Effects of topical anandamide-transport inhibitors, AM404 and olvanil, on intraocular pressure in normotensive rabbits.
OBJECTIVE
To evaluate the effects of topically applied anandamide transport inhibitors, AM404 and olvanil, on the intraocular pressure (IOP) of normotensive rabbits. To determine if the ocular hypotension induced by topical anandamide (AEA) can be potentiated by co-administered AM404.


METHODS
Test compounds, in either hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or propylene glycol, were administered unilaterally onto rabbit eyes. To determine if AM404 affects the IOP-profile of AEA, AM404 was administered ocularly 15 minutes before topical AEA. Phenylmethylsulfonyl fluoride (PMSF) (24 mg/kg, s.c.) was given 30 min before AEA to prevent its catabolism. IOPs of the treated and untreated eyes were measured. The cannabinoid agonist activities of AM404 and olvanil were studied by using [35S]GTPyS autoradiography.


RESULTS
Topical AM404 (62.5 micirog), in HP-beta-CD vehicle, decreased IOP significantly in treated eyes. AM404 (62.5 microg) induced a significant IOP increase without subsequent decrease when given in propylene glycol vehicle. Olvanil (312.5 microg) caused a significant IOP reduction without provoking an initial hypertensive phase. These compounds did not significantly affect the IOP of untreated eyes. Co-administered AM404 (125 microg in HP-beta-CD) had no significant effect on the IOP profile of AEA (62.5 microg).


CONCLUSIONS
Ocular administration of AM404 or olvanil decreased IOP in rabbits, although AM404 can provoke an initial ocular hypertension and did not potentiate the IOP responses induced by exogenous AEA.
Laine
K
K
Department of Pharmaceutical Chemistry, University of Kuopio, Finland. krista.laine@uku.fi
Järvinen
T
T
Savinainen
J
J
Laitinen
J T
JT
Pate
D W
DW
Järvinen
K
K
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D063388:Endocannabinoids; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D008297:Male; D053284:Polyunsaturated Alkamides; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C054256:olvanil; D002211:Capsaicin; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide