OCULAR HYPOTENSIVE, VASORELAXANT AND CYCLIC-AMP INTERMEDIATION ACTIVITIES OF CLOZAPINE DISPLAYING ANTIGLAUCOMA PROPERTIES

Clozapine, an atypical antipsychotic agent with multiple receptor anta gonist activities, was investigated in vivo and in vitro to discover i ts effects on intraocular pressure and blood flow, on the contractilit y of ciliary muscle and nonophthalmologic blood vessels, on calcium co ncentration in A7r5 smooth muscle cells, and on cyclic AMP intermediat ion. The adrenergic and muscarinic mechanisms involved in the above ef fects were also examined. In rabbits, clozapine (0.1, 0.25, and 0.5%) prolonged (IOP) recovery time and inhibited IOP response. Clozapine (0 .1 and 0.25%) also produced a significant increase in ocular blood flo w in this iris, ciliary, retina, and choroid at 30 to 180 min after dr ug administration. in isolated guinea pig thoracic aorta, clozapine re laxed phenylephrine (10 mu M)- and KCl (75 mM)-induced contractions, t he estimated IC50 values being 20.4 +/- 3.1 nM and 10.6 +/- 1.8 mu M, respectively. Clozapine (0.1-100 mu M) inhibited phenylephrine (10 mu M)-induced influx of Ca2+, the estimated IC50 Value being 0.4 +/- 0.1 nM. in isolated pig eye ciliary muscles, clozapine (1.0-100 mu M) inhi bited carbachol (10 mu M)-induced contractions, the estimated IC50 val ue being 5.8 +/- 1.2 mu M. Clozapine (0.1-100 mu M) increased cyclic A MP accumulation in pig's ciliary bodies, including ciliary process, ci liary muscle, and trabecular meshwork. Pretreatment with carbachol (10 0 mu M) first decreased, then increased, clozapine-induced cyclic AMP accumulation. Studies of pretreatments with various muscarinic recepto r antagonists at 100 mu M revealed that pirenzepine significantly enha nced clozapine (100 mu M)-induced cyclic AMP accumulations in trabecul ar meshwork, while 4-DAMP methiodide inhibited it in ciliary bodies, a nd methoctramine decreased it in ciliary process. The ocular hypotensi ve effects of clozapine may be mostly related to its muscarinic agonis t/antagonist activities and associated cyclic AMP increasing activitie s, which lead to ciliary muscle relaxation and a possibly associated i ncrease in uveoscleral outflow. Clozapine's ability to increase blood flow and relax vessels may be attributed to its ability to block alpha -adrenergic and decrease intracellular calcium. IOP is considered the major cause of glaucoma, and compounds which are capable of reducing I OP are considered useful for glaucoma treatment. Based on the results above, clozapine may potentially be important in the development of ne w antiglaucoma agents. (C) 1998 Wiley-Liss, Inc.