Co-regulation of mucosal prostanoids and substance P by indomethacin in rat stomachs

The present investigation examined the correlation between the regulation of mucosal prostaglandin (PG) biosynthesis and the release of the neuropeptide substance P (SP) in rat stomachs by indomethacin, a cyclooxygenase inhibitor. When given subcutaneously at the dose of 5 mg/kg, indomethacin reduced mucosal biosynthesis of PGE₂ and concurrently lowered mucosal SP level. The inter-relationship between mucosal generation of PG and SP was further demonstrated by using [D-Pro², D-Trp^7,9]-SP, which also inhibited PGE₂ production besides its suppression on SP release. Co-administration of either arachidonic acid, the PGE₂ precursor, or SP reversed the inhibitory actions of indomethacin and [D-Pro², D-Trp^7,9]-SP, respectively, on mucosal levels of PGE₂ and SP. Our findings suggest that indomethacin, aside from its depletion of endogenous PG, also exerts a secondary action in regulating the release of SP, which is mediated indirectly through PG in the gastric mucosa. These actions may play a role in the modulation of gastric mucosal integrity.