Pharmacologic manipulation of conventional outflow facility in ex vivo mouse eyes.
OBJECTIVE
Mouse models are useful for glaucoma research, but it is unclear whether intraocular pressure (IOP) regulation in mice operates through mechanisms similar to those in humans. Our goal was to determine whether pharmacologic compounds that affect conventional outflow facility in human eyes exert similar effects in C57BL/6 mice.


METHODS
A computerized perfusion system was used to measure conventional outflow facility in enucleated mouse eyes ex vivo. Paired eyes were perfused sequentially, either immediately after enucleation or after 3 hours storage at 4°C. Three groups of experiments examined sphingosine 1-phosphate (S1P), S1P with antagonists to S1P(1) and S1P(2) receptors, and the prostanoid EP(4) receptor agonist 3,7-dithia PGE(1). We also examined whether a 24-hour postmortem delay affected the response to 3,7-dithia prostaglandin E(1) (PGE(1)).


RESULTS
S1P decreased facility by 39%, and was blocked almost completely by an S1P(2), but not S1P(1), receptor antagonist. The S1P(2) receptor antagonist alone increased facility nearly 2-fold. 3,7-dithia PGE(1) increased facility by 106% within 3 hours postmortem. By 24 hours postmortem, the facility increase caused by 3,7-dithia PGE(1) was reduced 3-fold, yet remained statistically detectable.


CONCLUSIONS
C57BL/6 mice showed opposing effects of S1P(2) and EP(4) receptor activation on conventional outflow facility, as observed in human eyes. Pharmacologic effects on facility were detectable up to 24 hours postmortem in enucleated mouse eyes. Mice are suitable models to examine the pharmacology of S1P and EP(4) receptor stimulation on IOP regulation as occurs within the conventional outflow pathway of human eyes, and are promising for studying other aspects of aqueous outflow dynamics.
Department of Bioengineering, Imperial College London, London, UK.
Alexandra
A
Boussommier-Calleja
Jacques
J
Bertrand
David F
DF
Woodward
C Ross
CR
Ethier
W Daniel
WD
Stamer
Darryl R
DR
Overby
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D004195:Disease Models, Animal; D015353:Eye Enucleation; D005260:Female; D007429:Intraocular Pressure / Q000502:physiology; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009926:Organ Preservation; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D014065:Tonometry, Ocular; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
C464981:3,7-dithia(11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid; D008246:Lysophospholipids; C545651:Ptger4 protein, mouse; D049349:Receptors, Lysosphingolipid; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D000527:Alprostadil; D013110:Sphingosine