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Biomedical subjects

R L Kinlough-Rathbone

Publications and source records attributed to R L Kinlough-Rathbone.

At least 91 records · Page 5Linked to original sources
PubMed1982

The inhibitory effects of exogenous arachidonic acid on rabbit platelet aggregation and the release reaction.

Although arachidonic acid causes rabbit platelet aggregation and the release of granule contents in suspensions of washed platelets when used in concentrations of approximately 50-300 microM, higher concentrations (500 microM) cause neither aggregation nor release. Suspensions of platelets from rabbits wee exposed to arachidonic acid (250 microM) for 15 min, allowed to recover in the presence of PGE1 for 30 min, washed, and resuspended; in some experiments, the platelets were treated with aspirin before being exposed to arachidonic acid. Aggregation of platelets pretreated with arachidonic acid was inhibited in response to ADP; this effect was greater with the non-aspirin-treated platelets and persisted for at least 4 hr after resuspension. The association of 125I-fibrinogen with the platelets as a result of ADP stimulation was also inhibited. Aggregation and release of granule contents in response to collagen and low concentrations of thrombin was inhibited, but the inhibition could be overcome by higher concentrations. Thrombin induced further release of granule contents from platelets exposed to arachidonic acid without pretreatment with aspirin. Platelets that had been exposed to arachidonic acid, either with or without pretreatment with aspirin, did not aggregate or undergo further release upon stimulation with arachidonic acid after they were washed and resuspended. Inhibition of the lipoxygenase pathway with eicosatetraynoic acid (ETYA) or nordihydroguaiaretic acid (NDGA) did not affect the inhibition caused by arachidonic acid, so it is unlikely that a product of this pathway is responsible for the inhibition. Mixing experiments indicated that the pretreated platelets did not form a thromboxane-A2-like activity, and that they were unresponsive to aggregation and release induced by products formed from arachidonic acid. Experiments with 3H-arachidonic acid showed that after 45 min of incubation with platelets, only 1.1% of the 3H-arachidonic acid remained as free arachidonic acid in the platelets. Although cyclic-AMP was slightly increased 1 min after the addition of arachidonic acid, the cyclic-AMP concentration was the same as that of control platelets after the platelets were washed and resuspended, indicating that increased cyclic-AMP is not likely to be responsible for the persistent inhibitory effect. Thus, the inhibitory effect of pretreatment with arachidonic acid is a general effect on responses to a variety of aggregating agents that act through different mechanisms, and the inhibition is not related to thromboxane-A2 formation. The possibility of membrane perturbation resulting in the unavailability of receptors may explain the persistent inhibitory effect, but the responsible reactions have not been identified.

Adenosine Diphosphate↗
PubMed1982

Effect of dipyridamole and prostacyclin on rabbit platelet adherence in vitro and in vivo.

The adherence of 51Cr-labeled platelets to the subendothelium of rabbit aortas was inhibited in vitro and in vivo by high concentrations of dipyridamole (100 microM in vitro, 2.5 or 12.5 mg/kg in vivo). Dipyridamole (100 microM) inhibited release of 14C-serotonin from platelets that adhered to the subendothelium or to a collagen-coated glass surface; lower concentrations of dipyridamole had only a slight inhibitory effect. Scanning electron microscopy showed that many of the platelets that adhered to the subendothelium were rounded, with few pseudopodia. The combination of dipyridamole with PGI2 was no more inhibitory of platelet adherence than either agent alone; however, this combination of inhibitors exerted synergistic inhibitory effects on aggregation and release of 14C-serotonin from platelets aggregated by collagen. The effects of dipyridamole on platelet adherence are a consequence of the action of dipyridamole alone and do not appear to result from its interaction with PGI2 formed by injured vessels in vivo, since the inhibitory effect is not influenced by aspirin inhibition of PGI2 formation, either at the shear rates in the in vitro studies or under the shear conditions found in rabbit aortas in vivo.

Animals↗
PubMed1982

Thrombin generation and fibrin formation following injury to rabbit neointima. Studies of vessel wall reactivity and platelet survival.

Using platelets prelabeled with 51Cr, we have quantified the effect of injury to the neointima on platelet accumulation, thrombus formation at different times following injury, and the effect of injury to the neointima on platelet survival. Platelet accumulation on the neointima is largely determined by activation of coagulation and thrombus formation; this contrasts with platelet accumulation on the subendothelium where coagulation does not play a major role and where few thrombi form. Heparin treatment significantly inhibits platelet accumulation on the injured neointima but is without effect on platelet accumulation on the subendothelium. Like the subendothelium, the neointima rapidly becomes nonreactive to further platelet accumulation, and the platelets and platelet-fibrin thrombi are lost from the surface in the first few days after injury. Despite the formation of extensive platelet thrombi on the injured neointima, platelet survival is unaffected.

Animals↗
PubMed1982

Changes in phosphatidylinositol-4,5-bisphosphate 10 seconds after stimulation of washed rabbit platelets with ADP.

Adenosine diphosphate (ADP) induced aggregation of rabbit platelets, without the release reaction, causes a significant decrease (7%) in the amount of phosphatidylinositol-4,5-bisphosphate (PIP2) at 10 sec and at 60 sec (11%). In platelets prelabeled with 32P-phosphate, this decrease in PIP2 is associated with a decrease in PIP2 radioactivity, which is significant at 50 sec. The decrease in PIP2 is sufficient to mobilize about 0.18 nmole Ca2+/10(9) platelets. In view of the key role played by Ca2+ in ADP-induced platelet shape change and aggregation, this evidence is compatible with the hypothesis that changes in PIP2 can be a source of calcium for cellular responses to agonists.

Adenosine Diphosphate↗
PubMed1981

Inhibitors of ADP-induced platelet aggregation prevent fibrinogen binding to rabbit platelets and cause rapid deaggregation and dissociation of bound fibrinogen.

125I-fibrinogen binds to washed rabbit platelets when they ar stimulated wit ADP, and it has previously been observed that fibrinogen binding is prevented by several inhibitors of ADP-induced aggregation. We have now shown that other inhibitors of aggregation, the phosphodiesterase inhibitors caffeine and dipyridamole, and colchicine and cytochalasin B which affect the platelet cytoskeleton, also inhibit specific 125I-fibrinogen binding. A positive correlation was observed between ADP-induced aggregation and fibrinogen binding at limiting concentrations of these inhibitors. Colchicine and cytochalasin B appear to act independently, with no indication of synergism. When any of these inhibitors, as well as those previously tested (EDTA, EGTA, PGE1 and PGI2) was added to platelets that had already been stimulated with ADP and undergone considerable aggregation and fibrinogen binding, it caused rapid deaggregation of the platelets and dissociation of bound fibrinogen, although in some cases the inhibitory effects were not as pronounced as when the inhibitor was added before ADP stimulation. These observations reinforce the concept that fibrinogen plays an essential role in the formation of ADP-induced platelet aggregates.

Adenosine Diphosphate↗
PubMed1980

Prostaglandins and platelets.

Release of arachidonate from cell membrane phospholipids by activation of phospholipase A1 is a key step in the formation of prostaglandins and thromboxanes. In platelets PGH2 and TXA2 are formed from arachidonate and can cause aggregation and the release of granule contents; in vascular tissue, PGI2 is formed instead and, by increasing platelet cAMP, inhibits platelet reactions. There is considerable interest in inhibitors of the enzymes in these pathways as drugs to modify thrombus formation. Results of the clinical trials, however, indicate that drugs which inhibit cyclo-oxygenase may not have a major effect on the thromboembolic complications of arterial disease.

Arachidonic Acids↗
PubMed1979

The influence of red blood cells on the effects of aspirin or sulphinpyrazone on platelet adherence to damaged rabbit aorta.

The effects of acetylsalicylic acid (ASA; aspirin) or sulphinpyrazone (SP) on the adherence of washed rabbit platelets to the subendotheilial surface of an everted aorta mounted on a probe or to the subendothelial surface of a rabbit aorta attached to a perfusion apparatus were examined. ASA had no effect on platelet adherence to a damaged aorta perfused with a suspension of washed platelets in a medium containing 10% red blood cells (RBC); SP was slightly inhibitory at high concentration. When damaged rabbit aortae were everted on a probe and rotated in a suspension of washed platelets to which RBC were added to a packed cell volume of 10%, both ASA and SP inhibited platelet adherence to the damaged vessel wall. When the PCV was 40%, ASA was not inhibitory and SP reduced platelet adherence only at very high concentrations. It is therefore unlikely that, at the concentrations achieved in man, SP exerts an effect on platelet adherence. The different effects of ASA and SP on platelet survival do not appear attributable to their effects on platelet adherence.

Animals↗
PubMed1979

Platelet interaction with damaged rabbit aorta.

We have quantified the accumulation of 51Cr-labeled washed rabbit platelets on the subendothelium of rabbit aortae following injury with a balloon catheter. The amount of radioactivity that became associated with the damaged wall within 10 minutes of the injury did not change appreciably during the following 24 hours, indicating that there was little turnover of platelets on the injured vessel wall. In addition, by injecting 51Cr-labeled platelets into rabbits at different times after injury, it was possible to estimate the reactivity of the exposed surface to newly injected platelets. Scanning electron microscopy showed that a monolayer of platelets initially formed on the injured surface; the number of platelets associated with the surface decreased over the 7-day observation period. The amount of 51Cr associated with the injured vessel wall also diminished during this period. The ability of the damaged surface to attract fresh platelets gradually decreased during the 7 days following injury. Platelet survival in rabbits was not significantly reduced following the removal of the aortic endothelium (balloon catheter injury 66.3 +/- 12.2 hours, sham operated 72.1 +/- 7.2 hours, untreated controls 76.2 +/- 3.8 hours). Thus, in rabbits, it cannot be assumed that platelet survival provides an estimate of endothelial injury in all circumstances.

Animals↗
PubMed1979

Comparison of fibrinogen association with normal and thrombasthenic platelets on exposure to ADP or chymotrypsin.

Although 125I-fibrinogen becomes associated with washed platelets from normal human subjects during ADP-induced shape change and aggregation, 125I-fibrinogen did not become associated with washed plateletes from a thrombasthenic subject during ADP-induced shape change and the platelets did not aggregate. Platelets from control and thrombasthenic subjects were treated with chymotrypsin, which is known to degrade platelet membrane glycoproteins. More 125I-fibrinogen became associated with chymotrypsin-pretreated platelets from normal subejcts than with untreated platelets, and fibrinogen caused the enzyme-treated platelets to aggregate. 125I-fibrinogen did not become associated with chymotrypsin-pretreated thromobasthenic platelets, and fibrinogen did not aggregate them. Thus, there appears to be a defect in thrombasthenic platelets that prevents the association of fibrinogen with them.

Adenosine Diphosphate↗
PubMed1978

Drug effects on platelet adherence to collagen and damaged vessel walls.

The interaction of platelets with damaged vessel walls leads to the formation of platelet-fibrin thrombi and may also contribute to the development of atherosclerotic lesions because platelets adherent to exposed collagen release a mitogen that stimulates smooth muscle cell proliferation. The first step in thrombus formation, platelet adherence to an injured vessel wall, can be studied quantitatively by the use of platelets labeled with 51chromium. In these investigations, rabbit aortas were damaged by passage of a balloon catheter and segments of the aortas were everted on probes that were rotated in platelet suspensions. Collagen-coated glass cylinders were also used. Adherence was measured in a medium containing approximately physiologic concentrations of calcium, magnesium, protein and red blood cells. Conditions of testing influence the effect of non-steroidal anti-inflammatory drugs, sulfinpyrazone, and dipyridamole on platelet adherence. Aspirin and sulfinpyrazone were not inhibitory when tested in a medium with a 40% hematocrit; this indicates that products formed by platelets from arachidonate probably do not play a major part in the adherence of the first layer of platelets to the surface, although they may be involved in thrombus formation. Indomethacin, dipyridamole, prostaglandin E1, methylprednisolone and penicillin G and related antibiotics did inhibit platelet adherence although the concentrations required were higher than would likely be achieved in vivo upon administration to human patients. None of the non-steroidal anti-inflammatory drugs inhibited the release of granule contents from adherent platelets. Pretreatment of the damaged vessel wall with aspirin increased platelet adherence, presumably because it prevented the formation of PGI2 by the vessel wall. Platelet adherence to undamaged or damaged vessel walls was enhanced by prior exposure of the wall to thrombin. Platelet reactions with aggregating agents and platelet survival can be modified by changes in dietary lipids but there is very little evidence concerning the effects of lipids on platelet adherence. If some forms of dietary fat damage the endothelium, platelet interaction with the damaged area and release of the mitogen for smooth muscle cells would contribute to the development of atherosclerotic lesions.

Animals↗