TY - JOUR T1 - Melatonin and Its Analog 5-Methoxycarbonylamino-<em>N</em>-Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 138 LP - 145 DO - 10.1124/jpet.112.202036 VL - 346 IS - 1 AU - Almudena Crooke AU - Fernando Huete-Toral AU - Alejandro Martínez-Águila AU - Alba Martín-Gil AU - Jesús Pintor Y1 - 2013/07/01 UR - http://jpet.aspetjournals.org/content/346/1/138.abstract N2 - Melatonin is currently considered a promising drug for glaucoma treatment because of its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on β2/α2A-adrenergic receptor mRNA as well as protein expression in cultured rabbit nonpigmented ciliary epithelial cells. Quantitative polymerase chain reaction and immunocytochemical assays revealed a significant β2-adrenergic receptor downregulation as well as α2A-adrenergic receptor up-regulation of treated cells (P &lt; 0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a nonselective β-adrenergic receptor (timolol) and a selective α2-adrenergic receptor agonist (brimonidine) in normotensive rabbits. Intraocular pressure (IOP) experiments showed that the administration of timolol in rabbits pretreated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02% ± 5.8% or 16.75% ± 5.48% (P &lt; 0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26% ± 5.21% or 39.07% ± 5.81% (P &lt; 0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 15.57% ± 5.15%, P &lt; 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. ER -