title: Refractoriness of platelets to prostaglandins after infusion in rabbits.
abstract: Continuous intravenous infusion of prostacyclin (prostaglandin I2, PGI2) in rabbits induced refractoriness to PGI2-induced inhibition of platelet function. Although inhibited during earlier stages, platelet response to adenosine diphosphate and thrombin became normal within 24 hours of PGI2 infusion. Cross-mixing experiments with platelets and plasma from infused and control animals suggested that the altered response to PGI2 was caused by a defect intrinsic in the platelets. PGI2-stimulated cyclic adenosine monophosphate (cAMP) production was reduced in platelets from infused rabbits as compared with those from controls. Platelets refractory to PGI2 were refractory to PGE1 and PGD2, as well. Because PGE1 but not PGD2 shares the same platelet receptor as PGI2, the phenomenon could not be ascribed to receptor-specific downregulation, which was also shown by refractoriness of platelets from infused rabbits to the nonprostanoid inhibitor of platelet function adenosine. Either increased concentrations of ineffective inhibitors or their combination with phosphodiesterase inhibitors overcame refractoriness of resistant platelets, which also responded to inhibition by dibutyryl cAMP, indicating residual activity of adenylate cyclase. That at least the catalytic subunit of the enzyme was still working in refractory platelets was shown by inhibition of aggregation induced by forskolin, a non-receptor-mediated activator of adenylate cyclase. Impairment of the adenylate cyclase regulatory subunit, possibly accompanied by multireceptor downregulation, may explain the paradoxical refractoriness of platelets to prolonged infusion of PGI2. Such an effect may limit the benefit of PGI2 in treatment of thromboembolic disease.
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000097:blood; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D015230:Prostaglandin D2; D011457:Prostaglandins D / Q000494:pharmacology; D011817:Rabbits; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: D011457:Prostaglandins D; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D005576:Colforsin; D015121:6-Ketoprostaglandin F1 alpha; D003994:Bucladesine; C022950:6-ketoprostaglandin E1; D011464:Epoprostenol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000527:Alprostadil; D015230:Prostaglandin D2