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Biomedical subjects

M T Santos

Publications and source records attributed to M T Santos.

At least 37 records · Page 2Linked to original sources
PubMed1993

Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.

Unstimulated neutrophils inhibited activation and recruitment of thrombin- or collagen-stimulated platelets in an agonist-specific manner. This occurred under conditions of close physical cell-cell contact, although biochemical adhesion between the cells as mediated by P-selectin was not required. Moreover, in the presence of monoclonal P-selectin antibodies that blocked biochemical platelet-neutrophil adhesion, thrombin-stimulated platelets were more efficiently downregulated by neutrophils. This suggested a prothrombotic role for P-selectin under these circumstances. The neutrophil downregulatory effect on thrombin-stimulated platelets was amplified by lipoxygenase inhibition with 5,8,11,14-eicosatetraynoic acid. In contrast, the neutrophil inhibitory effect on platelets was markedly reduced by platelet-derived 12S-hydroxy-5,8-cis, 10-trans, 14-cis-eicosatetraenoic acid (12S-HETE), as well as by the platelet-neutrophil transcellular product, 12S,20-dihydroxy-5,8,10,14-eicosatetraenoic acid (12S,20-DiHETE), but not by another comparable metabolite, 5S,12S-dihydroxy-6-trans, 8-cis, 10-trans, 14-cis-eicosatetraenoic acid (5S,12S-DiHETE), or the neutrophil-derived hydroxy acid leukotriene B4. The neutrophil downregulatory effect on thrombin-induced platelet reactivity was enhanced by aspirin treatment. This may represent a novel action of aspirin as an inhibitor of platelet function. These results provide in vitro biochemical and functional evidence for the thromboregulatory role of neutrophils and emphasize the multicellular aspect of hemostasis and thrombosis.

Adenosine Diphosphate↗
PubMed1991

Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment.

Erythrocytes promoted platelet reactivity in a plasma medium, as demonstrated in an in vitro system that independently evaluated the biochemistry of platelet activation and recruitment. The prothrombotic erythrocyte effects were metabolically regulated, as evidenced by lack of activity of ATP-depleted or glutaraldehyde-fixed erythrocytes. They occurred in the absence of cell lysis as verified by lactate dehydrogenase assays, and had an absolute requirement for platelet activation. The presence of erythrocytes induced a twofold increase in platelet thromboxane B2 (TXB2) synthesis upon collagen stimulation, indicating that erythrocytes modulated platelet eicosanoid formation. Cell-free releasates from stimulated platelet-erythrocyte suspensions, which exhibited increased recruiting capacity, contained 6.9-fold more ADP and 4.9-fold more ATP than releasates from stimulated platelets alone. Following aspirin ingestion, TXB2 formation was blocked, but erythrocyte promotion of platelet reactivity persisted at those doses of collagen that reinduced platelet activation. Moreover, when platelet mixtures consisted of as little as 10% obtained before aspirin plus 90% obtained post-aspirin ingestion, significant erythrocyte enhancement of platelet reactivity occurred, even at low agonist concentrations. These erythrocyte effects would decrease the therapeutic potential of inhibition of platelet cyclooxygenase by aspirin. The erythrocyte-induced modulation of platelet biochemistry and function emphasizes the importance of cell-cell interactions in stimulus-response coupling.

Adenosine Diphosphate↗
PubMed1991

Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment.

Erythrocytes are known to influence hemostasis. Bleeding times are prolonged in anemia and corrected by normalizing the hematocrit. We now demonstrate that intact erythrocytes modulate biochemical and functional responsiveness of activated platelets. A two-stage procedure, permitting studies of cell-cell interactions and independently evaluating platelet activation and recruitment within 1 min of stimulation, was developed. Erythrocytes increased platelet serotonin release despite aspirin treatment, enzymatic adenosine diphosphate removal, protease inhibition, or combinations thereof. The data suggested that erythrocyte enhancement of platelet reactivity can reduce the therapeutic effectiveness of aspirin. Erythrocytes metabolically modified platelet arachidonate or eicosapentaenoate release and eicosanoid formation. They promoted significant increases in cyclooxygenase and lipoxygenase metabolites upon platelet stimulation with collagen or thrombin. However, with ionophore, erythrocytes strongly reduced platelet lipoxygenation. These erythrocyte modulatory effects were stimulus-specific. Activated platelet-erythrocyte mixtures, with or without aspirin, promoted 3-10-fold increases in extracellular free fatty acid, which would be available for transcellular metabolism. Erythrocyte-induced increases in free eicosapentaenoate may contribute to antithrombotic and anti-inflammatory effects of this fish oil derivative. These results provide biochemical insight into erythrocyte contributions to thrombosis and hemostasis, and support the concept of thrombus formation as a multicellular event.

Adenosine Diphosphate↗
PubMed1989

Arachidonate incorporation into rat aorta lipid fractions and eicosanoid formation. Effect of prolonged prostacyclin production.

Endogenous arachidonic acid (AA) content, incorporation of radiolabelled AA (AA*) into total lipids, main lipid fractions and different phospholipids (PL), and prostanoid formation have been evaluated in fresh (control) rat arteries and in arteries after 180 min of incubation in buffer (exhausted). The results show that PGI2 formation from endogenous AA decreased 90% in exhausted arteries while AA content decreased only 30%. The total AA* incorporation was significantly higher in exhausted arteries than in controls (p less than 0.01). The distribution of AA* in lipids is altered in exhausted arteries; it increases in total PL, particularly in phosphatidylethanolamine, and decreases in phosphatidylcholine and phosphatidylserine + phosphatidylinositol. AA* content was also lower in triglycerides and esterified cholesterol of exhausted arteries than in control arteries. The AA* metabolized to PGI2 was 83% lower in exhausted arteries than in controls, while PGE2 and TXB2 formation were not modified by the exhaustion process. When the effect that longer incubation in plasma (180 min) has on AA metabolism and turnover was evaluated, PGI2 formation from endogenous AA was found to be increased in comparison with arteries incubated for the de same period in buffer, and the changes observed in the distribution of AA in lipid fractions are smaller than those found in buffer-exhausted aortas. The results of the present study indicate that prolonged production of prostanoids leads to an alteration in AA turnover and to an inactivation of the PGI2-forming system. Plasma seems to protect AA metabolism.

Animals↗
PubMed1988

Antiplatelet activity of dipyridamole in non anticoagulated whole blood.

Dipyridamole has been reported to inhibit platelet aggregation in citrate anticoagulated whole blood (WB). However, citrate may alter the response of platelets and/or the effect of antiplatelet drugs. The present study evaluates the "ex vivo" effect of dipyridamole, two hours after a single dose (3 mg/Kg) in 25 normal subjects in non-anticoagulated (native) WB and in WB anticoagulated with citrate or hirudin. We have used the BASIC anticoagulated with citrate or hirudin. We have used the BASIC wave as analytical method, which can evaluate the early steps of platelet activation with collagen in less than 1 min after venoclysis, thus allowing the study in native WB. The results show that dipyridamole significantly inhibits (p less than 0.001) platelet activation to collagen in citrated WB (66%) while the drug's effect is much lower (21%) and non-significant if evaluated in native or hirudine anticoagulated WB. These results suggest that citrate or low calcium concentration amplify the drug's platelet inhibitory action in WB and, therefore, the laboratory results may overestimate the drug's effect "in vivo".

Adult↗
PubMed1988

Composition of platelet fatty acids and their modulation by plasma fatty acids in humans: effect of age and sex.

This study evaluates the influence of sex on platelet fatty acid (FA) composition, and whether sex differences are conditioned by age. Since plasma FA have a specific relationship with platelet FA their variations with age and sex are also considered. Forty-nine male-female human couples (16-75 years), where within each couple the partners were on qualitatively similar diets and of similar age, were studied. Few differences were found between the whole groups of men and women in platelet FA. A comparison of data on FA in platelet phospholipids (PL) from 3 age groups (16-40, 40-60 and over 60) showed an increase in saturated FA of middle-aged subjects, an age-dependent decrease in 20: 5 in both sexes and of 18: 2 mainly in women. The percentage of plasma phosphatidylserine plus phosphatidylinositol decreased in middle-aged subjects. With regard to the influence of FA of plasma PL on FA of platelet PL, we found a higher correlation coefficient (r) for 16:0 and 18:0 and 20:4 and a lower one for 20:5 in middle-aged men and post-menopausal women. Considering that an increase in saturated FA and 20:4 and a decrease in 20:5 in platelet PL may increase platelet function, the plasma FA influence on platelets may help to explain the higher incidence of CHD in those groups of subjects.

Adolescent↗
PubMed1987

Effect of postprandial lipaemia on platelet function in man evaluated in whole blood.

The effect of a fatty meal (100 g of fat) on platelet function is evaluated. Two hours after the fat intake (dairy cream) there is a significant reduction in the initial stages of platelet activation by collagen (1 and 0.5 micrograms/ml) as measured by a new analytical method, the BASIC wave, and by the decrease in the beta-Thromboglobulin released by stimulated platelets. This effect is greater in platelet rich plasma (PRP) than in whole blood. Red blood cells (RBC) have a potentiating effect on platelet activation by collagen both before and after the fat intake which is indicated by an increase in the BASIC wave intensity. No significant differences were found, however, in platelet aggregation in PRP or whole blood evaluated by impedance aggregometry. These results suggest that the increase of chylomicrons after fat intake has an inhibitory effect on platelet activation but does not modify platelet aggregation. In addition, it seems that lipaemia does not modify RBC interactions with platelets in collagen stimulated samples.

Animals↗
PubMed1986

Role of red blood cells in the early stages of platelet activation by collagen.

Red blood cells (RBC) increase the proaggregatory capacity of a cell-free supernatant obtained by stimulating platelet-rich plasma (PRP) samples with collagen (1 microgram/ml) as measured by the BASIC wave; this effect increases with the number of RBC and is proportionally greater with a lower number of platelets or when lower collagen concentrations are used. Aspirin (ASA) modifies the RBC behaviour in relation to their platelet-collagen interaction. This is demonstrated by the fact that when PRP and RBC obtained from the same subjects before and two hours after the ingestion of ASA (0.5 g) were mixed, it was found that non-ASA-RBC stimulate ASA-PRP, probably through a platelet cyclooxygenase independent pathway; ASA-RBC, however, stimulate non-ASA-PRP, but not ASA-PRP, which suggests that they may need an active platelet cyclooxygenase system for their action. This effect of ASA on RBC is not transient and was also observable 48 h after ASA ingestion. In addition, it was found that ASA-RBC greatly increase the activation of a mixture containing a small proportion of non-ASA-PRP in ASA-PRP, a situation that is expected to be encountered "in vivo" after ASA treatment. This effect of ASA-RBC on platelet activation may help to explain the sometimes contradictory clinical effect of aspirin as an antithrombotic drug.

Adult↗
PubMed1986

Effect of oral contraceptives on plasma and platelet lipid composition. Influence of the length duration of time of ingestion.

The action of oral contraceptives (OC) (50 micrograms ethinylestradiol +250 micrograms levonorgestrel) on plasma and platelet lipid composition was studied in two groups of women who took this OC for one year, or for a longer period of time (2-9 years). Comparison with the control group showed that the ingestion of OC modifies the composition of some fatty acids in plasma and platelets. This modification is more marked in the women who took OC for one year. In plasma a decrease in linoleic acid (18:2) was found in the cholesterol and phospholipid fractions. In platelets, an increase of stearic acid (18:0) was observed in phospholipids, triglycerides and free fatty acid fractions. The modifications observed in plasma and platelets were not parallel, which suggests a specific and different action of OC on both plasma and platelets. Finally, it is suggested that the lipid variations found in the group that took the OC for one year may be compatible with a platelet hyperfunction.

Adult↗
PubMed1985

Early platelet-collagen interactions in whole blood and their modifications by aspirin and dipyridamole evaluated by a new method (BASIC wave).

It is shown that the supernatant of unstirred whole blood at 37 degrees C, stimulated by 1 microgram/ml of collagen for 10 sec, produces a rapid generation of pro and antiaggregatory compounds with a final proaggregatory activity which can be detected for more than 60 min on a platelet rich plasma (PRP) by turbidometric aggregometry. A reversible aggregation wave that we have called BASIC wave (for Blood Aggregation Stimulatory and Inhibitory Compounds) is recorded. The collagen stimulation of unstirred PRP produces a similar but smaller BASIC wave. BASIC's intensity increases if erythrocytes are added to PRP but decreases if white blood cells are added instead. Aspirin abolishes "ex vivo" the ability of whole blood and PRP to generate BASIC waves and dipyridamole "in vitro" significantly reduces BASIC's intensity in whole blood in every tested sample, but shows little effect in PRP.

Adult↗
PubMed1985

Prostacyclin production by rat aorta "in vitro" is increased by the combined action of dipyridamole plus pentoxifylline.

The present study evaluates the effect of dipyridamole and pentoxifylline, individually and in combination, on PGI2-like production and arachidonic acid metabolism of rat aorta "in vitro". Pentoxifylline 100 microM and dipyridamole 92 and 184 microM increased PGI2-like activity, as measured by the platelet aggregation inhibitory capacity of the aortic ring incubates, by 71%, 46% and 60% respectively; a greater increase in PGI2-like activity was observed with the combination of the drugs than when they were used separately. This effect was observed even at the lowest doses assayed. In fact, dipyridamole 9.2 microM plus pentoxifylline 1 microM increased the PGI2-like activity by 30% while the individual increase was 4.5% and 10.6% respectively. To obtain more information on the effect of the dipyridamole-pentoxifylline combination on arachidonic acid metabolism, arteries were incubated with (1-14C) arachidonic acid, and the 6-keto-PGF1 alpha and PGE2 quantified. Dipyridamole 92 microM plus pentoxifylline 1 and 10 microM increased 6-keto-PGF1 alpha and PGE2 production by about 30% and 48% respectively while the combination with pentoxifylline 100 microM increased the 6-keto-PGF1 alpha 76.5% and the PGE2 50%. The possible biological effect and therapeutic implications of increased PGI2 production by the arteries due to the dipyridamole-pentoxifylline combination remains to be ascertained.

Animals↗
PubMed1984

Influence of some plasma fatty acids on the phospholipid fatty acid pattern of human platelets--an "ex vivo" experience.

Some correlations between plasma and platelet fatty acids (FA) were evaluated "ex vivo" in 94 normal subjects. The highest relationships between total FA from plasma and platelets were found for 18:1 (r = 0.74) and 18:2 (r = 0.67). Low correlations were obtained for free fatty acids (FFA). The most significant correlations between fatty acids esterifying plasma and platelet phospholipids were found for the 18:1 (r = 0.66); 18:2 (r = 0.74) and 20:5 (r = 0.66). Our results suggest that the platelet phospholipid FA could be more easily modified by plasma variation in the FA composition of phospholipids than by variations in the plasma FA composition of the FFA fraction. In addition, the incorporation of FA from plasma into the platelet phospholipids "in vivo" may take place through an acylation-deacylation process and also by the incorporation of whole plasma phospholipid molecules into the platelets, probably through an exchange of plasma lipoproteins and platelets. Finally, arachidonic acid seems to have a different and selective way of incorporation into platelet phospholipids.

Adult↗
PubMed1984

Effect of smoking on plasma and platelet fatty acid composition in middle-aged men.

The effect of tobacco cigarette smoking on plasma and platelet fatty acid composition was studied in 219 male subjects. The effect of tobacco on plasma malondialdehyde-like material (MDA-LM) was also evaluated. In the total fatty acid percentage composition in plasma, an increase in the saturated fatty acids at the expense of polyunsaturated fatty acids was observed in those subjects who smoked more than 20 cigarettes/day. In the total fatty acid composition of platelets, an increase in myristic acid (14:0) and palmytoleic acid (16:1) was found. Additionally, when the fatty acid composition of the different platelet lipid fractions was evaluated, an increase in 14:0 and 16:0 + 16:1 was observed in phospholipids. Finally, the plasma MDA-LM level was significantly higher in those subjects who smoked more than 10 cigarettes/day. The biochemical variations found in this study may be compatible with the greater incidence of CHD observed in smokers.

Adult↗
PubMed1983

Serum malondialdehyde-like material (MDA-LM) in acute myocardial infarction.

Serum malondialdehyde-like material (MDA-LM), as an index of lipid peroxidation, and the serum enzymes CK, CK-MB, LDH, LDH1 and, alpha-HBDH were evaluated in a group of 26 patients with acute myocardial infarction (AMI), seven with angina pectoris (AP), and in a normal control group of 94 subjects. MDA-LM values were within the normal range in AP patients, while in AMI patients a significant increase in serum MDA-LM was observed in the days following the acute event, reaching a maximum 6-8 days later, when 90% of the patients had values higher than the upper normal limit (mean +/- 2SD) of the control group. A significant correlation was found between the integrated concentration-time MDA-LM curve and the integrated serum enzymes activity curves reached during the nine days after the acute event. The "in vivo" relevance of the increased serum MDA-LM in the post-infarct period is unknown at the present, but as lipid peroxides are known to harm cellular structures and to inhibit prostacyclin synthesis, it may be of interest with regard to the long term secondary effects in AMI patients.

Adult↗
PubMed1982

Elevated lipid peroxide levels in platelets of chronic ischemic heart disease patients.

A significantly higher platelet malondialdehyde-like material (MDA--LM) content after physical and N-ethylmaleimide (NEM) stimulation is found in chronic ischemic heart disease (CHD) patients when compared to the control group. In subjects under aspirin treatment "in vivo" (1 gr/day) no difference is found between CHD and control group. It is suggested that the enhanced amount of lipid peroxides in CHD platelets is produced by a cyclooxygenase-dependent mechanism. This enhanced platelet lipid peroxide production in CHD may be another platelet-dependent risk factor for atherosclerosis in these patients.

Anticoagulants↗