Effect of the enzyme inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles of topical anandamides.
OBJECTIVE
Earlier studies have suggested that the intraocular pressure (IOP) effects of topical arachidonylethanolamide (AEA) are mediated through its fatty acid metabolite, rather than through AEA, per se. The purpose of this study was to investigate whether the topical anandamides AEA and arachidonyl propionitrileamide (APN) decrease IOP when their enzymatic degradation is prevented by phenylmethylsulfonyl fluoride (PMSF) and whether the neuronal cannabinoid (CB1) receptor mediates the IOP responses of an undegraded AEA, through the use of its specific antagonist SR141716A.


METHODS
AEA or APN were each formulated in aqueous 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and administered unilaterally to the rabbit eye (dose, 62.5 microg per rabbit). To prevent the degradation of AEA or APN, the rabbits were pretreated with a subcutaneous (SC) PMSF injection (0.22-22 mg/kg) 30 minutes before eye drop instillation. To determine whether the neuronal cannabinoid (CB1) receptor mediates the hypotensive IOP effects of undegraded AEA, the rabbits were pretreated with simultaneous SC injections of a CB1 receptor antagonist SR141716A (1.2-2.1 mg/kg) and PMSF (2.2 mg/kg) before the ocularly applied AEA.


RESULTS
In the absence of PMSF, the IOP profiles of AEA and APN showed a biphasic ocular effect--that is, an initial increase of IOP followed by IOP hypotension in the treated eye. In the presence of PMSF (2.2 mg/kg for AEA and 22 mg/kg for APN), IOP profiles showed immediate IOP reduction in the treated eye. SR141716A antagonized the IOP reduction caused by the undegraded AEA.


CONCLUSIONS
These results indicate that the apparently undegraded AEA and APN decrease IOP in normotensive rabbits. AEA-induced IOP reduction in the presence of PMSF is probably mediated through a CB1 receptor.
Laine
Krista
K
Department of Pharmaceutical Chemistry, University of Kuopio, Kuopio, Finland. krista.laine@uku.fi
Järvinen
Kristiina
K
Pate
David W
DW
Urtti
Arto
A
Järvinen
Tomi
T
D000287:Administration, Topical; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000008:administration & dosage*; D002186:Cannabinoids / Q000008:administration & dosage*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007213:Indomethacin / Q000008:administration & dosage; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009883:Ophthalmic Solutions; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000008:administration & dosage; D011817:Rabbits; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007213:Indomethacin; D009883:Ophthalmic Solutions; D010664:Phenylmethylsulfonyl Fluoride; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide