title: Ocular hypotensive action of topical flunarizine in the rabbit: role of sigma 1 recognition sites.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Bologna, Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Campana
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Murari
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D005444:Flunarizine / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D015814:Ocular Hypotension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D011817:Rabbits; D017480:Receptors, sigma / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D000242:Cyclic AMP; D005444:Flunarizine; D009638:Norepinephrine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor