Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A constant intravenous infusion of digoxin (2 micrograms/kg/min) to alpha-chloralose-anesthetized cats produced a progressive decrease in intraocular pressure with increasing doses of digoxin between 60 micrograms/kg and drug-induced ventricular arrhythmia which occurred at a mean dose of 172 micrograms/kg. Digoxin elicited a 40% decrease in intraocular pressure just prior to ventricular arrhythmia compared to a decrease of only 10% with a control infusion of diluent in the same animal (P less than 0.05). There was no significant difference (P less than 0.1) between changes in blood pressure and heart rate observed in the experimental versus the control infusions. The decrease in intraocular pressure may result from inhibition of the Na-K-ATPase in the ciliary body.
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PMID:Digoxin-induced decrease in intraocular pressure in the cat. 43 41

Bovine, non-pigmented, ciliary body epithelial cells were isolated and grown in culture to determine whether timolol maleate might affect the activity of their plasma membrane ATPases. The possible effects were tested in drug concentrations in a range of 5 x 10(-19) to 5 x 10(-5) M over an incubation period of 30 min at 37 degrees. Assays of specific activity showed that the drug significantly (p less than .001 for most concentrations) inhibited both Na,K-ATPase and Mg-ATPase. However, the inhibition was partially reversed in concentrations greater than 10(-6) M for Na,K-ATPase and 10(-5) M for Mg-ATPase. The latter enzyme also indicated a second partial reversal in activity at concentrations between 10(-12) and 10(-9) M. These reversals in activity suggest that more than one binding site is involved in the inhibition of both enzymes. Since Na,K-ATPase in non-pigmented, ciliary body cells is responsible for the generation of aqueous fluid and the intraocular pressure (IOP), this inhibition demonstrates a possible mechanism for the pharmacological action of timolol maleate in lowering IOP.
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PMID:The inhibition of Na, K-ATPase, and Mg-ATPase by timolol maleate in cultured non-pigmented epithelial cells of the ciliary body. 132 85

Ciliary epithelium was isolated from the rabbit eye and used as a source of plasma membrane material for sodium, potassium-adenosine triphosphatase (Na,K-ATPase) measurements. In the presence of 12(R)-hydroxyeicosatetraenoic acid [12(R)HETE], Na,K-ATPase (ouabain-sensitive ATPase) activity was reduced from 22.5 to 16.3 microM phosphate released/mg protein/hr. Ouabain-insensitive ATPase activity was not altered by 12(R)HETE. No changes in ciliary epithelium ATPase activity were observed in the presence of 12(S)HETE. In parallel studies with conscious rabbits, 12(R)HETE applied topically to the eye was found to lower intraocular pressure (IOP). It is possible that the IOP-lowering effect of 12(R)HETE may be, in part, associated with its ability to suppress the Na,K-ATPase activity of the ciliary epithelium.
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PMID:The influence of 12(R)-hydroxyeicosatetraenoic acid on ciliary epithelial sodium, potassium-adenosine triphosphatase activity and intraocular pressure in the rabbit. 165 Dec 97

If beta-blockage does not cause lowering of aqueous humor secretion, in itself responsible for the maintenance of intraocular pressure, what is the mechanism of action? The antagonism for indolamines, recently measured in aqueous humor, the absence of nocturnal effect, and the amplitude diminution of diurnal variations thus produced suggest that beta-blockers could interact with indolamines, since the latter are probably responsible for intraocular pressure regulation. Aqueous humor secretion depends to a major extent on the sodium-potassium pump and its enzyme, Na+K(+)-ATPase. Serotonin, known for its activating action on Na+K(+)-ATPase, is present in the greatest amounts in the morning, precisely when the aqueous humor secretion is the highest. Moreover, timolol is a potent antagonist of serotonin, suggesting that beta-blockers could decrease the secretion by antagonism with serotonin at the level of Na+K(+)-ATPase. Since serotonin is metabolized to melatonin during sleep, beta-blockers might simulate a state of sleep of the ciliary epithelium.
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PMID:[Mechanism of action of beta-blockers]. 197 78

The formation of aqueous humour by the ciliary body is a complex process. Active transport of solutes by the ciliary process epithelium is an energy-dependent mechanism that selectively transports substances against an electrochemical gradient across the cell membranes. Water passively follows the active solute transport. In addition to these active transport processes, ultrafiltration contributes to the formation of aqueous humour. The ciliary epithelium contains enzyme systems that function in the production of aqueous humour. The enzymes sodium-potassium-activated adenosine triphosphatase [(Na+:K+)ATPase] and carbonic anhydrase participate in the active transport across this epithelium. Inhibition of these enzymes lowers intraocular pressure (IOP) by decreasing aqueous humour production. the ciliary epithelium contains both alpha- and beta-adrenergic receptors. Electrophysiologic studies on the isolated iris-ciliary body (I-CB) preparation provide a means to study direct effects of the adrenergic agents on transepithelial properties of the ciliary epithelium. This paper will discuss the enzymatic and adrenergic properties of the ciliary epithelium as they relate to active transport and thereby aqueous humour production.
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PMID:Aqueous production. 302 67

Some biochemical factors of the iris-ciliary body of the rabbit have been examined for effects induced by water-soluble marihuana-derived material (MDM). Adenylate cyclase activity and sensitivity to beta-adrenergic agonists were unchanged, as measured 4 hours after MDM administration in vivo. Magnesium-dependent and anion-sensitive, but not sodium-potassium, ATPase activities were inhibited 6 hours after MDM administration in vivo, although they were unaffected by in vitro incubation. Topical administration of a potent substance P antagonist had no effect on the time course or magnitude of intravenous MDM-induced ocular effects in rabbit. Intravenously administered sugars antagonized the effects of MDM on intraocular pressure. A variety of drugs which display a range of biochemical effects varying from beta-adrenergic receptor agonism, to alteration of glycoprotein residues were employed. None of the agents employed, ranging from cAMP modifiers to protein synthesis blockers, had any effect on the MDM-induced response. It is apparent that the mechanism underlying the ocular hypotensive effect of MDM does not reside in mediation through adenylate cyclase, ATPase or substance P, but rather through a mechanism mediated by terminal sugar moieties on the molecule. The data suggest that modification of the surface membrane glycoprotein residues on the ciliary epithelium can induce marked alterations in aqueous humor flow rate.
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PMID:Marihuana-derived material: biochemical studies of the ocular responses. 316 May 44

Open-angle glaucoma is treated primarily with drugs, some of which have been used clinically for years. These drugs include: 1) cholinergic agonists that increase aqueous humor outflow, 2) adrenergic agonists and antagonist that affect both aqueous humor formation and outflow, and 3) carbonic anhydrase inhibitors that decrease aqueous humor formation. Several new classes of drugs are being tested for efficacy and mechanism of action. They include: 1) the D-isomer of timolol that reduces aqueous humor formation without producing adrenergic blockade, 2) dopaminergic agonists and antagonists, including bromocriptine and butyrophenones that reduce intraocular pressure, and 3) cannabinoids that reduce aqueous humor formation and increase outflow. In addition, several other types of drugs, such as prostaglandins, diuretics, Na+,K+-ATPase inhibitors, and adenyl cyclase stimulators are just now beginning to be studied.
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PMID:A synopsis of recent developments in antiglaucoma drugs. 391 48

Topical administration of 50 microliter of 1% Na3VO4 caused a significant fall in intraocular pressure (IOP) in the rabbit eye at 90 min. Assay of ATPase of the iris and ciliary body in vitro at 90 min posttreatment showed no differences between control and treated (Na+, K+)ATPase, ouabain sensitive ATPase or vanadate sensitive ATPase. Accumulation of 48V-labelled orthovanadate in iris and ciliary body reached a plateau of 12 pmoles/mg dry tissue weight 4 hr after a single 25-microliter topical dose of 1% orthovanadate. In vitro inhibition of Na+ sensitive ATPase by sodium metavanadate had an IC50 of 1.8 mM, whereas a 1.8-fold stimulation of adenylate cyclase in iris-ciliary body (ICB) membranes in vitro occurred at 10 mM but not at 10 microM Na metavanadate. These results indicate that the vanadate content of the iris and ciliary body at the time of lowered intraocular pressure is too small to inhibit a significant fraction (greater than 10%) of (Na+, K+)ATPase, or cause a significant stimulation of adenylate cyclase, and that other cellular mechanisms are likely to be involved in the ocular hypotensive response to vanadate.
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PMID:Vanadate effects on ocular pressure, (Na+, K+)ATPase and adenylate cyclase in rabbit eyes. 609 95

Topical administration of 0.5% vanadate lowers intraocular pressure in monkey and rabbit eyes. This appears to be a consequence of a reduction in the rate of aqueous humor secretion, probably resulting from the inhibition of ciliary epithelium membrane. NaK ATPase. The ubiquitous vanadate and its interactions with catecholamines and ascorbate may play a role in regulating the sodium pump of the ciliary epithelium. Adrenergic blocking agents may also lower intraocular pressure by inhibiting the NaK ATPase of the ciliary epithelium.
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PMID:Vanadate and aqueous humor dynamics. Proctor Lecture. 610 42

The corneal epithelium of several species, has the capacity to metabolize arachidonic acid (arachidonic acid) via an NADPH-dependent cytochrome P450 mechanism. The major metabolites are 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), both of which exist in stereoisomeric configurations. However, the R enantiomers are predominantly produced by this enzyme system and exhibit potent biological activities. 12(R)-HETE inhibits Na-K-ATPase, increases corneal thickness and reduces intraocular pressure. 12(R)-HETrE causes vasodilation, neutrophil chemoattraction and angiogenesis. The formation of these metabolites is unaffected by cyclooxygenase and lipoxygenase inhibitors (indomethacin, diclofenac and BW755C) but inhibited by cytochrome P450 enzyme inhibitors such as carbon monoxide, SKF-525A and clotrimazole. The capacity of the normal corneal epithelium to metabolize arachidonic acid via cytochrome P450 is very low although under certain conditions this enzymatic pathway may become greatly induced. Corneal epithelial hypoxia in response to contact lens wear results in the time-dependent formation of NADPH-cytochrome P450-dependent arachidonate metabolites, 12(R)-HETE and 12(R)-HETrE. Under this condition, metabolite production correlates strongly with the in situ inflammatory response and inhibition of their formation significantly attenuates inflammation. It is evident that the cytochrome P450 arachidonate metabolites should be added to the realm of cyclooxygenase and lipoxygenase-derived eicosanoids as possible inflammatory mediators. Therefore, studies to evaluate eicosanoid involvement in inflammation should examine inhibitors of this pathway in addition to the classically studied non-steroidal antiinflammatory drugs (NSAIDs).
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PMID:Effect of metabolic inhibitors on arachidonic acid metabolism in the corneal epithelium: evidence for cytochrome P450-mediated reactions. 820 35


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