Effects of enprostil on platelets, endothelial cells, and other cell types, and second messenger systems by which these effects are mediated.

In human blood platelets, thromboxane A2, prostaglandin E2, and its analogue enprostil activate protein kinase C and promote the second phase of aggregation, whereas prostacyclin and prostaglandin E1 activate adenylate cyclase and inhibit aggregation. In each case, a characteristic group of proteins is phosphorylated following agonist binding. These observations may be related to the inhibitory effect of enprostil on the activation of adenylate cyclase in gastric parietal cells, which follows binding of histamine to H2 receptors. Another system in which enprostil opposes the effect of histamine is the microvasculature. Histamine binds to H1 sites on endothelial cells and induces changes in their shape that allow macromolecules to pass between them into the extravascular compartment. This effect may be mediated by activation of protein kinase C. Pretreatment with enprostil antagonizes the increase in vascular permeability induced by histamine and presumably other inflammatory mediators. Preservation of the integrity of the microvasculature of the gastric mucosa against the effects of cyclo-oxygenase inhibitors, ethanol, and other damaging agents may contribute to the mucosal protective effects of enprostil and some other prostaglandins.