Effects of antiglaucoma drops on MMP and TIMP balance in conjunctival and subconjunctival tissue.
OBJECTIVE
To study the effects of antiglaucoma drugs on metabolism within the extracellular matrix (ECM) of the ocular surface, including corneal, conjunctival, and subconjunctival tissue.


METHODS
Several antiglaucoma drugs--including beta-blockers, alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative-were topically administrated to rat eyes daily for 2 weeks or were incubated with human corneal cells or human fibroblasts for 72 hours. Thereafter, expression and enzymatic activity of the matrix metalloproteinases (MMPs), a group of enzymes proteolyzing ECM and their inhibitors, called tissue inhibitors of metalloproteinase (TIMPs), were evaluated.


RESULTS
Quantitative RT-PCR revealed significantly upregulated and downregulated expression of MMPs and TIMPs, respectively, in rat conjunctival and subconjunctival tissue on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, suggesting that these drugs may enhance ECM degradation. However, in contrast, beta-blocker administration caused reverse effects--that is, upregulation and downregulation of TIMPs and MMPs, respectively. Enzymatic activity of MMPs in rat conjunctival and subconjunctival tissue analyzed by biochemical assay and zymography was markedly enhanced on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, but not of beta-blockers. Similar effects of these antiglaucoma drugs were observed in cultured human corneal cells and human fibroblast cells.


CONCLUSIONS
The present experimental observations suggest that some alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative stimulate ECM degradation of ocular surface tissue by modulating the balance between MMPs and TIMPs.
Ito
Tadashi
T
Department of Ophthalmology, Hirosaki University School of Medicine, Hirosaki, Japan.
Ohguro
Hiroshi
H
Mamiya
Kazuhisa
K
Ohguro
Ikuyo
I
Nakazawa
Mitsuru
M
D000287:Administration, Topical; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003228:Conjunctiva / Q000187:drug effects* / Q000378:metabolism; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005901:Glaucoma / Q000188:drug therapy; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D015854:Up-Regulation
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011465:Prostaglandins, Synthetic; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases