Mechanisms of Actions of Drugs Which Alter Intraocular Pressure

Millar, John Cameron (1993) Mechanisms of Actions of Drugs Which Alter Intraocular Pressure. PhD thesis, University of Glasgow.

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The bovine perfused eye model has been validated as an inexpensive and convenient method for the assessment of the ability of drugs to lower intraocular pressure (IOP), free from the complicating effects of the cardiovascular system, the nervous system (including the CNS) and the presence of circulating hormones. This preparation also facilitates the comparison of drug effects on pressure with effects on the uveal vasculature, as well as rapid access to living tissue for biochemical analysis. Using this preparation, the ocular hypotensive effects of several beta-adrenoceptor antagonists have been demonstrated. The pressure lowering effect of the beta-adrenoceptor antagonists probably does not involve a classical beta-adrenoceptor or ciliary cyclic AMP as a signal transduction pathway, and is not dependent upon intact adrenergic innervation. The presence of a ciliary beta2-drenoceptor population positively coupled via Gg protein to a membrane channel is postulated. Atrial natriuretic factor (Atriopeptin - AP) and the nitrovasodilators sodium nitroprusside (SNP) and sodium azide, all of which are known to activate guanylate cyclase, also reduce IOP. Further, certain L-type Ca2+ channel antagonists and the channel agonist pinacidil reduce IOP in this preparation. A comparative investigation of the pressure lowering and vascular effects of certain of these drugs has been undertaken. It is concluded that the pressure lowering effect of these drugs cannot be an outcome of their vascular effects, but rather probably results from a direct effect on the ciliary epithelial cells. The bovine perfused eye may be the first isolated organ to be subjected to analysis of drug induced changes in regional blood flow using a labelled microsphere technique. The effects of these drugs on the uveal vasculature are varied and complex. Timolol at maximal ocular hypotensive dose was found to significantly reduce perfusion in the choroid, whereas at supramaximal dose it was found to significantly reduce perfusion in the iris. By contrast, a maximal ocular hypotensive dose of carteolol significantly reduced perfusion in the iris, ciliary body and choroid. Doses of SNP or verapamil which are known to reduce IOP in this preparation were found to significantly increase perfusion in the iris, ciliary body and choroid. Doses of AP or of sodium azide which are capable of producing submaximal decreases in IOP in the bovine perfused eye have been shown to produce a significant increase in ciliary cyclic GMP. It is concluded that ciliary cyclic GMP or Ca2+ may be involved in the control of IOP.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: William Wilson
Keywords: Pharmacology
Date of Award: 1993
Depositing User: Enlighten Team
Unique ID: glathesis:1993-74804
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Nov 2019 15:58
Last Modified: 13 Nov 2019 15:58

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