Mechanisms of Action of Drugs Lowering Intraocular Pressure of the Eye

Bellashher, Ahlam Hashmi (1998) Mechanisms of Action of Drugs Lowering Intraocular Pressure of the Eye. MSc(R) thesis, University of Glasgow.

Abstract

An in vitro preparation of the bovine perfused eye has been used to study the mechanisms of action of drugs on intraocular pressure (IOP) in isolation from the complicating influence of the cardiovascular system, hormones and central nervous system as in most previous reports using the rabbit. This method also avoids the necessity to kill animals for experimental purposes and provides rapid access to the living tissues for biomedical analysis. In this model the isolated bovine eye is perfused through the long posterior ciliary artery to provide simultaneous monitoring of drug effects on IOP and on the ciliary blood vessels. In this research most of the drugs have been tested by using various routes of administration in our effort to provide logical and more understandable mechanisms of action for their effect upon IOP. IOP values were measured for 60-90 min following drug administration and were compared against similar experiments in which water was used as a control. Results obtained with adenosine and its selective agonists cyclohexyl adenosine (CHA), the selective adenosine Ai receptor agonist and N-6-(2-(3,5-Dimethoxyphenyl)-2(2-methylphenyl)-ethyl adenosine (DPMA), the selective adenosine A2 receptor agonist showed that they produced small transient effects on arterial perfusion pressure. Their effects on IOP were insignificant, whether inserted into the reservoir as an arterial perfusate solution or when injected into the posterior ciliary artery as a bolus injection. ATP produced a significant effect on both perfusion pressure and IOP when injected intra-arterially. The increase in perfusion pressure produced immediately after ATP injection probably was due to its vasoconstrictor effect on the uveal vasculature. ATP produced a statistically significant dose- dependent decline in IOP in a dose range of 300 to 3000nmol. The mechanism of action of ATP on IOP is still obscure. Preliminary experiments with 5-hydroxytryptamine (5-HT) using arterial routes indicate that this drug has no effect on perfusion pressure or IOP. On the other hand intracameral (I.C) Injection of 5-HT produced a transient increase in perfusion pressure and a statistically significant decrease in IOP in a dose range of 3 to 30 nmol. 100nmol 5-HT produced a statistically insignificant decrease in IOP, suggesting that 30nmol was the maximum dose of 5-HT to produce decreases in IOP. Doses of 8-hydroxy-2-(di-n-propylamino)-tetralin) (8-OH-DPAT), the selective 5-HT1A receptor agonist, produced an insignificant effect on bovine IOP by the arterial routes. I.C 8-OH-DPAT produced no effect on perfusion pressure, but significant decline of IOP was produced in a dose-dependent manner. Single bolus injections of 5-carboxamidotryptamine (5-CT) (20 to 200nmol) produced no effect on perfusion pressure, but produced a statistically significant dose-dependent decrease in IOP. The conclusion is reached that the mechanism by which 5-HT, 8-OH-DPAT and 5-CT reduce IOP is probably through increase in the drainage of aqueous humour when these drugs are injected by the I.C route. The enzyme-immuno assay for cyclic AMP was performed to study the effects of adenosine, 5-HT and 8-OH-DPAT in bovine ciliary processes (CP) and trabecular meshwork (TM) homogenates. The aim of that was to make a correlation between the effects of these drugs on cAMP and their effects on IOP. 5-HT produced an increase in cAMP synthesis in CP and TM homogenates, although this effect was not dose-dependent. 5-HT produced changes in cAMP of CP homogenate which were too variable to give any conclusion. The conclusion reached is that 5-HT may reduce IOP through increases in cAMP synthesis in TM tissue, which may produce a rise in facility of outflow. The results for 8-OH-DPAT on cAMP in both TM and CP were too variable to draw any meaningful conclusion.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Keywords: Ophthalmology, Pharmacology
• Date of Award: 1998
• Depositing User: Enlighten Team
• Unique ID: glathesis:1998-74473
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 18:11
• Last Modified: 27 Sep 2019 18:11
• URI: https://theses.gla.ac.uk/id/eprint/74473