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Alejandro Martínez-Águila, Almudena Crooke, Fernando Huete-Toral, Alba Martin-Gil, Begoña Fonseca, Jesus Pintor; Melatonin, IIK7 and 5-MCA-NAT potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: significance for combination therapy in glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2897.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the possible potentiating effect of melatoninergic drugs upon the ocular hypotensive action of brimonidine, a selective α2-adrenergic receptor agonist (Alphagan), and timolol, a nonselective β-adrenergic receptor antagonist (Timoftol).
Male New Zealand white rabbits, weighing 3-4 kg, were used for IOP studies. IIK7, melatonin and 5-MCA-NAT were formulated in isotonic saline containing 1% dimethylsulfoxide (DMSO) and were tested at a final concentration of 100 μM. Alphagan 0.2% (brimonidine) and Timoftol 0.5% (timolol) were instilled at a fixed volume of 40 μl. Studies of mRNA and protein expression were conducted using immortalized rabbit nonpigmented ciliary epithelial (NPE) cells. Total RNA was isolated using the RNeasy Minikit (Qiagen), according to the manufacturer’s protocol. Immunofluorescent staining was performed to evaluate α2A- and β2-adrenergic receptor expression in rabbit NPE cells treated with melatonin and 5-MCA-NAT.
Intraocular pressure (IOP) experiments showed that the pretreatment with IIK7, melatonin or 5-MCA-NAT increased the hypotensive effect of timolol in 10.84% ± 4.11% (P< 0.05), 14.02% ± 5.8% and 16.75% ± 5.48% (P< 0.01), respectively, in rabbits for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 32.11% ± 4.68%, 29.26% ± 5.21% and 39.07% ± 5.81% (P< 0.001) were observed in rabbits pretreated with IIK7, melatonin or 5-MCA-NAT, respectively, when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of IIK7 and 5-MCA-NAT were seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 16.61% ± 5.12% and 15.57% ± 5.15% (P< 0.05), compared with brimonidine alone).
These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α2-adrenergic receptor agonists but also of β-adrenergic antagonists.
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