Prostanoid EP4 receptor stimulation produces ocular hypotension by a mechanism that does not appear to involve uveoscleral outflow.
OBJECTIVE
As part of a systematic elucidation of the pharmacology of prostaglandin's (PG) effects on intraocular pressure in the monkey, the prototypical selective prostanoid EP(4) receptor agonist (3,7-dithia PGE(1)) was examined. It was found to be highly efficacious in nonhuman primates, and its mechanism of ocular hypotensive activity was investigated.


METHODS
Intraocular pressure (IOP) was measured by pneumatonometry in conscious monkeys restrained in custom-designed chairs. All other animal experiments were performed in animals sedated with ketamine or anesthetized with ketamine/diazepam and given drug or vehicle for various lengths of time. Aqueous flow was determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure method and by 2-minute tonography in both normotensive and hypertensive monkey eyes. Uveoscleral outflow was measured by perfusing the anterior chamber with FITC-labeled dextran for 30 minutes at a fixed IOP of approximately 15 mm Hg. Isometric responses to drugs were measured in longitudinal and radial preparations of monkey and human isolated ciliary smooth muscle specimens.


RESULTS
The selective EP(4) receptor agonist 3,7-dithia PGE(1) and an isopropyl ester prodrug thereof reduced IOP in monkeys. A single dose of 3,7-dithia PGE(1) isopropyl ester, at a 0.01% or 0.1% dose, decreased IOP in the glaucomatous monkey in the range of 40% to 50%. Studies on total outflow facility by the two-level, constant-pressure perfusion method and tonography indicated that EP(4) receptor stimulation facilitated aqueous humor outflow facility. No effect on aqueous flow was apparent. In contrast to all PGs and prostamides studied to date, 3,7-dithia PGE(1) exerted no effect on uveoscleral outflow measured directly. Moreover, it did not relax longitudinal or radial preparations of isolated human or monkey ciliary muscles.


CONCLUSIONS
The EP(4) receptor agonist 3,7-dithia PGE(1) is a highly efficacious IOP-lowering drug in monkeys. It has no effect on uveoscleral outflow but does increase total outflow facility, which accounts for a substantial proportion of the ocular hypotensive activity.
Woodward
David F
DF
Department of Biological Sciences, Allergan, Inc, Irvine, California 92612-1599, USA. woodward_david@allergan.com
Nilsson
Siv F E
SF
Toris
Carol B
CB
Kharlamb
Alexander B
AB
Nieves
Amelia L
AL
Krauss
Achim H-P
AH
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism*; D001285:Atropine / Q000494:pharmacology; D002924:Ciliary Body / Q000187:drug effects; D003911:Dextrans / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D015590:Fluorophotometry; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D007537:Isometric Contraction / Q000502:physiology; D008252:Macaca fascicularis; D009130:Muscle, Smooth / Q000502:physiology; D015814:Ocular Hypotension / Q000209:etiology* / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012590:Sclera / Q000378:metabolism*; D014065:Tonometry, Ocular; D014162:Transfection; D014602:Uvea / Q000378:metabolism*
C464981:3,7-dithia(11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid; D000959:Antihypertensive Agents; D003911:Dextrans; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C015219:fluorescein isothiocyanate dextran; D001285:Atropine; D000527:Alprostadil; C048491:butaprost; D016650:Fluorescein-5-isothiocyanate; D015232:Dinoprostone