endothelin-1 and iganidipine

To evaluate the potential of topical iganidipine ophthalmic solution to exert Ca(2+)-antagonistic activity in the posterior parts of the eye without inducing systemic effects, ocular and periocular penetration of topically instilled iganidipine was studied in pigmented rabbits.. First, (14)C-iganidipine solution (0.03%, 30 microL) was instilled into one eye, and vehicle into the other eye to determine the intraocular penetration of iganidipine and to measure the radioactivity of ocular tissues 0.25, 0.5, 1, 2, 4, and 12 hours after a single instillation (n = 3, respectively). Second, iganidipine (0.03%) or betaxolol (0.5%) was unilaterally instilled twice daily for 20 days to study the effects on intravitreously injected various doses of endothelin (ET)-1-induced retinal artery constriction to evaluate whether a pharmacologically active level of the drug penetrated to the posterior retina and to estimate the drug level in the posterior retina (n = 6, respectively). Third, iganidipine (0, 10, or 30 microg/kg: n = 6, 3, and 6, respectively) was intravenously injected to study the effects on intravitreously injected ET-1-induced retinal artery constriction to evaluate iganidipine levels in the posterior retina. Fourth, periocular penetration of iganidipine was studied by means of whole-head autoradiography after a single instillation of (14)C-iganidipine (0.09%, 30 microL; n = 5).. Penetration of topically applied iganidipine to the cornea or aqueous humor was high and estimated to be at least 10 times higher than that reported for timolol or carteolol. Concentrations in the iris-ciliary body or retina-choroid were much higher than in the plasma, both in the treated and control eyes, suggesting that iganidipine binds to uveal pigments. Twice-daily 20-day instillation of iganidipine (0.03%), but not of betaxolol (0.5%), significantly suppressed constriction of the retinal arteries induced by intravitreous injection of ET-1 at a dose of 2.5 or 0.5 ng in the ipsilateral eye. Intravenous injection of iganidipine at a dose of 30 microg/kg (giving a free plasma concentration of approximately 10(-8) M), but not at a dose of 10 microg/kg, significantly suppressed intravitreous ET-1-induced (0.5 ng) constriction of the retinal artery to a similar degree as twice-daily 20-day instillation of 0.03% iganidipine. After a single instillation of 0.09% iganidipine, the equivalent concentration of iganidipine in the ipsilateral retrobulbar periocular space estimated from autoradiography was approximately 3.9 x 10(-8) M between 15 minutes and 1 hour after instillation, consistently higher than in the untreated contralateral eyes by approximately 3.0 x 10(-8) M (P = 0.043).. In rabbits, topically instilled iganidipine, a Ca(2+) antagonist, in a 0.03% solution reaches the ipsilateral posterior retina or retrobulbar periocular space by local penetration at concentrations sufficient to act as a Ca(2+) antagonist.

Topics: Administration, Topical; Animals; Anterior Eye Segment; Autoradiography; Betaxolol; Calcium; Calcium Channel Blockers; Calcium Channels; Endothelin-1; Eye; Injections, Intravenous; Ophthalmic Solutions; Piperazines; Pyridines; Rabbits; Retina; Retinal Artery; Solubility; Vasoconstriction; Vasodilator Agents

To investigate the effect of topical iganidipine, a new dihydropyridine derivative calcium channel blocker, on impairment of the ocular circulation caused by endothelin-1 (ET-1), we examined modification of the effect of ET-1 on visual-evoked potential (VEP) in albino rabbits.. To clarify whether VEP could be used to indicate the extent of ocular circulatory impairment, we evaluated the dose dependency of changes in VEP over 2 hours after intravitreal injection of 3 ET-1 doses (1.0, 3.3, or 10 pmol) and the vehicle. Then modification of the effect of ET-1 on the VEP by iganidipine was examined. One hour after the topical instillation of 0.1% iganidipine (20 microl) or its vehicle, 10 pmol of ET-1 was injected into the vitreous in rabbits. The VEP was measured for 2 hours after ET-1 application, and the response was compared between the eyes with iganidipine and vehicle pretreatment.. Intravitreal injection of ET-1 dose-dependently reduced the VEP amplitude. Topical administration of 0.1% iganidipine significantly suppressed the reduction of VEP amplitude for the entire 2-hour monitoring period after intravitreal injection of 10 pmol ET-1. There was no significant change of the systemic blood pressure as well as intraocular pressure after topical administration of iganidipine.. Iganidipine eyedrops may be useful for the treatment of ischemic retinal and optic nerve disorders related to abnormal ET-1 production for the maintenance of visual function.

Topics: Administration, Topical; Analysis of Variance; Animals; Calcium Channel Blockers; Dose-Response Relationship, Drug; Endothelin-1; Evoked Potentials, Visual; Humans; Injections; Instillation, Drug; Intraocular Pressure; Piperazines; Pyridines; Rabbits; Vitreous Body