thromboxane-a2 and Alcoholism

We had previously reported a decrease in agonist-induced platelet dense granule secretion in blood samples from male adolescents with and without Conduct Disorder (CD). In an augmented sample, we have now employed multivariate modeling to examine the simultaneous effects of CD and regular monthly alcohol and marijuana use on both the dense granule secretion and aggregation phases of agonist-induced platelet responses.. Blood samples were obtained from adolescents with and without a CD diagnosis. Platelet dense granule secretion and aggregation responses to a variety of agonists were examined in the laboratory.. Significant multivariate interactions of CD status with regular marijuana use were found for responses to collagen, ADP alone, and ADP plus 0.2 microgram. of serotonin. Responses in platelets from youth with CD, but without regular marijuana use differed from other subjects. Multivariate main effects of marijuana use alone on platelet responses to arachidonic acid and ADP plus 1.0 microgram. of serotonin were found. No effects of alcohol use were found.. The results demonstrate an interaction between CD and the effects of chronic marijuana use for several agonists in this platelet model system, and further support the possibility of a variation in signal transduction mechanisms in CD.

Topics: Adenosine Diphosphate; Adolescent; Alcoholism; Cell Communication; Cell Count; Chronic Disease; Conduct Disorder; Cytoplasmic Granules; Humans; Male; Marijuana Abuse; Platelet Aggregation; Psychiatric Status Rating Scales; Serotonin; Signal Transduction; Thromboxane A2

The effects of dietary cholesterol and chronic administration of moderate amounts of ethanol on collagen-induced platelet responses were investigated. Three groups of rabbits were fed the following diets for 8 weeks: a normal chow diet, a cholesterol-enriched (0.25% wt/wt) chow diet, and a cholesterol-enriched chow diet plus 6% ethanol in the drinking water for the final week of the dietary period. Cholesterol feeding enhanced collagen-induced responses-aggregation, secretion of [14C]serotonin from prelabeled platelets, and thromboxane formation--of suspensions of washed platelets, and chronic ethanol treatment significantly reduced these enhanced responses. These effects are mediated by thromboxane A2 (TxA2) rather than ADP. Experiments with collagen-stimulated platelets in which feedback amplification of TxA2 was blocked with the prostaglandin H2/TxA2 receptor blocker BM 13.177 and experiments with aspirin-treated platelets stimulated with the stable TxA2 mimetic U46619 showed that cholesterol feeding enhanced platelet sensitivity to TxA2 rather than formation of TxA2 by platelets that had interacted with collagen. Without BM 13.177 or aspirin, TxA2 increased the amount of TxA2 formed by feedback amplification. In contrast, decreased responsiveness to collagen by platelets from cholesterol-fed rabbits given ethanol was due to inhibition of TxA2 formation rather than reduced sensitivity to TxA2. Platelets from cholesterol-fed rabbits given ethanol did not develop tolerance to the acute inhibitory effects of ethanol. Our results indicate that administration of moderate amounts of ethanol to cholesterol-fed rabbits inhibits enhanced collagen-induced responses of platelets by a TxA2-dependent pathway that involves reduction of TxA2 formation rather than reduction of platelet responses to TxA2.

Topics: Alcoholism; Animals; Blood Platelets; Cholesterol, Dietary; Collagen; Hypercholesterolemia; Male; Rabbits; Sensitivity and Specificity; Thromboxane A2

The paper considers the significance of prostacyclin-thromboxane (PGI2/TxA2) balance for cardiovascular performance in health and in angina pectoris and myocardial infarction. The functional interaction between prostacyclin and thromboxane was examined in terms of a number of risk factors for coronary heart disease (CHD), such as ageing, atherosclerosis, arterial hypertension, diabetes mellitus, obesity, hypokinesia, smoking, alcoholism, sex differences, and predisposition to the disease. A unidirectional pattern of changes in the PGI2/TxA2 balance towards TxA2 was found in CHD and in the presence of all the aforementioned risk factors. The paper discusses possible mechanisms responsible for these changes, as well as their contribution to the pathogenesis and prevention of CHD.

Topics: Adult; Aged; Alcoholism; Coronary Disease; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Risk Factors; Smoking; Thromboxane A2

Platelet function in alcoholic patients was assessed on admission and during abstinence in hospital. On admission platelets from these patients were significantly less responsive (percentage aggregation and thromboxane A2 release) to conventional in vitro aggregating agents (adrenaline, adenosine diphosphate, and collagen) than platelets from healthy, moderate drinkers. Initially, platelet counts in platelet rich plasma tended to be low and the Simplate II bleeding times frequently prolonged. Platelet aggregation and thromboxane A2 release, however, were inhibited even in patients with normal platelet counts on admission. Platelet aggregation and thromboxane A2 release returned to normal or became hyper-responsive during two to three weeks of abstinence. Platelet counts rose during this period, the largest responses occurring in those patients with the lowest counts on admission. Bleeding times reverted to normal during abstinence and correlated significantly with changes in platelet aggregation, thromboxane A2 release, and platelet count and with the estimated ethanol consumption during the week before admission. Chronic, heavy alcohol ingestion evidently exerts an inhibitory effect on platelet function even in the absence of alcohol in the blood, and this phenomenon is reversible on abstaining. The impaired platelet function, together with the reduced platelet count, may contribute to the bleeding diathesis associated with chronic alcoholism and to the increased incidence and recurrence of gastrointestinal haemorrhage associated with excessive alcohol intake.

Topics: Adult; Alcohol Drinking; Alcoholism; Bleeding Time; Blood Platelets; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Thromboxane A2; Thromboxane B2

To study the effects of chronic alcohol consumption on platelet functions, the rate of arachidonate-induced platelet aggregation, the production of malondialdehyde in platelets, and plasma levels of prostaglandin endoperoxide metabolites were examined in 88 chronic alcoholics and 24 healthy controls. The rate of platelet aggregation and the production of malondialdehyde in platelets were greater in chronic alcoholics both on admission and 1 week after. However, these alterations returned to the level of healthy controls within 4 weeks of abstinence from alcohol and were independent of the number of circulating platelets. Furthermore, on admission, plasma levels of thromboxane B2 were significantly increased in chronic alcoholics when compared with those of healthy controls (400.8 +/- 36.5 versus 241.7 +/- 28.9 pg/ml plasma; p less than 0.025) and were also significantly correlated with malondialdehyde production in washed platelet debris (r = 0.6049; p less than 0.001). In contrast, plasma levels of 6-keto prostaglandin F1 alpha and prostaglandin E were not altered after chronic alcohol consumption. As a result, the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 was markedly decreased in chronic alcoholics (0.31 +/- 0.03 versus 0.62 +/- 0.13; p less than 0.001). These results strongly suggest that the imbalance in prostaglandin endoperoxide metabolites is produced by chronic alcohol ingestion. Moreover, a significant correlation was observed between platelet aggregation rate and malondialdehyde production during platelet aggregation (r = 0.559; p less than 0.005). Thus, we conclude that chronic alcohol consumption alters platelet thromboxane metabolism, which is likely associated with the increased ability of platelets to aggregate.

Topics: Adult; Alcoholism; Blood Platelets; Humans; Male; Malondialdehyde; Middle Aged; Platelet Aggregation; Platelet Count; Prostaglandin Endoperoxides; Prostaglandins; Thromboxane A2; Thromboxane B2

Formation of thromboxane B2 (TXB2), a metabolite of the potent platelet-aggregating and vasoconstrictor agent thromboxane A2 (TXA2), during ADP-induced platelet aggregation was studied in 10 healthy men and in 10 male alcoholics during the 2-week period of detoxification. None of the alcoholics had anemia or thrombo-embolic disease. The platelets of the alcoholics were more sensitive for ADP and synthesized as much as triple the amount of TXB2 compared to those of the nonalcoholic donors. The effect was most striking during the rebound thrombocytosis and suggests that it could possible contribute to the increased incidence of various thrombotic diseases in the alcoholic.

Topics: Adult; Alcoholism; Cerebrovascular Disorders; Humans; Male; Platelet Aggregation; Substance Withdrawal Syndrome; Thromboxane A2; Thromboxanes