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Vanessa Andres-Guerrero, Rocio Herrero-Vanrell, Asuncion Peral, Jesus Pintor, Marta Vicario, Irene T. Molina-Martinez; IOP Circadian Rhythm Influence In The Hypotensive Efficacy Of A Melatonin Analog, 5-MCA-NAT, In Rabbit Eyes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6690.
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© ARVO (1962-2015); The Authors (2016-present)
In rabbits, intraocular pressure (IOP) has a biphasic pattern with the highest levels occurring at night. It has been suggested that the neurohormone melatonin influences the IOP rhythm. 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT, a melatonin receptor agonist) produces a clear IOP reduction, when applied topically, in New Zealand rabbits and glaucomatous monkeys. The goal of this study was to evaluate the influence of the IOP circadian rhythm in the efficacy of 5-MCA-NAT in healthy rabbit eyes.
Two groups of 6 New Zealand white rabbits were used in this study (2.5-3 Kg). Each group was maintained under different controlled 12h/12h light/dark cycles: (a) Normal cycle (NC) with light from 8 a.m. to 8 p.m. and (b) inverted cycle (IC) with light from 8 p.m. to 8 a.m. 25 µl of the solution 5-MCA-NAT 100 µM in PBS were instilled in the rabbit eyes (PBS was used as control). After instillation, IOP was measured (Tonovet; Medicalmix, Spain) once every hour for 8 hours, starting at 9.30 a.m. All the experiments were performed in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and in accordance with the European Communities Council Directive (86/609/EEC).
IOP parameters such as basal IOP, mean IOP and mean of minimum and maximum IOP were always higher for the IC group (p<0.0001 in all cases). The formulation was able to maintain a hypotensive effect in both groups providing different maximal effects. The maximum IOP reduction was reached by the IC group (3±0.63 vs. 2±0.50 mm Hg, p=0.026). No significant differences were found between NC tmax and IC tmax (4±1 and 3±0.5 hours, respectively; p=0.724). Regarding AUC, NC group reached the highest value (14±3.11 vs. 8±0.91, p=0.0001).
The hypotensive agent 5-MCA-NAT appeared to lower IOP during the nighttime but had less effect during the daytime. This may be related to the normal reduction in aqueous production at daytime produced in rabbits, influenced by the circadian variation of circulating melatonin.
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