Acute effects of H-7 on ciliary epithelium and corneal endothelium in monkey eyes.
OBJECTIVE
Topical or intracameral administration of H-7 doubles outflow facility and reduces intraocular pressure in cynomolgus monkeys, by relaxing and expanding the trabecular meshwork (TM) and Schlemm's canal (SC). Since H-7 may have anti-glaucoma potential, we determined its effects on the corneal endothelium and ciliary epithelium for safety considerations.


METHODS
Following topical H-7, aqueous humor flow (AHF), corneal endothelial transfer coefficient (k(a)) and anterior chamber (AC) entry of i.v. fluorescein were measured by fluorophotometry; AC aqueous protein concentration ([Protein](AC)) was determined by Lowry assay; and corneal thickness and endothelial cell density and morphology were measured by ultrasonic pachymetry and specular microscopy respectively. Following intracameral H-7, specular and/or light and electron microscopy of the corneal endothelium or ciliary epithelium were performed.


RESULTS
Following unilateral topical H-7: (1) AHF and k(a) were essentially unchanged at 0.5--3.0, 3.5--6.0, and 0.5--6.0 hr, with an insignificant increase from 0.5--1.5 hr; (2) [Protein]( AC) was insignificantly increased at 1-1.5 hr but had returned to baseline by 2.5 hr; (3) entry of i.v. fluorescein into aqueous or cornea was modestly and transiently increased; (4) the central cornea thickened significantly at 1--2.5 hr, gradually returning to baseline 2.5 hr after H-7, while peripheral corneal thickness was less affected; (5) corneal endothelial cell borders became indistinct by 1 hr, but cell morphology was recovering by 3--5 hr and had completely returned to normal by 24 hr; (6) corneal endothelial cell density was unchanged at 5--24 hr. Following intracameral H-7, no significant changes were observed in corneal endothelial cell density or morphology by specular microscopy, nor in corneal endothelial or ciliary epithelial morphology by light and electron microscopy.


CONCLUSIONS
A facility-effective intracameral dose of H-7 had no discernible structural effect on the corneal endothelium or ciliary epithelium. It is not yet clear whether carefully chosen topical doses of H-7 or analogues can enhance outflow facility without meaningfully affecting the cornea and ciliary processes.
Tian
B
B
Department of Ophthalmology & Visual Sciences, University of Wisconsin, Madison, Wisconsin 53792-3220, USA.
Sabanay
I
I
Peterson
J A
JA
Hubbard
W C
WC
Geiger
B
B
Kaufman
P L
PL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000494:pharmacology*; D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002452:Cell Count; D048429:Cell Size; D002924:Ciliary Body / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004353:Drug Evaluation, Preclinical; D004728:Endothelium, Corneal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D019793:Fluorescein / Q000378:metabolism; D015590:Fluorophotometry; D008252:Macaca fascicularis; D008297:Male; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005136:Eye Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D019793:Fluorescein