Ocular hypotensive action of topical flunarizine in the rabbit: Role of σ1 recognition sites

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 (K1 = 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 HCI] 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.