Isobutylmethylxanthine enhances adrenergic-induced ocular hypotension in rabbits and beagles.

Isobutylmethylxanthine (IBMX), a phosphodiesterase/adenosine receptor inhibitor, was combined with norepinephrine (nE), epinephrine (Epi) and isoproterenol, respectively, to evaluate their effect on intraocular pressure (IOP). Application of topical IBMX alone had no measurable effect on IOP. When IBMX was combined with nE or Epi the ocular hypotension in rabbits and beagles increased. The Emax for nE alone was 2.9 +/- 0.4 mmHg, for Epi alone 7.3 +/- 0.5 mmHg and for isoproterenol alone 5.1 +/- 0.3 mmHg. The EC50 was 0.2 +/- 0.05% (nE), 0.05 +/- 0.01% (Epi) and 0.003 +/- 0.001% for isoproterenol. When given in combination with 1% IBMX the Emax for nE was 7.4 +/- 1.7 mmHg, for Epi 9.0 +/- 0.8 mmHg and for isoproterenol 6.1 +/- 0.3 mmHg. The corresponding values for EC50 were 0.07 +/- 0.03% (nE), 0.02 +/- 0.006% (Epi) and 0.002 +/- 0.001% for isoproterenol. Combining 1% IBMX with 0.1% Epi increased the aqueous humour cyclic AMP-levels at 1, 3 and 5 hr in rabbits. The results of this study demonstrate that a phosphodiesterase/adenosine receptor inhibitor such as IBMX enhances the reduction in IOP induced by adrenergic agonists.

Prostaglandin F2 alpha isopropyl ester versus iloprost phenacyl ester in rabbit and beagle eyes.

One and 2 micrograms of prostaglandin F2 alpha isopropyl ester (PGF2 alpha -IE) applied topically to the rabbit eye caused a biphasic response. The hypotensive phase was dose-dependent with a maximum reduction in intraocular pressure (IOP) of 9.4 +/- 1.7 mmHg at a dose of 2 micrograms. In beagles, 0.4 to 2 micrograms topical PGF2 alpha-IE resulted in a sustained IOP reduction; 2 micrograms produced the maximum reduction of 7-9 mmHg. No initial hypertensive response was observed. Iloprost phenacyl ester (Iloprost-PE) caused a greater decrease in IOP when dissolved in 0.5% hydroxypropyl methylcellulose (AT) than in saline. In rabbits, doses of 0.1 to 1 microgram in AT caused a biphasic response with a sustained IOP decrease fluctuating between 7 and 8 mmHg. In beagles 1 and 2 micrograms Iloprost-PE resulted in a mean IOP reduction of 5.8 +/- 0.4 mmHg and 5.8 +/- 0.5 mmHg (P less than 0.005), respectively; the decrease persisted for 5 hrs. No initial hypertensive response was observed. In beagles PGF2 alpha-IE induced a strong miosis lasting more than 6 hours; Iloprost-PE had no effect on pupil size. Both PG-esters induced a slight hyperemia in rabbit and beagle eyes. In rabbits Iloprost-PE affects the blood-aqueous barrier more than PGF2 alpha-IE, since higher protein concentrations are seen in the aqueous humor after application of Iloprost-PE. Neither PG-ester had a noticeable effect on aqueous protein in beagles. In rabbits, both PG-esters led to slightly increased aqueous humor cyclic-AMP concentrations. In beagles aqueous humor cyclic-AMP was elevated only after Iloprost-PE.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of prostacyclin and its stable analog on intraocular pressure.

Prostacyclin, a natural arachidonic acid derivative that has potent vasodilatory and anti-platelet aggregatory effects in vivo can effectively reduce IOP in rabbits when applied topically to the eye. However, great care has to be taken to apply this highly labile autacoid immediately after the pH of the solution is brought down from the alkaline side, where the compound is more stable, to the neutral region, where it can be applied to the eye. A stable analogue of prostacyclin, Iloprost, especially its esterified form which can be expected to penetrate the eye more rapidly, was found to be an even more potent ocular hypotensive agent in both rabbits and dogs. While in the present studies prostacyclin or its analogue was only studied for six hours, it has already been shown that some PGs can maintain IOP reduction in cats, monkeys and humans for weeks or months as long as daily PG application is continued (see Bito et al., 1989; Alm and Villumsen, 1989). Thus, the stable analogues of prostacyclin must be considered, together with the stable classical prostaglandins of the E and F type, as potential therapeutic agents for the long-term management of glaucoma.