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S Bunting

Publications and source records attributed to S Bunting.

At least 73 records · Page 4Linked to original sources
PubMed1990

Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils.

Aggregation of human platelets induced by a variety of agonists was inhibited by 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl]-1H-pyrrole-2,5-dionel (U-73122) (IC50 values 1-5 microM), but not by the close analog 1-[6-[[17 beta-3-methoxyestra- 1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine-dione (U-73343) in which pyrrolidinedione was substituted for pyrroledione. Inhibition by U-73122 was not mediated by an increase in intracellular cyclic AMP. In contrast, the production of inositol 1,4,5-trisphosphate (IP3) and the subsequent rapid increase in cytosolic Ca++ induced by either thrombin or the thromboxane-mimetic, (5Z,9 alpha, 11 alpha, 13E, 15S) 15-hydroxy-11,9-(epoxymethano)prosta- 5,13,-dien-1-oic acid (U-46619), was inhibited by U-73122 but not by U-73343. Reduction of IP3 levels appeared to reflect an inhibition of IP3 production because the hydrolysis of phosphatidyl[3H]inositol and phosphatidyl[3H]inositol 4,5-bisphosphate catalyzed by a soluble fraction from platelets was inhibited by U-73122 (Ki = 9 and 40 microM, respectively). In addition, U-73122 inhibited thromboxane B2 production induced by collagen but not that supported by exogenously added arachidonic acid, suggesting that U-73122 also inhibited receptor-coupled mobilization of arachidonic acid. After preincubation of platelets with [3H]arachidonic acid, the loss of [3H]phosphatidylinositol and accumulation of [3H]phosphatidic acid induced by thrombin was attenuated by U-73122. U-73122 did not inhibit the activities of phospholipases A2 purified either from porcine pancreas or from the venoms of Crotalus adamanteus and Naja naja. Although U-73122 inhibited neither the conversion of exogenous arachidonic acid to thromboxane B2 nor the binding of the thromboxane receptor antagonist [1S-[1 alpha, 2 beta (5Z), 3 beta, 4 alpha]]-7-[3-[[2- [2-[(phenylamino)-carbonyl]- hydrazino]methyl]-7-oxabicyclo [2.2.1]-hept-2-yl-5-heptenoic acid to platelet membranes, it was an effective inhibitor of arachidonic acid-induced aggregation of platelets. These data are consistent with the observed inhibition by U-73122 of platelet activation by the thromboxane receptor agonist, U-46619, via a mechanism that involves inhibition of a phospholipase C-dependent component(s) of signal transduction. U-73122, but not U-73343, inhibited also N-formyl-methionyl-leucyl-phenylalanine-induced aggregation of human polymorphonuclear neutrophils (PMN) and the associated production of IP3 and diacyglycerol. Diradylglycerol produced in PMN stimulated with N-formyl- methionyl-leucyl-phenylalanine was 74 +/- 7% saponifiable and inhibited by U-73122 (Ki = 2 microM).(ABSTRACT TRUNCATED AT 400 WORDS)

Arachidonic Acid↗
PubMed1987

In vivo characterization of synthetic thromboxane A2 in canine myocardium.

Recently, total chemical synthesis of thromboxane was achieved. The in vitro activity of synthetic thromboxane A2 is indistinguishable from biologically generated material. The present study describes the in vivo characterization of synthetic thromboxane A2 on the regional blood flow distribution of the canine heart. Local injections of synthetic thromboxane A2 into the coronary vasculature caused marked reductions in coronary blood flow, measured by both radiolabeled microsphere injection and an electromagnetic flow device. The threshold concentration required to bring about this effect varied greatly between dogs and ranged from 0.125 microgram/kg to 2.0 micrograms/kg. Similarly, the dose of thromboxane A2 required to aggregate dog platelets in vitro varied from 30 ng/ml to 1,000 ng/ml. Bolus injections of 2 micrograms/ml thromboxane A2 into the circumflex or left anterior coronary artery resulted in a simultaneous reduction in platelet count in coronary sinus blood of 83 +/- 5.2% (mean +/- SEM, n = 4, p = .0005). Both flow reduction and platelet effects were transient and localized. The time taken from onset to recovery of the response to control levels was 77 +/- 6.0 seconds (mean +/- SEM) for flow and 70-80 seconds for platelet count. Injections of thromboxane A2 caused a small but significant increase in heart rate with no change in systemic blood pressure. In conclusion, the in vivo actions of synthetic thromboxane A2 are consistent with the vasoconstrictor and platelet aggregatory effects seen in vitro, but dogs vary considerably in their sensitivity.

Animals↗
PubMed1986

Leukotriene B4 and 20-hydroxyleukotriene B4 contract guinea-pig trachea strips in vitro.

In contrast to its established myotropic effect on guinea-pig lung parenchyma, the myotropic action of leukotriene B4 on the trachea is uncertain. Our characterization of its effects on the latter organ indicates that leukotriene B4 contracts guinea-pig trachea zig-zag strips in a concentration-dependent manner from 5 X 10(-9) to 5 X 10(-7) M. Leukotriene B4 was at least 10 times more potent than histamine, but 10 times less potent than leukotriene C4. Similar effects were evident with 20-hydroxyleukotriene B4; however, this metabolite contracted the trachea less forcefully. Tracheas developed tachyphylaxis after cumulative administration of leukotriene B4, but not 20-hydroxyleukotriene B4. The myotropic effect of leukotriene B4 was attributable to an indirect mechanism involving formation of cyclooxygenase metabolites of arachidonic acid. For example, the levels of prostaglandin E2 and prostaglandin F2 alpha released into the incubation medium correlated with the contractile response, and suppression of their biosynthesis with cyclooxygenase inhibitors eliminated that response. We conclude that myotropic effects of leukotriene B4 occur in central airways in addition to peripheral airways. The contribution of leukotriene B4 to tracheal bronchospasm is not necessarily negligible.

Animals↗
PubMed1984

Metabolism of leukotriene A4 by human erythrocytes. A novel cellular source of leukotriene B4.

Human erythrocytes transformed leukotriene A4 into leukotriene B4. Metabolism was proportional to the erythrocyte concentration, even at subphysiological levels (0.08-4 X 10(9) erythrocytes/ml). Comparative metabolic studies excluded the possibility that leukotriene B4 originated from trace amounts of polymorphonuclear leukocytes or platelets present in the purified erythrocyte suspensions. For example, suspensions of isolated platelets (100-500 X 10(6) cells/ml) failed to convert leukotriene A4 into leukotriene B4; and conversion by suspensions of isolated polymorphonuclear neutrophils was insufficient to account for the amounts of leukotriene B4 formed by erythrocytes. Leukotriene B4 formation was maximal within 2 min and substrate concentration dependent. Enzymatic activity originated from a 56 degrees C labile nondialyzable (Mr greater than 30,000) soluble component in the 100,000 X g supernatant obtained from lysed erythrocytes. In contrast to the contemporary view, our results indicate that human erythrocytes are not metabolically inert in terms of eicosanoid biosynthesis. The role of human erythrocytes during inflammatory or pulmonary disorders deserves re-examination in this context.

Arachidonic Acids↗
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↗
PubMed1982

[Clinical study of prostacyclin in extracorporeal circulation. Effects on hemodynamics and coagulation].

The effects of prostacycline (PGI2), the most powerful known platelet antiaggregant on platelet count and function during cardiopulmonary bypass, were assessed in a double blind study. One group of 13 patients received 2,5 mg/Kg of Heparin with an infusion of 25 ng/Kg/min of prostacycline instituted 15 minutes before the Heparin, continued at the beginning of cardiopulmonary bypass at a dose of 50 ng/Kg/min and terminated at the end of bypass. A second group of 15 patients were studied by the same protocol with a placebo infusion. The platelet count was significantly higher at the end of cardiopulmonary bypass in the Prostacycline group. Platelet aggregation was reduced by comparison with the control group from the beginning of Prostacycline infusion. The active thrombin time was significantly longer in the Prostacycline group. However, blood loss did not differ significantly between the two groups although it was less in the study group. The platelet count and function during cardiopulmonary bypass with Prostacycline was therefore increased and resulted in a reduction in Heparin consumption.

Anticoagulants↗
PubMed1980

Effects of intravenous infusion of prostacyclin (PGI2) in man.

Prostacyclin infused intravenously in human volunteers induces ex vivo inhibition of platelet aggregation, tachycardia and hypotension. The inhibition of platelet aggregation is obtained with slightly lower doses than those which exhibit cardiovascular effects. The cardiovascular effects disappeared within a few minutes after discontinuing the infusion of prostacyclin but the platelet effects were longer lasting. Prostacyclin did not have any effect on platelet count, platelet factor 3, accelerated partial thromboplastin time, prothrombin time, euglobulin clot lysis time, fibrinogen degradation products, blood glucose concentration or urine sodium potassium ratio.

Adult↗
PubMed1980

Prostacyclin eliminates the thrombocytopenia associated with charcoal hemoperfusion and minimizes heparin and fibrinogen consumption.

To evaluate the effects of prostacyclin (PGI2) on the bioincompatibility of charcoal hemoperfusion (CHP), platelet counts, platelet aggregate formation as measured by screen filtration pressure (SFP), plasma fibrinogen levels, and heparin activity monitored by calcium-thrombin clotting times (Ca-TCT) were compared during CHP in healthy dogs with heparin alone or heparin plus PGI2. Platelet losses (25 +/- 6 vs 83 +/- 2%: mean +/- SEM), rise in SFP (65 +/- 6 vs 249 +/- 25 mmHg), and fibrinogen consumption (20 +/- 5 vs 46 +/- 6%) were significantly less during CHP with PGI2 than with heparin only. In addition, rapid neutralization of heparin, as monitored by Ca-TCT, during CHP was prevented by PGI2. The use of PGI2 may allow a proper evaluation of the efficacy of CHP in conditions such as fulminant hepatic failure where, hitherto, incompatibility between blood and charcoal may have had deleterious effects.

Animals↗
PubMed1979

Prostacyclin: a solution to some problems of extracorporeal circulation. Experiments in greyhounds.

In cardiopulmonary-bypass experiments in greyhounds the effects of adding prostacyclin, prostacyclin plus heparin, and heparin alone to the extracorporeal circulation were compared. With heparin alone platelet count and function were reduced, the pressure differential across the arterial filters rose, platelet deposits were found on the arterial filters, and plasma-fibrinogen levels fell. Plasma from these dogs was toxic to fetal-mouse hearts in culture. With prostacyclin alone, fibrinogen levels fell, but the platelets were preserved. With a combination of prostacyclin and heparin, platelet count and function were maintained, there was no consumption of fibrinogen, and there was little deposition on the arterial filters.

Animals↗
PubMed1979

Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man.

1 Isolated strips of human or baboon basilar, middle cerebral, vertebral or common carotid arteries were set up in an isolated organ bath or in a superfusion cascade system. 2 These arteries relaxed to prostacyclin but contracted to prostaglandin endoperoxide (PGH2). 3 Human and baboon isolated arteries also generated prostacyclin from exogenous endoperoxide (PGH2). 4 Human arteries generated prostacyclin 36 h post-mortem but not 40 h post-mortem. The biologically generated prostacyclin relaxed the basilar artery and overcame the contractile effects of PGH2. 5 Thromboxane A2-like activity generated during human platelet aggregation by arachidonic acid caused contractions of the human basilar artery. 6 Prostacyclin reversed contractions of human basilar arteries caused by an unidentified vasoconstrictor factor in cerebrospinal fluid obtained from patients with cerebral arterial vasospasm after subarachnoid haemorrhage following rupture of cerebral arterial aneurysms. 7. The above vasospasm may be due at least in part to disordered physiological control of the calibre of cerebral arteries caused by diminished synthesis of prostacyclin.

Animals↗
PubMed1979

Prostacyclin eliminates the bioincompatibility of charcoal haemoperfusion.

During charcoal haemoperfusion (CHP) in dogs, use of prostacyclin (PGI2) in addition to heparin reduced the loss of platelets (25 +/- 6 vs 83 +/- 2%), the formation of platelet aggregates as judged by screen filtration pressure (65 +/- 6 vs 249 +/- 25mm Hg) and fibrinogen consumption (20 +/- 5 vs 46 +/- 6%). Prostacyclin also delayed neutralisation of heparin during CHP. This improvement of biocompatibility may now allow a proper assessment of CHP in liver failure.

Animals↗