Ocular pharmacology of bicyclic hexahydroaporphines.

ABSTRACT

This paper explores the ocular hypotensive actions of bicyclic analogs of hexahydroaporphine (HHA), specifically nor-HHA, in an attempt to shed light on the mechanism(s) by which they lower intraocular pressure (IOP). Studies involving the measurement of IOP and aqueous humor production were conducted in ocular normotensive albino rabbits, while those involving smooth muscle contractility utilized isolated bovine iris. The ability of nor-HHA to produce a sustained drop in IOP is linked to both a functioning adrenergic nervous system and the availability of the products of cyclooxygenase metabolism. Although aqueous flow is not impacted by the bicyclic structures, the significant enhancement of outflow facility points to a probable mechanism of IOP-lowering action. Nor-HHA had no direct contractile or relaxant action on bovine irides, but does cause a concentration-dependent inhibition of carbachol-evoked contractions. This inhibition was reversed by inhibitors of phospholipase A(2) and cyclooxygenase, but not by inhibitors of lipoxygenase, again indicating a role for prostaglandins in the ocular pharmacological action of bicyclic HHAs. Pretreatment with a nitric oxide (NO) scavenger also reversed the ability of nor-HHA to inhibit carbachol-induced contractions, implying a role for NO in the postjunctional actions of HHAs.