Alpha-adrenergic antagonists: Correlation of the effect on intraocular pressure and on α₂-adrenergic receptor binding specificity in the rabbit eye

Six alpha-adrenergic antagonists, which have a range of selectivities for α₁- and α₂-adrenoreceptor subtypes, were compared with respect to their ability to reduce intraocular pressure (IOP) after topical application to the rabbit eye, and their affinity and selectivity for α₂-adrenoreceptors, as determined by binding to membranes prepared from rabbit iris-ciliary body. A routine assay for α₂-adrenoreceptors using [³H]-rauwolscine was developed for this purpose. ICB contained 200-300 fmol (mg protein)^-1 α₂-adrenoreceptors which represents approximately two-thirds of the total number of α-adrenoreceptor sites present in this tissue. All six antagonists bound at α₂-adrenergic receptor sites in an apparently simple competitive manner. The K_d for three of the drugs was about 10 nm (rauwloscine, yohimbine, WB-4101) and the K_d for the other three was > 3500 nm (prazosin, corynanthine, thymoxamine). However, all six antagonists were effective ocular hypotensive agents when given topically in a 50 μl dose of 1% (w/v) concentration. The ability of α-adrenergic antagonists to lower IOP in the rabbit did not correlate with a single α-receptor subtype and appears to involve at least two separate mechanisms, one mediated by α₂-adrenergic receptors and one mediated by α₁-adrenergic receptors.