Latanoprost-induced changes in rat intraocular pressure: direct or indirect?
BACKGROUND
The topical application of prostaglandin F(2 ) (FP)-receptor agonists has been shown to significantly lower intraocular pressure (IOP) in humans and is now considered the first-line treatment for ocular hypertension. Despite the prominent role FP-receptor agonists play in the treatment of glaucoma, our understanding of how these agents lower IOP remains incomplete. The present study was designed to evaluate the role of matrix metalloproteinase (MMP) activation and the cytokine, tumor necrosis factor alpha (TNF-alpha), in latanoprost-induced changes in IOP.


METHODS
Changes in IOP following an acute topical administration of latanoprost (60 ng) in normotensive Brown Norway rats were evaluated by means of a commercially available rebound tonometer. To examine the role of MMPs and TNF-alpha in this response, the rats were pretreated with a broad-spectrum MMP inhibitor, GM-6001 (100 microg), or the TNF-alpha inhibitor, thalidomide (25 microg).


RESULTS
The topical administration of latanoprost (60 ng) alone produced a biphasic change in ipsilateral IOP: an initial hypertension (4.21 +/- 0.52), followed by a prolonged hypotension (-4.79 +/- 0.65). In rats, pretreatment with GM-6001 blocked the latanoprost-induced reduction in IOP but did not prevent the initial rise in IOP. Pretreatment with thalidomide also blocked the ocular hypotension induced by latanoprost; however, thalidomide pretreatment enhanced the duration of the initial hypertension.


CONCLUSIONS
These results provide evidence that the secretion and activation of MMPs and the release of TNF-alpha play a central role in the ocular hypotension induced by FP-agonists. The administration of FP-agonists appears to lower IOP directly by inducing the activation of MMPs within the ciliary body, leading to improved uveoscleral outflow and indirectly through the release of TNF within the ciliary body. Secreted TNF-alpha may then activate TNF-receptors in the uvea and trabecular meshwork, increasing both uveoscleral and conventional outflow.
Husain
Shahid
S
Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA. husain@musc.edu
Yates
Phillip W
PW
Crosson
Craig E
CE
D000287:Administration, Topical; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology*; D000077338:Latanoprost; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage*; D051381:Rats; D011914:Rats, Inbred BN; D013792:Thalidomide / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011461:Prostaglandins F, Synthetic; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D000077338:Latanoprost; D020782:Matrix Metalloproteinases