Different mechanisms of homologous and heterologous desensitization of thrombin-induced endothelial prostacyclin production

Several workers have described desensitization of endothelial prostacyclin production but conflicting evidence has been published regarding the mechanism of desensitization, whether it is homologous (agonist specific) or heterologous, and whether inactivation of cyclooxygenase is involved. The purpose of the present study was to determine the relation between the intensity of a first thrombin stimulus and the subsequent response to a repeat thrombin, histamine, ionophore A23187 or aluminium fluoride (AlF₄) stimulation and to determine possible targets of desensitization. Following thrombin stimulation of confluent cultured human umbilical vein endothelial cells (HUVEC) only homologous desensitization of inositol phosphate production was observed. Both homologous and heterologous desensitization of arachidonic acid release and prostacyclin production occurred, the latter towards both histamine and the ionophore A23187. For any given dose of the first stimulant there was a much greater effect on the homologous response than on the heterologous response. These differences suggest different mechanisms. The homologous desensitization probably involves the receptor whereas the present results suggest that the target of heterologous desensitization is distal to calcium mobilization in the signal transduction pathway. The possibilities include decreased activity of phospholipase A₂ or a decreased pool of accessible arachidonic acid.