg/kg-1 i.v.), which do not affect leukocyte migration into the ischemic myocardium, do not reduce infarct size. It is proposed that migrating leukocytes contribute to the tissue injury accompanying myocardial ischemia, possibly by the release of proinflammatory mediators such as lipoxygenase products, free radicals (oxygen metabolites) and hydrolytic enzymes. Drugs which reduce the migration and/or activation of leukocytes may be useful in reducing infarct size.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1983

The effect of cyclo-oxygenase and thromboxane synthetase inhibitors on shock induced by injection of heterologous blood in cats.

The injection of rabbit blood into cats causes hypotension, thrombocytopaenia, leukopaenia, a rise in central venous pressure and right ventricular and pulmonary artery pressures and a fall in circulating levels of fibrinogen. Death occurred rapidly after injection of the rabbit blood in 50% of control animals and was associated with respiratory distress. Measurement of plasma thromboxane B2 and 6-oxo PGF1 alpha levels in surviving controls demonstrated a marked elevation in the former with no significant change in the latter. Pretreatment with either the thromboxane synthetase inhibitor, 1-(cyclo octyl methyl) imidazole or aspirin prevented respiratory distress and death and reduced or prevented the elevations in cardiovascular pressures observed in control animals. Neither compound prevented thrombocytopaenia or leukopaenia but did attenuate the rise of thromboxane B2 following injection of rabbit blood. In addition, pretreatment with 1-(cyclo octyl methyl) imidazole resulted in an approximately five-fold increase in circulatory levels of 6-oxo PGF1 alpha five minutes after inducing the shock. We conclude that thromboxane A2 plays an important role in pulmonary (and other organs) dysfunction during the shock induced by injection of heterologous blood. In addition we have shown that inhibition of thromboxane synthetase in vivo under conditions where thromboxane A2 is produced leads to an increase in the synthesis of prostacyclin.

Animals↗
PubMed1983

The release of leukotriene B4 during experimental inflammation.

Leukotriene B4 (LTB4) has been detected by radioimmunoassay in inflammatory exudates obtained following the implantation of saline- or carrageenan-soaked polyester sponges in rats. The immunoreactive material was confirmed as LTB4 after extraction and purification by high pressure liquid chromatography. The peak concentration (6.9 +/- 0.5 ng/ml) was detected 6 hr after implantation of sponges soaked in 0.5% carrageenan; thereafter the level declined and was undetectable after 16-24 hr. The concentration of LTB4 during the early phase of the inflammatory response (4-8 hr) is sufficient to induce leukocyte aggregation, chemotaxis and degranulation of polymorphonuclear leukocytes (PMN) in vitro. Therefore, LTB4 may mediate, at least in part, the influx of PMN and contribute to other events which characterise the inflammatory response. The level of thromboxane B2 (TXB2) in the inflammatory exudate followed a similar time-course to that of LTB4 although the maximum concentration was higher (15-30 ng/ml). However, prostaglandin E2 (PGE2) exhibited a different time-course; the maximum level (20-30 ng/ml) was also reached 6-8 hr after implantation but remained elevated at 24 hr. The PMN count in the sponges and the concentrations of both LTB4 and TXB2, but not PGE2, were significantly reduced by prior treatment of the animals with colchicine. This suggests that PMN are the major source of LTB4 and TXB2 in the inflammatory exudate whereas PGE2 is produced in significant amounts by other tissues.

Animals↗
PubMed1983

Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue.

The platelet anti-aggregating, cardiovascular and gastro-intestinal actions of a hydantoin prostaglandin analogue, BW245C have been compared with prostacyclin and PGD2 in several species. In human plasma in vitro, BW245C was 0.2 times as active as prostacyclin and 8 times as active as PGD2 in inhibiting platelet aggregation. In rat and rabbit plasma, BW245C was only weakly active but was more potent in sheep and horse plasma. Since the activity of PGD2 varied in a parallel fashion, BW245C may interact with PGD2 binding sites on platelets. The potency of BW245C as a vasodepressor also varied between species, being 0.5, 0.1, 0.06 and less than 0.02 times as active as prostacyclin in the anaesthetised dog, monkey, rat and rabbit respectively. The relative activity of BW245C as an inhibitor of platelet aggregation ex vivo was more comparable, being 0.08, 0.04 and 0.05 times as active as prostacyclin following intravenous infusion in the rabbit dog and monkey respectively. In the rabbit, BW245C was a highly selective platelet inhibitor with minimal cardiovascular actions, whereas in the dog and monkey, BW245C lowered BP in anti-aggregating doses. The potent platelet anti-aggregating actions of BW245C following parenteral or oral administration makes this hydantoin a potentially-useful anti-thrombotic prostaglandin analogue.

Animals↗
PubMed1983

The source of thromboxane and prostaglandins in experimental inflammation.

Although cyclo-oxygenase products have been detected at inflammatory sites the tissue of origin remains uncertain. Inflammatory exudates were collected from rats 4, 6, 8, 12 or 24 h after subcutaneous implantation of carrageenin-impregnated sponges. Concentrations of the cyclo-oxygenase products prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) in inflammatory exudates and serum (obtained from blood clotted at 37 degrees C) were measured by specific radioimmunoassays. TXB2 concentrations in exudates increased to about 100 ng ml-1 at 8 h but decreased to less than 20 ng ml-1 after 24 h. PGE2 concentrations increased from 4-12 h and remained between 80 and 120 ng ml-1 from 12-24 h. 6-oxo-PGF1 alpha had the same time course as that of PGE2 but concentrations were approximately one third of PGE2 values. TXB2 concentrations in serum from thrombocytopaenic rats were less than 5% of control values. Thrombocytopaenia did not affect TXB2, PGE2 or 6-oxo-PGF1 alpha concentrations or total leukocyte numbers in inflammatory exudates. Methotrexate-induced neutropaenia did not affect serum TXB2 concentrations but cyclo-oxygenase products (including TXB2) in 6 h inflammatory exudates were reduced by 60-95%. Colchicine (1.0 mg kg-1 s.c.) prevented leukocyte accumulation in sponge exudates and this was accompanied by a reduction in TXB2, PGE2 and 6-oxo-PGF1 alpha concentrations at 6 h. These results indicate that platelets are the source of TXB2 in clotting blood but do not contribute to cyclo-oxygenase activity in experimental inflammation. The results also suggest that migrating leukocytes are the major source of thromboxane and to a lesser degree prostaglandins in acute 6 h inflammatory exudates.

Animals↗
PubMed1983

The effects of BW755C and other anti-inflammatory drugs on eicosanoid concentrations and leukocyte accumulation in experimentally-induced acute inflammation.

BW755C (3-amino-1-[m-trifluoromethyl)phenyl]-2-pyrazoline HCl) reduced the concentration of leukotriene B4 (LTB4), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) in exudate derived from the subcutaneous implantation in rats of 0.5% carrageenan-impregnated polyester sponges. Polymorphonuclear leukocyte (PMN) migration into the inflammatory exudate was also decreased. The inhibition of LTB4 may, in part, account for the lower number of cells in the exudate since LTB4 is a potent leukotactic agent. Inhibition of LTB4-formation and cell migration by BW755C was dose-related, but the two dose-response curves were not parallel. Cell influx still occurred at doses of BW755C that completely inhibited formation of LTB4: this indicates that, although LTB4 may have a chemotactic role in-vivo, other factors must also contribute to cell migration into the inflammatory exudate. Treatment of rats with dexamethasone also caused a reduction in leukocytes and eicosanoids in the exudate. As with BW755C, there was a differential effect on PMN and LTB4: dexamethasone (1 mg kg-1) reduced PMN accumulation by 40% but LTB4 formation was inhibited by 70%. Leukocyte accumulation was also inhibited by the non-steroidal anti-inflammatory drugs (NSAID's), indomethacin and flurbiprofen. These drugs reduced the concentration of both PGE2 and TXB2 in exudate but that of LTB4 was unchanged. This suggests that reduction of PMN accumulation by indomethacin and flurbiprofen is mediated by a mechanism other than inhibition of LTB4-synthesis. Aspirin also reduced the levels of PGE2 and TXB2 in the exudate but did not consistently affect PMN influx, thereby confirming that inhibition of cyclo-oxygenase does not reduce cell migration in inflammation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1982

The interactions of platelet-derived mediators on isolated canine coronary arteries.

The interactions of 5-hydroxytryptamine (5-HT) and a thromboxane A2 mimetic, U44069, were investigated on rings of canine coronary arteries. 5-HT (10(-8) - 10(-5) M) and U44069 (10(-9) - 10(-6) M) produce coronary vasoconstriction which is potentiated by indomethacin (3 X 10(-6) M). In the presence of 10(-9) M 5-HT, U44069-induced vasoconstriction is enhanced. Similarly, 10(-9) M U44069 enhances the effects of 5-HT. In both cases this potentiation is greatest in the presence of indomethacin. Synergism between the platelet-derived mediators could contribute to coronary vasospasm and myocardial ischaemia.

Animals↗
PubMed1982

Prostacyclin prolongs viability of washed human platelets.

The functional viability of stored human platelets, washed in the presence and absence of prostacyclin, was examined over a 96 h period. Platelet counts, aggregation responses and cyclic AMP levels were monitored as well as the spontaneous generation of thromboxane B2 and the liberation of labelled oleate from cellular phosphatides. In suspensions prepared without prostacyclin in the medium, platelet counts declined rapidly as did the sensitivity to aggregating agents. In addition, substantial amounts of thromboxane B2 were generated during preparation and storage and oleate liberation occurred at a rapid rate. In contrast, in prostacyclin-washed platelets, aggregation was maintained throughout the study period and there was little generation of thromboxane B2. Moreover, only a gradual decrease in platelet count and a slow increase in the rate of oleate liberation was observed when compared with controls. However, cyclic AMP levels rapidly declined when platelets were resuspended in prostacyclin-free medium.

Adult↗