On the Topically Effective Ocular Hypotensive Properties of ICI 147,798, a Natriuretic β‐Adrenoceptor Antagonist, in Rabbits

Abstract

The ocular antihypertensive effects of ICI 147,798, a natriuretic, non-selective beta-blocker lacking local anaesthetic and intrinsic sympathomimetic activities, were evaluated in unanaesthetized rabbits with water-load-induced ocular hypertension. The racemate was approximately 20 times more potent as a beta-blocker than its d-isomer. The magnitude of reductions in intraocular pressure (IOP) elicited by both compounds was equal following topical administration of an equal dose-concentration (100-300 microliters, 0.5% or 0.75%) to one or both eyes, and the activities were similar to those obtained with timolol. A five-hour duration of the IOP lowering effect was achieved by ICI 147,798 and timolol in this rabbit model. ICI d-147,798 exhibited a shorter duration, which could be prolonged by increasing the concentration of the ophthalmic solution. Timolol caused a pronounced reduction of isoproterenol-induced tachycardia after a single dose (200 microliters, 0.5%) or by repeating the dose twice a day for four consecutive days. Following the same dose regimen, neither ICI 147,798 nor its d-isomer significantly altered the heart rate response produced by isoproterenol. These findings indicate that ICI 147,798, while effective as a potential antiglaucoma agent, does not display the characteristics of beta-blockers on heart rate effects noted with timolol. The results also cast some doubt on the contention that the IOP lowering effect of certain beta-blockers is predominantly determined by specific blockade of beta-adrenoceptors.

Sympathomimetic enantiomers and asthma

“…Application of beta-adrenoceptor antagonists cannot be used for confirmation of this conclusion since these compounds have significant effects upon intraocular pressure that are unrelated to antagonism of beta-adrenoceptors. 75 With the exception of trimetoquinol, the sympathomimetics currently available as asthma therapies are racemic mixtures. Trimetoquinol cannot be used as a racemic mixture because each stereoisomer has been shown to have significant pharmacological activity, namely, both S-(pD 2 = 7.10), and R-trimetoquinol (pD 2 = 5.54) relax isolated guinea-pig trachea by virtue of beta 2 -adrenoceptor occupancy 76 and R-(IC 50 = 0.99 µM) and S-trimetoquinol (IC 50 = 39.6 µM) both inhibit human platelet aggregation by U46619, the thromboxane A 2 mimetic.…”