Abstract

In a previous study we ascertained the presence of ς₁ and ς₂ recognition sites in the rabbit iris-ciliary body, an ocular structure involved in aqueous humor production and drainage. We characterized the ς₁ sites using the preferential ligand (+)-pentazocine, which caused a significant reduction of intraocular pressure (IOP). In the present study, flunarizine, a calcium channel blocker with a complex pharmacological profile, bound to ς₁ sites expressed in the iris-ciliary body with moderate affinity (K _i = 68 nM). Unilateral topical flunarizine (0.01–0.1%) caused a dose-related reduction of IOP in ocular normotensive rabbits and in the α-chymotrypsin model of ocular hypertension, without altering the IOP of the contralateral eye. This activity was blocked by the ς₁ site antagonist NE-100 [N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine HCl] which, by itself, had no effect on IOP. Detection of flunarizine in rabbit iris-ciliary body homogenates, after topical instillation, showed that it adequately penetrates the rabbit eye. To investigate mechanisms that may contribute to ocular hypotension induced by ς₁ agonists, we carried out in vitro studies on the isolated rabbit iris-ciliary body. Flunarizine (IC₅₀ = 5. 96 nM) and (+)-pentazocine (IC₅₀ = 3. 81 nM) inhibited [³H]norepinephrine release. Moreover, flunarizine (IC₅₀ = 6.34 nM) and (+)-pentazocine (IC₅₀ = 27.26 nM) also antagonized isoproterenol-induced cAMP accumulation. The action of flunarizine and (+)-pentazocine was sensitive to NE-100 antagonism; however, this latter compound partially prevented their effect on [³H]norepinephrine and cAMP accumulation. These findings indicate that flunarizine and (+)-pentazocine interact with ocular ς₁ sites and may prove effective in the control of ocular hypertension.