Desensitization of agonist-stimulated prostacyclin release in human umbilical vein endothelial cells.

Prostacyclin (PGI2) release was studied in perfused columns of human umbilical vein endothelial cells cultured on microcarrier beads. Substantial homologous desensitization of PGI2 release occurred when cells were exposed to agonist for 2 min after a previous exposure; the extent depended on the concentration and duration of the first challenge. Recovery from exposure to ATP or bradykinin was complete in less than 80 min; recovery from thrombin was incomplete after greater than 80 min, and this was apparently related to its proteolytic activity. Experiments with ibuprofen, a reversible inhibitor of cyclo-oxygenase, demonstrated that homologous desensitization did not involve inactivation of cyclo-oxygenase. ATP and bradykinin did not induce heterologous desensitization. Thrombin and trypsin induced cross-desensitization, but neither agonist significantly reduced responses to ATP or bradykinin, suggesting that a common proteolytic mechanism is responsible for their ability to induce PGI2 synthesis. We conclude that desensitization of PGI2 release in response to physiological agonists is generally agonist-specific and involves modulation of molecular events at or close to the receptors involved, rather than inactivation of prostanoid biosynthesis.