6-ketoprostaglandin-f1-alpha 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

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