Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes.
Aqueous outflow in the conventional outflow pathway is regulated by the contraction and relaxation of the ciliary muscle (CM) and the trabecular meshwork (TM). Rho-associated coiled coil-forming protein kinase (ROCK) is thought to regulate actomyosin-based contractility in many types of cells by phosphorylation of ROCK substrates. In animal models, ROCK inhibitor Y-39983 relaxed CM and TM and decreased intraocular pressure (IOP). Thus, ROCK is implicated in the regulation of aqueous outflow and IOP. However, the site of action of ROCK in monkey and man is unknown. In the present communication, RT-PCR analysis of monkey tissues showed higher levels of mRNAs for ROCK and ROCK substrates in TM compared to CM. Human TM also showed higher levels of mRNAs for ROCK and ROCK substrates compared to CM. Differences between TM and CM in human were not as high as in monkey. ROCK inhibitor Y-39983 led to a dose-dependent relaxation of carbachol-induced, contracted TM from monkey. In contrast, Y-39983 was only slightly effective in relaxing CM. Our results suggested that TM was one of the major sites for regulating IOP by ROCK. ROCK inhibitor Y-39983 might be a candidate drug for lowering IOP by increasing conventional outflow and producing fewer side effects on accommodation and miosis.
Nakajima
Emi
E
Laboratory of Ocular Sciences, Senju Pharmaceutical Corporation Limited, Beaverton, Oregon 97006, USA.
Nakajima
Takeshi
T
Minagawa
Yoko
Y
Shearer
Thomas R
TR
Azuma
Mitsuyoshi
M
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers; D005123:Eye / Q000187:drug effects / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014129:Trabecular Meshwork / Q000187:drug effects / Q000502:physiology*; D054460:rho-Associated Kinases
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D018721:Muscarinic Agonists; D012313:RNA; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human