Up-regulation of hepatic prostaglandin E receptors in vivo induced by prostaglandin synthesis inhibitors.

Up-regulation in vivo of liver plasma membrane receptors for prostaglandin E (PGE) was studied in Sprague-Dawley rats using the prostaglandin synthesis inhibitors, acetylsalicylic acid (ASA) and indomethacin (Indo). Following 4 days of treatment with ASA, the concentration of receptors and the affinity for binding were both significantly increased (Ro - +37%, KA = +62%). Following 4 days of treatment with Indo, the number of receptors was increased but the binding-site affinity was decreased (Ro = +40%, KA = -71%). Animals were then examined after treatment with either ASA or Indo for 1 day, a time when there was no significant decrease in PGE. After 1 day of treatment, the opposite changes in binding-site affinity were again observed, but there were no changes in the number of receptors with either drug, suggesting that the changes in affinity resulted from non-prostaglandin-related effects of the drugs. To ascertain the physiologic consequences of up-regulation, adenylate cyclase activity was measured in control and up-regulated membranes. There were no significant changes in basal or in PGE-stimulated adenylate cyclase activity. These data demonstrate that decreased endogenous PGE causes up-regulation of PGE receptors, but that this is not accompanied by increased adenylate cyclase activity. These data may indicate that PGE-stimulated adenylate cyclase operates maximally under normal receptor concentrations and that therefore its activity cannot be increased by regulatory changes in receptor density.