No abstract

Reflex tear secretion caused by corneal stimulation seems to be chiefly due to activation of corneal polymodal nociceptors, whereas selective excitation of corneal mechanonociceptors or cold receptors appears to be less effective in evoking an augmented lacrimal secretion. Conjunctival receptors stimulated at equivalent levels do not evoke an increased tear secretion.

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 ml) 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 e ect 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 a 2 -and b 2 -adrenoceptor antagonists (yohimbine and ICI 118,551) partially reversed the e ects 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 a 1 -adrenoceptor antagonist, corynanthine, had no signi®cant e ect. 6 The strong hypotensive e ect 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.

Adenine dinucleotides are present in many biological systems and may serve as physiological regulators of processes such as neurotransmitter release, vascular tone or corneal hydration. The presence of diadenosine polyphosphates was investigated in New Zealand White rabbit aqueous humor. , pyridoxal phosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS), suramin, and reactive blue 2 (RB-2) alone had no effect on intraocular pressure but attenuated responses to diadenosine polyphosphates by approximately 80%. It is concluded that Ap 2 A, Ap 3 A, and Ap 5 A increase intraocular pressure, and Ap 4 A decreases intraocular pressure via mechanisms that involve P2 receptors, and that Ap 4 A present in aqueous humor may serve to regulate intraocular pressure. Furthermore, we suggest that topical application of Ap 4 A to the cornea has therapeutic potential for lowering intraocular pressure, a major risk factor for glaucoma.

Extracellular diadenosine polyphosphates play important signaling functions in a number of physiological responses. Here we show that diadenosine polyphosphates are normal constituents of tear fluid and are potent stimulators of tear secretion through their interaction with P2Y receptors. Diadenosine tetraphosphate (Ap 4 A) and Ap 5 A were found in rabbit tears under basal conditions at concentrations of 2.92 and 0.58 M, respectively. Single applications of UTP, ATP, and Ap 4 A increased tear secretion to 160 Ϯ 8% (n ϭ 16) (P Ͻ 0.001), 131 Ϯ 6% (P Ͻ 0.05), and 162 Ϯ 11% (P Ͻ 0.05) of placebo values, respectively. Ap 4 A, Ap 5 A, and Ap 6 A, but not Ap 2 A and Ap 3 A, were able to stimulate tear secretion in a dose-dependent manner. Concentration-response studies produced pD 2 values of 5.56 Ϯ 0.03, 5.75 Ϯ 0.12, and 5.50 Ϯ 0.09 for Ap 4 A, Ap 5 A, and Ap 6 A, respectively, with Ap 4 A showing the greatest efficacy. Diadenosine polyphosphates also stimulated P2Y 1 and P2Y 2 receptors expressed in 1321N1 cells with no apparent effect on the other P2Y receptors tested. Nonselective P2 antagonists did not modify the tear secretion induced by UTP or Ap 4 A in rabbit eyes in vivo or in cloned receptors, except for a weak but significant reduction in stimulated tear secretion by reactive blue 2. These results suggest that diadenosine polyphosphates stimulate tear secretion via a P2Y receptormediated mechanism. Comparing the effects of diadenosine polyphosphates applied to the rabbit eye and to cloned P2Y receptors, it appears that the P2Y 2 receptor subtype is responsible for the prosecretory effects of these compounds.