thromboxane-b2 and Substance-Withdrawal-Syndrome

Urinary excretion of 2,3-dinor-thromboxane B2 as a marker of in vivo thromboxane A2 (TxA2) biosynthesis was measured in six alcoholics 1 and 14 days after the cessation of heavy drinking using gas chromatography/mass spectrometry. Six non-alcoholic healthy volunteers served as controls. One day after alcohol withdrawal the excretion of the dinor metabolite was significantly higher (P < 0.01) in the alcoholics (408 +/- 42 pg mg-1 creatinine) than in the controls (180 +/- 30 pg mg-1 creatinine) and was accompanied by a significantly reduced platelet count (103.0 +/- 20.2 x 10(9) l-1 vs. 194.0 +/- 13.9 x 10(9) l-1 in controls; P < 0.01). The metabolite excretion fell then significantly (P < 0.05) to 245 +/- 53 pg mg-1 creatinine 14 days after alcohol withdrawal and this was paralleled by an increase in platelet count to 453.5 +/- 72.0 x 10(9) l-1 (P < 0.05). The present results support the hypothesis that Tx-A2 biosynthesis is increased in early alcohol withdrawal and strongly suggest platelets as a cellular origin of the increased TxA2 formation.

Topics: Adult; Alcoholism; Female; Humans; Male; Platelet Count; Substance Withdrawal Syndrome; Thromboxane B2

Chronic administration of prostacyclin (PGI2) improves hemodynamics in patients with primary pulmonary hypertension, but abrupt cessation of infusion can cause severe dyspnea of unknown etiology. We hypothesized that the discontinuation of PGI2 results in platelet activation, thromboxane A2 production, and increased pulmonary vascular tone. To test this, six sheep with indwelling catheters were monitored during infusion of PGI2 and after its cessation. Infusion of PGI2 caused a reduction in mean systemic arterial pressure (MAP) and systemic (SVR) and pulmonary vascular resistances (PVR), a rise in cardiac output (CO), and no change in pulmonary arterial or pulmonary capillary wedge pressure (PCWP). After discontinuation of PGI2, MAP and SVR rebounded to 30 and 67% above baseline, respectively, and PVR rose 26%. CO was depressed 23% within 10 min, and PCWP nearly doubled after stoppage of the drug. Concurrent treatment with a cyclooxygenase inhibitor did not attenuate these responses. 11-Dehydro-thromboxane B2 levels were not elevated during infusion or after cessation of PGI2. We conclude that the abrupt cessation of PGI2 infusion leads to systemic and pulmonary hypertension and transient cardiac dysfunction not mediated by cyclooxygenase metabolites of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Hypertension; Hypertension, Pulmonary; Infusions, Intravenous; Platelet Activation; Platelet Aggregation Inhibitors; Pulmonary Circulation; Sheep; Substance Withdrawal Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasodilation

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.

Topics: Adult; Aged; Alcoholism; Blood Platelets; Calcium; Ethanol; Female; Hemorrhagic Disorders; Humans; Male; Middle Aged; Platelet Activating Factor; Platelet Aggregation; Serotonin; Smoking; Stimulation, Chemical; Substance Withdrawal Syndrome; Thromboxane B2

Collagen-, arachidonate- and ADP-stimulated platelet thromboxane B2 (TXB2) formation was studied in platelet-rich plasma (PRP) of 14 alcoholics, 7 of whom had a biopsy-verified alcoholic fatty liver. On admission for detoxication, the alcoholics showed decreased platelet count and aggregability (p less than 0.001) as compared to nonalcoholic healthy controls. Platelet TXB2 formation was decreased (p less than 0.01), if PRP was stimulated by arachidonate, but not if it was stimulated by ADP or collagen. In contrast, 9-14 days after ethanol withdrawal platelet TXB2 formation had increased to markedly higher levels than those seen in nonalcoholic controls (p less than 0.01), if PRP was stimulated by ADP, but not if it was stimulated by arachidonate or collagen. Skin bleeding time was found to be prolonged (p less than 0.05) on admission in alcoholics having fatty liver, but it normalized within 2 weeks after ethanol withdrawal. We conclude that the effect of ethanol withdrawal in alcoholics on platelet TXB2 formation is influenced by platelet count, aggregability and the agonist used to induce platelet aggregation.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Arachidonic Acid; Arachidonic Acids; Bleeding Time; Blood Platelets; Collagen; Ethanol; Female; Fibrinogen; Humans; Liver Diseases, Alcoholic; Male; Middle Aged; Platelet Aggregation; Platelet Count; Serum Albumin; Substance Withdrawal Syndrome; Thromboxane B2

The effect of ethanol on the formation of platelet thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2) was studied in vitro in six chronic alcoholics, admitted for detoxification, and in six healthy volunteers. Immediately after cessation of heavy drinking platelet count and ADP-induced TXB2 formation were lower in alcoholics than in nonalcoholic volunteers (P less than 0.05). Ten days after withdrawal of ethanol platelet count increased, and skin bleeding time shortened (P less than 0.05). Ethanol had no effect on arachidonate-induced platelet TXB2 formation, whereas ethanol added to platelet suspension prior to stimulation by ADP resulted in a concentration-related inhibitory tendency in both alcoholics and nonalcoholic control subjects. This effect of ethanol may be of significance for primary hemostasis in alcoholics.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Blood Platelets; Ethanol; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Thromboxane B2

Changes in the kinetic variables of the platelet serotonin uptake, Km and Vmax, were studied in 7 male alcoholics, admitted for detoxification and in sex- and age-matched volunteers. On admission the alcoholics had lower Km values than reference subjects (p less than 0.05). During detoxification the Km values normalized. Vmax was normal throughout the study in spite of the changes in platelet count. The results of the study suggest that the affinity of serotonin to its uptake receptor is transiently increased after a period of heavy drinking.

Topics: Adult; Alcoholism; Blood Platelets; Carbon Radioisotopes; Ethanol; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Receptors, Cell Surface; Serotonin; Substance Withdrawal Syndrome; Thromboxane B2

1. The rates of secretion into the circulation of prostaglandin E, prostacyclin, and thromboxane A2 were estimated in male alcoholics on the third day of withdrawal and in control subjects by measuring appropriate metabolites in urine. 2. Urinary levels of tetranor-5,11-diketo-7 alpha-hydroxyprostane-1,16-dioic acid (the major urinary metabolite of prostaglandins E1 and E2), of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) and of 6-keto-prostaglandin F1 alpha (the stable hydrolysis product of prostacyclin) were significantly different from the normal subjects in the alcoholic group. In contrast, 2,3-dinor-thromboxane B2 (the major urinary metabolite of thromboxane A2) and thromboxane B2 (the stable hydrolysis product of thromboxane A2) were not significantly different between the groups. 3. These data suggest that the ratio of the vasodilator prostanoids prostaglandin E and prostacyclin and the vasoconstrictor prostanoid thromboxane A2 is lower than in normal subjects, in alcoholics during withdrawal. This may be one causal factor for the higher incidence of hypertension observed in withdrawing alcoholics compared with control subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Alcoholism; Epoprostenol; Ethanol; Humans; Male; Middle Aged; Prostaglandins E; Prostanoic Acids; Substance Withdrawal Syndrome; Thromboxane B2; Thromboxanes

The excretion of 2,3-dinor-6-keto prostaglandin F1 alpha, a major urinary metabolite of prostacyclin, and the formation of thromboxane B2, a stable metabolite of thromboxane A2, by platelets stimulated by adenosine diphosphate, were studied in alcoholics, who had been admitted for detoxification. Once prolonged heavy drinking had stopped, platelet count and thromboxane formation, calculated either per 10(7) platelets or per litre of blood, significantly increased (p less than 0.05), while the skin bleeding time and urinary excretion of the metabolite of prostacyclin decreased (p less than 0.05). The balance between prostacyclin and thromboxane therefore seemed to favour the excretion of prostacyclin while it shifted to favour thromboxane formation about a week later.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Alcoholism; Bleeding Time; Blood Platelets; Humans; Male; Middle Aged; Platelet Count; Substance Withdrawal Syndrome; Thromboxane B2; Time Factors

Platelet phosphatidylinositol and phosphatidylcholine composition, ADP-induced platelet aggregation and associated thromboxane B2 formation were studied in alcoholics after a period of heavy drinking and in healthy non-alcoholic volunteers. The composition of these phospholipids in alcoholics was different from that seen in the control subjects. The most prominent change was a decrease in the relative amount of stearoyl-arachidonoyl species in the phosphatidylinositol fraction. Particularly this species of PI might be involved in the transmission of transmembrane signals. During detoxification changes were also observed in the extent of ADP-induced platelet aggregation and the amount of thromboxane B2 produced. Changes in platelet phospholipid composition might influence platelet reactivity in alcoholics.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Blood Platelets; Ethanol; Humans; In Vitro Techniques; Male; Middle Aged; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Platelet Aggregation; Substance Withdrawal Syndrome; Thromboxane B2

Platelet count, mean volume, aggregation and associated thromboxane (TXB2) formation, circulating platelet aggregates and bleeding time were examined in 19 noncirrhotic male alcoholic cigarette smokers for four weeks following cessation of prolonged heavy drinking, and in 24 nonalcoholic healthy male volunteers (10 smokers and 14 nonsmokers). The alcoholics showed a 9-fold increase (p less than 0.001) in ADP-stimulated platelet thromboxane formation one to two weeks after ethanol withdrawal. The effect was transient and coincided with a significant (p less than 0.01) shortening of skin bleeding time and a slight increase in circulating platelet aggregates suggesting proneness to thrombosis. No differences were seen between the smoking and nonsmoking healthy volunteers. We conclude that the recovery phase after prolonged heavy drinking is characterized by a transient increase in platelet reactivity which may lead to increased spontaneous formation of circulating platelet aggregates and shortening of bleeding time.

Topics: Adult; Alcoholism; Bleeding Time; Blood Platelets; Blood Volume; Ethanol; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Reference Values; Smoking; Substance Withdrawal Syndrome; Thromboxane B2