Enisoprost

Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity. The receptor binding potency of SC-46275 (IC50, 0.013 mM) in enriched canine parietal cell preparations was found to be much greater than misoprostol and enisoprost (IC50, 10 and 8 nM), whereas PGE1 had the least potency (IC50, 37 nM). Similar relative potencies for these PGs were also obtained in the inhibition of histamine-stimulated acid secretion in enriched parietal cell preparations. In small intestinal mucosal and muscle membranes, the receptor binding potency of SC-46275 (IC50, 13 and 20 microM) was much less than misoprostol or enisoprost (IC50, 0.39-1.2 microM) and substantially less than PGE1 (IC50, 0.017 and 0.066 microM). This weak binding activity of SC-46275 in intestinal tissues is consistent with its reported weak diarrheagenic activity in the rat. These results suggest that SC-46275 binds preferentially to gastric vs. intestinal PGE receptors and is specific for the EP3 receptors.

Recent studies suggest that prostaglandin E may have the ability to suppress cytokine responsiveness. We examined the effects of prostaglandin E administration on several parameters of the acute and chronic hepatic injury induced by bile duct ligation. Enisoprost, a prostaglandin E(1) analog was found to suppress early hepatic and Ito cell type I collagen gene expression without diminishing the induction of the fibrogenic cytokine, transforming growth factor beta. Overall hepatic inflammation and cell proliferation were not altered, suggesting that prostaglandin E acts distal to the initial injurious event(s). During the later phases, drug administration reduced total collagen accumulation as well as type I collagen periductular infiltration associated with early nodule formation. Ito cell mitogenesis occurs during liver injury and fibrogenesis in vivo coincident with the de novo expression of Ito cell platelet-derived growth factor beta (PDGFbeta) receptor messenger RNA. PDGF-induced mitogenesis was studied in cultured rat hepatic Ito cells which resemble the myofibroblast associated with liver injury. Pretreatment with prostaglandin E markedly suppressed the PDGF response in a dose-dependent fashion. The PDGF-induced cascade was studied plus minus PGE to determine the level of regulation which induced the observed suppression. PGE caused no apparent diminution in the abundance of the surface PDGFbeta receptor nor its subsequent activation and tyrosine phosphorylation following PDGF stimulation. The cytoplasmic "secondary messengers" mitogen-activated protein kinase pp42--44 and raf kinase appeared to be comparably induced and therefore unaffected by PGE. Raf perinuclear translocation was also intact, and comparable degrees of nuclear egr, fos, and jun expression occurred. Because other studies have suggested that many of these features of the PDGF cascade may be causally and sequentially linked, the data collectively suggest that the dominant PGE mitogenic suppressive effect resides at a Raf-MAP parallel pathway or at a nuclear level distal to the induction of these early growth response genes.