In a previous study we ascertained the presence of sigma1 and sigma2 recognition sites in the rabbit iris-ciliary body, an ocular structure involved in aqueous humor production and drainage. We characterized the sigma1 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 sigma1 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
alpha-chymotrypsin model of
ocular hypertension, without altering the IOP of the contralateral eye. This activity was blocked by the sigma1 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 sigma1 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 sigma1 sites and may prove effective in the control of
ocular hypertension.