Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain.
Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain
J Pharmacol Exp Ther. 2015 Jan;352(1):119-28. doi: 10.1124/jpet.114.218263. Epub 2014 Oct 24.
Melatonin and its analog 5-MCA-NAT (5-methylcarboxyamino-N-acetyl tryptamine) are active compounds reducing intraocular pressure (IOP). This action is mediated through MT2 and the putative MT3 melatonin receptor, producing a transient reduction of IOP that lasts for a few hours and has not yet been characterized. The use of melatonin and its analog are causing a decrease in chloride efflux from rabbit nonpigmented epithelial cells (NPE), possibly explaining the decrease in IOP. Melatonin and 5-MCA-NAT inhibited rabbit NPE chloride release in a concentration-dependent manner, whereas the pD2 values were between 4.5 ± 1.2 and 4.4 ± 1.0, respectively. Melatonin hypotensive action was enhanced by the presence of MT2 antagonists, such as DH97 (N-pentanoyl-2-benzyltryptamine) and 4-P-P-DOT (4-phenyl-2-propionamidotetralin) and by the nonselective melatonin receptor antagonist luzindole. Prazosin (1.5 µM) partially reverses the melatonin action by acting as a selective MT3 antagonist. However, at 15 nM it acts as an α-adrenergic receptor antagonist, enhancing the melatonin effect. Regarding the intracellular pathways triggered by melatonin receptors, neither phospholipase C/protein kinase C pathway nor the canonical reduction of intracellular cAMP was responsible for melatonin or 5-MCA-NAT actions. On the contrary, the application of these substances produced a concentration-dependent increase of cAMP, with pD2 values of 4.6 ± 0.2 and 4.9 ± 0.7 for melatonin and 5-MCA-NAT, respectively. In summary, melatonin reduces the release of chloride concomitantly to cAMP generation. The reduction of Cl(-) secretion accounts for a decrease in the water outflow and therefore a decrease in aqueous humor production. This could be one of the main mechanisms responsible for the reduction of IOP after application of melatonin and 5-MCA-NAT.
褪黑素及其类似物 5-MCA-NAT（5- 甲基羧基氨基 -N- 乙酰色胺）是降低眼内压（IOP）的活性化合物。这种作用是通过 MT2 和假定的 MT3 褪黑素受体介导的，产生持续数小时的 IOP 短暂降低，尚未得到表征。褪黑素及其类似物的使用导致兔非色素上皮细胞（NPE）氯离子外流减少，这可能解释了 IOP 的降低。褪黑素和 5-MCA-NAT 以浓度依赖性方式抑制兔 NPE 氯离子释放，而 pD2 值分别为 4.5±1.2 和 4.4±1.0。MT2 拮抗剂如 DH97（N- 戊酰基-2- 苯丙胺）和 4-P-P-DOT（4- 苯基-2- 丙酰胺四氢呋喃）以及非选择性褪黑素受体拮抗剂卢西诺尔增强了褪黑素的降压作用。普萘洛尔（1.5µM）通过作为选择性 MT3 拮抗剂部分逆转褪黑素作用。然而，在 15 nM 时，它作为α-肾上腺素能受体拮抗剂发挥作用，增强了褪黑素的作用。关于褪黑素受体触发的细胞内途径，磷脂酶 C/蛋白激酶 C 途径和细胞内 cAMP 的经典减少都不是褪黑素或 5-MCA-NAT 作用的原因。相反，这些物质的应用产生了浓度依赖性的 cAMP 增加，褪黑素和 5-MCA-NAT 的 pD2 值分别为 4.6±0.2 和 4.9±0.7。总之，褪黑素降低氯离子的释放同时伴随着 cAMP 的产生。Cl(-) 分泌的减少导致水流出减少，因此房水产生减少。这可能是褪黑素和 5-MCA-NAT 应用后降低 IOP 的主要机制之一。
