title: Melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: significance for combination therapy in glaucoma.
abstract: 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/α(2A)-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 α(2A)-adrenergic receptor up-regulation of treated cells (P < 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 < 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 < 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 < 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.
authors.affiliation: Departamento de Bioquímica, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Crooke
authors.forename: Fernando
authors.initials: F
authors.lastname: Huete-Toral
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martínez-Águila
authors.forename: Alba
authors.initials: A
authors.lastname: Martín-Gil
authors.forename: Jesús
authors.initials: J
authors.lastname: Pintor
mesh_terms: D000322:Adrenergic Agonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D058647:Adrenergic alpha-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015814:Ocular Hypotension / Q000139:chemically induced; D009883:Ophthalmic Solutions / Q000494:pharmacology; D011817:Rabbits; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014363:Tryptamines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C413586:5-methoxycarbonylamino-N-acetyltryptamine; D000322:Adrenergic Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009883:Ophthalmic Solutions; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2; D014363:Tryptamines; D008550:Melatonin