The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey.
OBJECTIVE
To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action.


METHODS
All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies.


RESULTS
Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 +/- 0.20 vs. 0.53 +/- 0.18 microL.min(-1). After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes.


CONCLUSIONS
The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar.
Nilsson
Siv F E
SF
Department of Medicine and Care, Division of Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. sivni@imv.liu.se
Drecoll
Enken
E
Lütjen-Drecoll
Elke
E
Toris
Carol B
CB
Krauss
Achim H-P
AH
Kharlamb
Alexander
A
Nieves
Amelia
A
Guerra
Teresa
T
Woodward
David F
DF
D000287:Administration, Topical; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D002924:Ciliary Body / Q000187:drug effects / Q000473:pathology; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D015590:Fluorophotometry; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000473:pathology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012590:Sclera / Q000187:drug effects* / Q000378:metabolism; D014129:Trabecular Meshwork; D014602:Uvea / Q000187:drug effects* / Q000378:metabolism
D003911:Dextrans; D011459:Prostaglandins E, Synthetic; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; C015219:fluorescein isothiocyanate dextran; D000527:Alprostadil; C048491:butaprost; D016650:Fluorescein-5-isothiocyanate