Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK.
OBJECTIVE
Goals of this study were to determine if pharmacological or genetic inhibition of Rho-associated coiled coil containing protein kinases (known as ROCK1 and ROCK2) alters intraocular pressure (IOP) in mice.


METHODS
Micro-cannulation of the anterior chamber was used to measure IOP in wild-type B6.129 hybrid mice following treatment with ROCK inhibitors Y-27632 or Y-39983. For comparative purposes, wild-type mice were also treated with timolol, acetazolamide, pilocarpine, or latanoprost. Mice deficient in either Rock1 or Rock2 were generated by homologous recombination or gene trapping, respectively, and their IOP was determined using identical methods employed in the pharmacology studies.


RESULTS
Treatment of wild-type B6.129 hybrid mice with ROCK inhibitors (Y-27632 and Y-39983) resulted in significant reductions in IOP. The magnitude of IOP reduction observed with topical Y-39983 was comparable to timolol, and exceeded the IOP effects of latanoprost in this study. Pilocarpine had no discernible effect on IOP in mice. Moreover, mice deficient in either Rock1 or Rock2 exhibited a significant decrease in IOP compared to their B6.129 wild-type littermates.


CONCLUSIONS
Pharmacological or genetic inhibition of ROCKs results in decreased IOP in mice. The magnitude of IOP reduction is significant as demonstrated with comparative pharmacology using agents that lower IOP in humans. These studies support the ROCK pathway as a therapeutic target for treating ocular hypertension.
Whitlock
N Andrew
NA
Department of Ophthalmology, Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA. awhitlock@lexpharma.com
Harrison
Bryce
B
Mixon
Travis
T
Yu
Xiang-Qing
XQ
Wilson
Alan
A
Gerhardt
Brenda
B
Eberhart
Derek E
DE
Abuin
Alejandro
A
Rice
Dennis S
DS
D000086:Acetazolamide / Q000008:administration & dosage / Q000494:pharmacology; D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007429:Intraocular Pressure / Q000187:drug effects*; D000077338:Latanoprost; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D010862:Pilocarpine / Q000008:administration & dosage / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D013999:Timolol / Q000008:administration & dosage / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*
D000319:Adrenergic beta-Antagonists; D000577:Amides; D000959:Antihypertensive Agents; D018721:Muscarinic Agonists; D011461:Prostaglandins F, Synthetic; D011725:Pyridines; C520365:Y-39983; D010862:Pilocarpine; C108830:Y 27632; D000077338:Latanoprost; D013999:Timolol; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; D000086:Acetazolamide