5-HT 2 Receptor-Mediated Phosphoinositide Hydrolysis in Bovine Ciliary Epithelium

Abstract

The serotonin 2 (5-HT₂) receptor antagonists, MCI-9042 (Anplag^®) and ketanserin, have been shown to lower intraocular pressure in rabbits (1) and humans (2). The mechanism of action of these drugs has not been determined, but it is hypothesized that 5-HT₂ receptors, and possibly α-adrenergic receptors, (3) may regulate in part aqueous humor production via an intracellular signal transduction pathway in the ciliary body. We therefore examined whether 5-HT₂ receptors were coupled to phosphoinositide hydrolysis in an organ culture system of isolated bovine ciliary epithelium. 5-HT stimulated [³H]inositol phosphates ([³H]InsPs) accumulation in a dose-dependent manner with a maximum increase approximately twice over the basal level. The mean EC₅₀ value was 1.1 μM, which was calculated from four dose-response curves. The 5-HT stimulated accumulation of [³H]InsPs was inhibited by spiperone (5-HT_2A/1A and dopamine 2 (D₂) antagonists), M-1 (a major metabolite of MCI-9042), ketanserin (5-HT_2A antagonist), SB-206553 (5- HT_2B/2C antagonist), and mesulergine (5-HT_2C antagonist and D₂ agonist). It was not inhibited by chlorpromazine, which is a D₂ receptor antagonist. Accordingly, our study demonstrates that 5-HT₂ receptors are coupled to phospholipase C in bovine ciliary epithelium.