Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor.

(1) Melatonin is involved in the control of intraocular pressure during the night and day photoperiod. We have investigated the receptor that regulates intraocular pressure in New Zealand white rabbits by means of agonists and antagonists of melatonin receptors. (2) Melatonin and its analogues: 2-Phe-melatonin, 6-Cl-melatonin, 2-I-melatonin, 5- methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) and N-acetyltryptamine all produced a reduction in intraocular pressure. Dose-response analysis for these compounds gave pD(2) values of 9.3+/-0.24 for melatonin; 9.0+/-0.09 for 6-Cl-melatonin; 9.0+/-0.84 for 2-I-melatonin; 8.9+/-0.07 for 5-MCA-NAT; 8.7+/-0.18 for 2-Phe-melatonin and 9.4+/-0.30 for N-acetyltryptamine (all n=8). (3) At a dose of 0.5 nmol (in 10 micro l) melatonin and the selective melatonin MT(3) agonist 5-MCA-NAT, induced greater reductions of intraocular pressure (22.8+/-2.3% and 32.5+/-1.4%, respectively) than the other compounds. (4) The melatonin-receptor antagonists, prazosin, DH-97 and 4-P-PDOT, reversed the effect of 5-MCA-NAT in a dose-dependent manner, with pA(2) values of 13.5+/-0.17 for prazosin, 10.6+/-0.16 for DH-97 and 9.4+/-0.20 for 4-P-PDOT (n=8). (5) Cholinoceptor antagonists (hexamethonium and atropine) and alpha(2)- and beta(2)-adrenoceptor antagonists (yohimbine and ICI 118,551) partially reversed the effects produced by melatonin and 5-MCA-NAT, suggesting the possible involvement of cholinergic and noradrenergic systems in the hypotensive actions mediated by melatonin agonists. The alpha(1)-adrenoceptor antagonist, corynanthine, had no significant effect. (6) The strong hypotensive effect of the MT(3) agonist, 5-MCA-NAT, suggests that this compound may be a useful agent for treating those pathologies where intraocular pressure is abnormally elevated.