Similarities and differences between rabbit and human platelet characteristics and functions.
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Animals↗
Biomedical subjects
M L Rand
Publications and source records attributed to M L Rand.
Acute in vitro effects of ethanol on responses of platelets from cholesterol-fed and Watanabe heritable hyperlipidemic rabbits.
The effects of ethanol on platelets from rabbits with two different types of hypercholesterolemia, diet-induced and genetically determined, were investigated. There were no differences between the hypercholesterolemic groups and their controls in the extent of (primary) ADP-induced aggregation of washed platelets, and this aggregation was not inhibited by ethanol. Platelets from cholesterol-fed rabbits were more sensitive to aggregation and secretion induced by collagen, whereas platelets from Watanabe heritable hyperlipidemic (WHHL) rabbits were less sensitive. Ethanol inhibited collagen-induced responses of platelets from both hypercholesterolemic groups, but the extent of inhibition of aggregation was not different compared with controls. Because ethanol did not affect U46619-induced responses of aspirin-treated platelets, ethanol does not inhibit aggregation and secretion stimulated by collagen via an effect on thromboxane A2 (TxA2)-induced responses. Platelets from cholesterol-fed rabbits were more sensitive to thrombin even when TxA2 formation was blocked by aspirin, and inhibition of aggregation by ethanol was less in cholesterol-fed rabbits than in controls. However, neither the extent of thrombin-induced responses nor the inhibitory effect of ethanol was different in platelets from WHHL rabbits compared with controls. Thus, different etiologies of hypercholesterolemia produce different changes in platelet function, and ethanol has different effects on the platelets from cholesterol-fed rabbits compared with the platelets from WHHL rabbits. The inhibitory effect of ethanol on the thrombin-induced aggregation of platelets from cholesterol-fed rabbits is attenuated compared with controls, and this finding contrasts with the reported greater inhibitory effect of ethanol on platelets enriched with saturated fats.
Adenosine Diphosphate↗
Inhibition by ethanol of thrombus formation induced by indwelling aortic catheters in rabbits.
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Animals↗
Platelet hypersensitivity in cholesterol-fed rabbits: enhancement of thromboxane A2-dependent and thrombin-induced, thromboxane A2-independent platelet responses.
Hypercholesterolemia (mean plasma cholesterol: 15 mM) was induced in rabbits by the feeding of a chow diet enriched with a low amount (0.25%, w/w) of cholesterol only. Platelet size and protein content decreased significantly, but the whole blood platelet count did not change. The platelets became enriched in cholesterol, as indicated by a significant increase in the cholesterol:phospholipid molar (C/P) ratio. Specific responses of washed platelets stimulated with various agonists were studied to determine the effects of hypercholesterolemia on the various pathways of platelet aggregation in the absence of plasma components. In platelets from hypercholesterolemic rabbits compared with controls: aggregation induced by ADP was not altered; collagen-induced responses (aggregation, secretion of [14C]serotonin from prelabelled platelets, thromboxane A2 (TXA2) formation, mobilization of [3H]arachidonate from prelabelled platelets) were enhanced; with aspirin-treated platelets, aggregation induced by the TXA2 mimetic U46619 was enhanced: and thrombin-induced responses of both untreated platelets (aggregation, secretion of granule contents, TXA2 formation) and aspirin-treated platelets (aggregation) were enhanced. Thus, platelets from cholesterol-fed rabbits not only form more TXA2, but they aggregate more extensively when stimulated by its mimetic. In addition, it has not been previously recognized that these platelets are also hypersensitive to thrombin-induced aggregation that is independent of TXA2.
Adenosine Diphosphate↗
Effect of calcium concentration and inhibitors on the responses of platelets stimulated with collagen: contrast between human and rabbit platelets.
1. Variations in the concentration of Ca2+ [Ca2+] in the suspending medium have different effects on the responses of human and rabbit platelets to collagen. 2. When rabbit platelets are stimulated with a low concentration of collagen (0.5 micrograms/ml), aggregation, release of granule contents, and formation of thromboxane are maximal when the suspending medium contains [Ca2+] in the physiological range (0.5-2.0 mM), and very slight in a medium with no added Ca2+. 3. In contrast, human platelets respond most strongly when the suspending medium contains no added Ca2+ [( Ca2+] approx. 20 microM); this is attributable to the enhanced formation of thromboxane A2 (TXA2) upon close platelet-to-platelet contact in this medium. 4. When TXA2 formation is blocked by inhibition of cyclo-oxygenase with aspirin or indomethacin, rabbit platelet aggregation and release in response to 1.25-10 micrograms/ml collagen is also maximal at [Ca2+] of 0.5-2.0 mM and least at 20 microM; human platelets do not aggregate and the extent of release is relatively independent of [Ca2+]. 5. In 1 mM [Ca2+], use of apyrase and/or ketanserin with rabbit platelets in which TXA2 formation is blocked shows that released ADP and serotonin make large contributions to aggregation and release in response to high concentrations of collagen; human platelet aggregation is largely dependent on TXA2. 6. Use of fura-2-loaded platelets shows that the collagen-induced rise in cytosolic [Ca2+] is only slightly inhibited by aspirin or indomethacin in rabbit platelets, but almost completely inhibited in human platelets. 7. Responses of rabbit platelets to collagen are less dependent on TXA2 than those of human platelets. Released ADP and serotonin make major contributions to the responses of rabbit platelets to collagen.
Animals↗
Effects of alcohol withdrawal on responses of platelets from alcoholics--a study using platelet-rich plasma from blood anticoagulated with D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2Cl).
Platelet responses stimulated by a range of concentrations of ADP or collagen were studied in platelet-rich plasma (PRP) from alcoholics 24-36 h and 6 days after cessation of drinking, and in PRP from age- and sex-matched controls. The studies were done using plasma from blood anticoagulated with the specific thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2Cl, PPACK); the use of this compound permits the study of platelet responses in plasma at physiological concentrations of ionized calcium. Responses of platelets to ADP (primary aggregation) and collagen (aggregation, secretion of [14C]serotonin from prelabelled platelets, and thromboxane formation) were lower in alcoholics 24-36 h after withdrawal of alcohol compared with controls. This inhibition of platelet function was not due to the presence of alcohol in the blood of the alcoholics. Aggregation in response to ADP did not change during the withdrawal period studied, while collagen-induced aggregation and secretion increased significantly and collagen-induced thromboxane formation tended to increase towards control values. The reduced platelet responses observed in alcoholics and the different rates of "recovery" of different pathways of aggregation towards control values must be due to alterations either in the platelets themselves and/or in the plasma brought about by the chronic presence of ethanol, and its withdrawal.
Adult↗
Reduced membrane fluidity in platelets from diabetic patients.
Platelets from diabetic patients are hypersensitive to agonists in vitro. Membrane fluidity modulates cell function, and reduced membrane fluidity in cholesterol-enriched platelets is associated with platelet hypersensitivity to agonists, including thrombin. Decreased membrane fluidity of these platelets is attributed to an increased cholesterol-phospholipid molar ratio in platelet membranes. We examined the response of platelets from diabetic subjects to thrombin, platelet membrane fluidity, and platelet cholesterol-phospholipid molar ratio. Twelve poorly controlled diabetic subjects were compared with 12 age- and sex-matched control subjects. In response to a low concentration of thrombin, mean values for release of [14C]serotonin from washed prelabeled platelets were not significantly different between diabetic and control subjects, but in 8 of 12 diabetic subjects, the release response was greater than in their paired control subjects. Mean steady-state fluorescence polarization values in 1,6-diphenyl-1,3,5-hexatriene-labeled platelets prepared from diabetic subjects were significantly greater than in control subjects; this indicates a decreased membrane fluidity in platelets from diabetic subjects. Total or very-low-density (VLDL), low-density (LDL), or high-density (HDL2, HDL3) lipoprotein cholesterol concentrations in plasma were not significantly different between groups; however, the ratio of VLDL + LDL to HDL2 + HDL3 was significantly greater in diabetic than in control subjects. There was no difference in the total platelet cholesterol-phospholipid molar ratio between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Acute administration of ethanol to rabbits inhibits thrombus formation induced by indwelling aortic catheters.
Platelet aggregation and secretion of granule contents in response to specific agonists are inhibited by acute ethanol (1 to 4 mg/ml in vitro or 4 to 5 mg/ml ex vivo). However, acute administration of ethanol, giving blood levels of 4 to 5 mg/ml, does not affect platelet adherence to de-endothelialized rabbit aortae in vivo, which is the initial step in thrombus formation. Whether ethanol inhibits subsequent reactions in thrombus formation induced by indwelling catheters in rabbit aortae was investigated. Before insertion of the catheters, the rabbits received injections of 51Cr-labeled platelets (and, in some experiments, [125I]fibrinogen), and were given ethanol by stomach tube, to achieve blood levels of approximately 4 mg/ml. Thrombus formation after 3 hours was assessed by determining the number of platelets and the amount of radiolabeled fibrin(ogen) associated with the aortae, and by determining the thrombus weights; all three measurements indicated a 64 to 84% reduction in thrombosis. Thus, experimentally induced thrombus formation in the aorta is significantly reduced by ethanol.
Animals↗
Platelet responses to platelet-activating factor are inhibited in alcoholics undergoing alcohol withdrawal.
Platelet aggregation, secretion of serotonin, and formation of thromboxane B2 induced by platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) were studied in plasma containing physiological concentrations of ionized calcium in eight alcoholics after cessation of heavy drinking. Responses of platelets of four nonalcoholic volunteers, matched with a subgroup of the alcoholics by age and sex, were also investigated. Aggregation of platelets from alcoholics was significantly less throughout the 6-day detoxification period compared with controls. Secretion of serotonin (5-hydroxy-tryptamine) was negligible and the production of thromboxane B2 was not detectable. Decreased platelet aggregability in response to aggregating agents, including platelet-activating factor, may be important in the development of hemorrhagic complications in alcoholics.
Adult↗
In vitro effects of ethanol on rabbit platelet aggregation, secretion of granule contents, and cyclic AMP levels in the presence of prostacyclin.
Ethanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin-treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.
Adenosine Diphosphate↗
Platelet function and survival in rats with genetically determined hypercholesterolaemia.
Platelets from rats with genetically determined hypercholesterolaemia are hypersensitive to aggregation induced by thrombin compared with platelets from their genetic controls without hypercholesterolaemia. Aggregation or release induced by thrombin of platelets from hypercholesterolaemic and control rats correlated significantly with plasma cholesterol concentrations. Platelet responses to ADP or collagen were not different between the groups. The hypersensitivity to thrombin-induced aggregation was independent of released ADP or products of arachidonic acid metabolism. The changes in platelet sensitivity occurred with only moderate increases in plasma cholesterol concentration and with no detectable changes in total platelet cholesterol. The hypersensitivity of platelets from hypercholesterolaemic rats was not associated with a reduction in platelet survival or any significant injury to the aortic endothelium in these animals. Platelets from hypercholesterolaemic rats were smaller than platelets from controls. Thus, platelets from rats with genetically determined hypercholesterolaemia have alterations in function similar to those found with platelets from rats with diet-induced hypercholesterolaemia indicating that this strain can be used to study the mechanisms by which cholesterol can change platelet function without the possible complicating effects of dietary factors. Since platelet hypersensitivity occurred in rats with genetically determined hypercholesterolaemia without a reduction in platelet survival, these studies are also consistent with the reduced platelet survival found in animals with diet-induced hypercholesterolaemia being independent of platelet changes.
Animals↗
Effects of ethanol on pathways of platelet aggregation in vitro.
Ethanol, at physiologically tolerable concentrations, did not affect the primary phase of ADP-induced aggregation of human or rabbit platelets, which is not associated with the secretion of granule contents. Potentiation by epinephrine of the primary phase of ADP-induced aggregation of rabbit platelets was also not inhibited by ethanol. However, ethanol did inhibit the secondary phase of ADP-induced aggregation which occurs with human platelets in citrated platelet-rich plasma and is dependent on the formation of thromboxane A2. Inhibition by ethanol of thromboxane production by stimulated platelets is likely due to inhibition of the mobilization of arachidonic acid from membrane phospholipids, as ethanol had little or no effect on aggregation and secretion induced by arachidonic acid or the thromboxane mimetic U46619. Rabbit platelet aggregation and secretion in response to low concentrations of collagen, thrombin, or PAF were inhibited by ethanol. Inhibition of the effects of thrombin and PAF was also observed with aspirin-treated platelets. Thus, in addition to inhibiting the mobilization of arachidonate for thromboxane formation that occurs with most agonists, ethanol can also inhibit aggregation and secretion through other effects on platelet responses.
Adenosine Diphosphate↗
Thrombin-induced inositol trisphosphate production by rabbit platelets is inhibited by ethanol.
Ethanol has an inhibitory effect on some platelet functions, but the mechanisms by which it exerts this effect are not known. Using suspensions of washed platelets, we observed that ethanol (1-9 mg/ml) did not affect the aggregation of rabbit platelets stimulated with ADP (0.5-10 microM). When platelets were prelabelled with 5-hydroxy[14C]tryptamine, aggregation and secretion of granule contents in response to thrombin (0.01-0.10 unit/ml) were not inhibited by ethanol, but these responses to thrombin at lower concentrations (less than 0.01 unit/ml) were inhibited by ethanol (2-4 mg/ml). Platelets were prelabelled with [3H]inositol so that increases in inositol phosphates upon stimulation could be assessed by measuring the amount of label in these compounds. ADP-induced increases in IP (inositol phosphate) and IP2 (inositol bisphosphate) were not affected by ethanol. IP3 (inositol trisphosphate) was not changed by ADP or ethanol. Although ethanol did not affect the increases in IP, IP2 and IP3 caused by stimulation of platelets with thrombin at concentrations greater than 0.01 unit/ml, ethanol did inhibit the increases observed at 2 and 3 min in these inositol phosphates caused by lower concentrations of thrombin (less than 0.01 unit/ml). Since ADP did not cause formation of IP3 in rabbit platelets, and since no thromboxane B2 was detected in platelets stimulated with the lower concentrations of thrombin, it is unlikely that the inhibitory effect of ethanol in IP3 formation was due to effects on further stimulation of platelets by released ADP or by thromboxane A2. Ethanol may inhibit platelet responses to thrombin by inhibiting the production of the second messenger, IP3.
Adenosine Diphosphate↗
Effects of dietary palm oil on arterial thrombosis, platelet responses and platelet membrane fluidity in rats.
Wistar rats were fed a control diet containing 5 energy % (en %) sunflowerseed oil or diets containing 50 en % of either palm oil, rich in saturated fatty acids, or sunflowerseed oil, high in linoleic acid, for at least eight weeks. Arterial thrombosis tendency, measured by the aorta loop technique, tended to be lowered by the palm oil diet and was lowered significantly by the sunflowerseed oil diet, compared with the control. Aggregation of platelets in whole blood activated with collagen was not altered by palm oil feeding, but was enhanced in the sunflowerseed oil group, compared with the control. The concomitant formation of thromboxane A2 was decreased by palm oil feeding, although formation of prostacyclin did not change; the ratio of thromboxane/prostacyclin formed was decreased significantly in the palm oil group. Compared with the control diet, platelet membrane fluidity, measured by fluorescence polarization, was not altered in the palm oil group and was significantly increased only by sunflowerseed-oil feeding. Thus, although palm oil contains about 50% saturated fatty acids, it did not increase arterial thrombosis tendency and tended to decrease platelet aggregation, as compared with highly polyunsaturated sunflowerseed oil.
Animals↗
Thrombin binding to platelets from hypercholesterolaemic rats.
Platelets from rats made hypercholesterolaemic with a diet enriched with milk fat and cholesterol and containing taurocholate to promote hypercholesterolaemia aggregated more extensively to a low concentration of thrombin than platelets from rats given a milk fat-enriched diet containing sitosterol. Total and specific binding of thrombin to platelets from hypercholesterolaemic rats was significantly greater than in controls when expressed per mg platelet protein, per mumol platelet cholesterol, or per unit relative surface area. Total and specific binding of thrombin per platelet were not different between the groups. However, platelets from hypercholesterolaemic rats had less protein and cholesterol, were smaller and had less surface area than control platelets; platelet cholesterol content expressed per mg platelet protein was not different. Thus, the increase in thrombin-binding to the smaller platelets from hypercholesterolaemic rats during the first 10 s after its addition may be responsible, at least in part, for the hypersensitivity of these platelets to thrombin.
Animals↗
Effects of ethanol on rabbit platelet responses to collagen in vitro and ex vivo and on platelet adhesion to de-endothelialized aortae in vivo.
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Animals↗
Dietary lipids and macrophage procoagulant activity.
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Administration, Oral↗
Effects of dietary sunflowerseed oil and marine oil on platelet membrane fluidity, arterial thrombosis, and platelet responses in rats.
The relationships among platelet membrane fluidity, arterial thrombosis tendency, and platelet aggregation and prostanoid formation were investigated after feeding rats diets enriched in (n-6) or (n-3) polyunsaturated fatty acids. For at least 8 weeks, rats were fed a control diet containing 5 energy % (en%) sunflowerseed oil, a diet high in sunflowerseed oil (50 en%) which contains large amounts of 18:2(n-6), or a diet high in marine oil (5 en% sunflowerseed oil plus 45 en% sperm-whale oil) which contains considerable amounts of 20:5(n-3) and its desaturation and elongation products. Compared with the control diet, platelet membrane fluidity, measured by fluorescence polarization using platelets labelled with 1,6-diphenyl-1,3,5-hexatriene, was significantly increased upon feeding of the sunflowerseed-oil diet or the marine-oil diet. Both of these diets lowered arterial thrombosis tendency, measured by Hornstra's loop technique. Aggregation of platelets in whole blood activated with collagen tended to be higher upon sunflowerseed-oil feeding and lower in the marine-oil group. The concomitant formation of thromboxane A2 was not altered in the sunflowerseed-oil group, but was significantly reduced upon feeding the marine-oil diet. The results indicate that an increase in platelet membrane fluidity may be associated with a reduction in arterial thrombosis tendency. With the techniques used, no direct relationship could be observed among platelet membrane fluidity, platelet aggregation and platelet prostanoid production.
Animals↗