Analysis of the Pharmacology of Prostanoid Induced Intraocular Pressure Effects in Non-Human Primates: The Importance of Examining Normal and Ocular Hypertensive Eyes

Abstract

Purpose:: The pharmacology of prostanoid induced effects on primate intraocular pressure has been previously analyzed but only in part. The recent reports of new selective agonists has enabled a complete analysis.

Methods:: Intraocular pressure (IOP) was measured by pneumatonometry in conscious monkeys trained to accept the procedure. Both ocular normotensive and laser-induced ocular hypertensive monkeys were used. Selective agonists for each prostanoid receptor were examined as follows:DP₁=BW245C; DP₂=13,14-dihydro,15-keto PGD₂; EP₁=ONO-D1-004; EP₂=Butaprost; EP₃=11,15-methoxy PGE₂; EP₄=3,7-dithia PGE₁; FP=17-phenyl PGF _2α; IP=Cicaprost; TP=U-46619. They were dissolved in 1% polysorbate-10mM TRIS-HCl.

Results:: Selective agonists for CRTH₂ (DP₂) and EP₁ receptors have recently been introduced but these drugs, 13,14-dihydro, 15-keto PGD₂ and ONO-D1-004 had no effect on intraocular pressure. In contrast EP₂ agonists such as butaprost, its free acid, and its 5,6-cis free acid were highly efficacious ocular hypotensive agents, similar to the prototypical EP₄ agonist 3,7-dithia PGE₁. The selective EP₃ agonist 11,15-methoxy PGE₂ had only a very modest effect on IOP.The selective IP agonist cicaprost had a moderate ocular hypotensive effect in ocular normotensive and hypertensive eyes. The most complex IOP response occurred with the DP agonist BW 245C and the TP agonist U-46619. A 0.1% dose of both drugs produced an ocular hypertensive spike in normal monkeys. This was not seen in "glaucomatous" monkey eyes and both drugs behaved as ocular hypotensives, albeit BW 245C being decidedly more efficacious than U-46619.

Conclusions:: Perhaps the most interesting finding was the transient ocular hypertension produced by DP₁ and TP receptor stimulation in ocular normotensive monkeys. This was not seen in "glaucomatous" monkeys, where the IOP was in the 30-40 mm Hg range. Although not manifest at the high IOP level, this ocular hypertensive spike may occur at IOP levels in the typical range for glaucoma patients (20-30 mm Hg). Indeed, this response to DP₁ and TP receptor stimulation has been observed in clinical studies (Nakajima M. et al., Graefe’s Arch. Clin. Exp. Ophthalmol. 229: 411,1991; Flach AJ and Eliason, J. Ocular Pharmacol. 4: 13, 1998). It is, therefore, important to examine drug effects in normal and ocular hypertensive eyes. The rank order for ocular hypotension in the "glaucomatous" monkey model was EP₂=EP₄>FP=DP₁>IP>EP₃=TP>EP₁=DP₂ (CRTH₂).

Keywords: eicosanoids • receptors • intraocular pressure