Systemic and pulmonary hypertension after abrupt cessation of prostacyclin: Role of thromboxane A(2)

Chronic administration of prostacyclin (PGI(2)) 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 PGI(2) results in platelet activation, thromboxane A(2) production, and increased pulmonary vascular tone. To test this, six sheep with indwelling catheters were monitored during infusion of PGI(2) and after its cessation. Infusion of PGI(2) 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 PGI(2), 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 B-2 levels were not elevated during infusion or after cessation of PGI(2). We conclude that the abrupt cessation of PGI(2) infusion leads to systemic and pulmonary hypertension and transient cardiac dysfunction not mediated by cyclooxygenase metabolites of arachidonic acid.