The ocular hypotensive effects of medetomidine, a relatively selective (X2-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 > MPV-1440 > detomidine > MPV-1441 and MPV-305 Bu. 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

Alpha2-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 uM isoproterenol was increased with increasing NaCl concentrations from 0 to 200 mM. Clonidine, an ct2-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<0.05). NaCl concentrations had no effect on basal adenylate cyclase activities and activity in the presence of clonidine alone. The cc2-adrenergic agonists, lofexidine, clonidine andp-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 apartial agonists producing 55% of the inhibition obtained with lofexidine. The specificity of inhibition of isoproterenol-stimulated adenylate cyclase by a2-agonists and blockade by pertussis toxin was examined by adenine labelling in rabbit ICB. The results demonstrate that cc2-adrenergic receptors exert specific inhibitory effects on adenylate cyclase activity in rabbit ICB, which are mediated by an inhibitory guanine nucleotide regulatory protein, Gi.

Bennett, D.A., J.J. DeFeo, E.E. Elko, and L. Harbans: Naloxone reversal of clonidine, but not hydralazine, hypotension. Drug Dev. Res. 2175Res. -179, 1982 Normotensive rats of the Sprague-Dawley strain were administered either the centrally acting hypotensive drug clonidine (0.16 mglkg IP) or the peripherally acting hypotensive drug hydralazine (1.25 rnglkg IP) to induce reliable hypotension (blood pressure reductions of 60-90 mm Hg), as measured by a tail cuff procedure. The opiate antagonist, naloxone (10-20 rnglkg IP), reversed clonidine but not hydralazine hypotension. Naloxone also failed to reverse hydralazine's hypotensive action in rats made hypertensive by renal ligation. Naloxone's reversal of clonidine (0.01 mglkg IV) hypotension was confirmed in experiments in which blood pressure was measured through direct cannulation of the carotid artery. It is suggested that naloxone's antagonism of clonidine hypotension is located at a central nervous system site, and that clonidine hypotension may be mediated through an interaction with the brain opiate systems.

No abstract

The present study examines the ocular hypotensive efficacy end pupillary response of the alpharadrenergic receptor agonists lofexidine and clonidine. The topical administration of lofexidine to rabbit eyes in concentrations ranging from 0.25 to 5%, produced a dosedependent bilateral reduction in intraocular pressure (IOP), with the contralateral (untreated) eye exhibiting a significantly greater reduction in IOP than the ipsilateral (treated) eye, particularly at the lower concentrations. The maximum decrease in IOP was observed at 60 min postdrug with the IOP recovering gradually to predrug values with time. Pupillary dilatation was observed only in the drug-treated eye. Unlike lofexidine, clonidine had no effect on pupillary diameter. Clonidine decreased IOP predominantly in the untreated contralateral eye at doses ranging from 0.625% to 5%, whereas a significant ocular hypertensive effect of clonidine was noted at the 7.5% dose in the treated ipsilateral eye. The present data provide evidence that topically administered lofexidine lowers IOP in normotensive New Zealand White (NZW) rabbits.