thromboxane-a2 and Substance-Withdrawal-Syndrome

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

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