Ocular hypotensive effects of medetomidine and its analogs.

The ocular hypotensive effects of medetomidine, a relatively selective alpha 2-agonist, and its analogs were tested in rabbits and cats and their inhibition of adenylate cyclase in the isolated bovine ciliary process was also studied. It was found that topical unilateral administration of medetomidine (0.5-2.0%) to the normotensive rabbits produced a dose-dependent bilateral decrease in IOP with peak reduction in IOP at 2 hr in the treated eye and 1 hr in the untreated eye. A dose-dependent mydriasis was also observed in the treated eye. The dose-response curves of medetomidine and its analogs showed that the ranked order of intrinsic activity at lowering IOP was medetomidine greater than or equal to MPV-1440 greater than detomidine greater than MPV-1441 and MPV-305 BII. At concentrations lower than those used in rabbits, topical application of medetomidine to the normotensive cats lowered IOP in both treated and untreated eyes. Medetomidine and detomidine caused a dose-dependent inhibition of isoproterenol-stimulated adenylate cyclase activity. Detomidine was found to be a partial agonist producing about 43% of maximum inhibition obtained by medetomidine. The IOP efficacy of these alpha 2-agonists paralleled their effects on adenylate cyclase activity. The results demonstrated that these imidazoline derivatives are effective ocular hypotensive agents which may be useful in understanding the contribution of alpha 2-receptors to the regulation of IOP.

Inhibition of adenylate cyclase in bovine ciliary process and rabbit iris ciliary body to alpha 2-adrenergic agonists.

Alpha 2-adrenergic inhibition of adenylate cyclase in bovine ciliary processes and rabbit iris ciliary body (ICB) was studied. With bovine ciliary process membrane, it was found that cAMP production in the presence of 1 microM isoproterenol was increased with increasing NaCl concentrations from 0 to 200 mM. Clonidine, an alpha 2-adrenergic agonist, produced a NaCl concentration-dependent inhibition of cAMP production in the presence of isoproterenol with a maximum inhibition at 200 mM NaCl (P less than 0.05). NaCl concentrations had no effect on basal adenylate cyclase activities and activity in the presence of clonidine alone. The alpha 2-adrenergic agonists, lofexidine, clonidine and p-amino-clonidine were tested for their ability to inhibit isoproterenol-stimulated adenylate cyclase in bovine ciliary process membrane in the presence of 200 mM NaCl. Their dose-response curves showed that they had similar IC50's but the maximum inhibition differed among these agonists. Clonidine was found to be a partial agonists producing 55% of the inhibition obtained with lofexidine. The specificity of inhibition of isoproterenol-stimulated adenylate cyclase by alpha 2-agonists and blockade by pertussis toxin was examined by adenine labelling in rabbit ICB. The results demonstrate that alpha 2-adrenergic receptors exert specific inhibitory effects on adenylate cyclase activity in rabbit ICB, which are mediated by an inhibition guanine nucleotide regulatory protein, Gi.