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)

Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits alpha and beta held together by noncovalent forces. Each subunit contains about 30% carbohydrate and is extensively crosslinked by disulfide bonds. Previous work from our laboratory with commercial preparations of hCG indicated that intravitreal injection of hCG lowered intraocular pressure (IOP). Our work has been extended by using purified hCG obtained by reverse phase high performance liquid chromatography of a commercial preparation. With a wide pore octyl silica column and a step gradient composed of dilute aqueous trifluoroacetic acid and methanol, several peaks were obtained. The major peak was shown by sodium dodecylsulfate-polyacrylamide gel electrophoresis and amino acid analysis to contain both alpha and beta subunits. That this major peak contained intact hormone rather than a mixture of subunits was revealed by its ability to enhance the fluorescence of 8-anilino-1-naphthalene sulfonate and stimulate the release of cyclic AMP from isolated rat testes; subunits of hCG lack these properties. Physiological doses of hCG from this major peak injected intravitreally in rabbit eyes resulted in significant decreases in IOP without associated irritation when compared with contralateral control eyes.
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PMID:Intravitreal injection of purified human chorionic gonadotropin lowers IOP in rabbits. 350 1

Recent reports suggest that forskolin can produce ocular hypotension in laboratory animals and man by enhancing formation of cyclic AMP. This proposed mechanism of action implies that forskolin lowers intraocular pressure (IOP) by activating adenylate cyclase at some postjunctional site. Intra-arterial (i.a.) injections of forskolin (10, 33, 100 & 333 micrograms) into the cat nictitating membrane (CNM) preparation produced dose-related inhibition of contractions elicited by electrical stimulation of pre-and postganglionic sympathetic neurons. Interestingly, contractions elicited by i.a. norepinephrine were inhibited less than neuronally mediated contractions. Topically applied forskolin (0.5 mg) to the eyes of unilaterally sympathectomized (SX) rabbits and normal rabbits elicited ocular hypotension in the innervated eyes only. Forskolin (0.5 mg, topically) suppressed the rise in IOP induced by water loading in normal rabbits but was significantly less effective in SX rabbits. These results suggest that forskolin lowered IOP in rabbits and suppressed contraction of the electrically-stimulated CNM, in part, by inhibiting sympathetic neuronal function.
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PMID:Forskolin suppresses sympathetic neuron function and causes ocular hypotension. 403 43

The secretory tissue of the eye, the ciliary processes, contains an enzyme receptor complex, composed of membrane proteins, the catalytic moiety of the enzyme adenylate cyclase, a guanyl nucleotide regulatory protein (or N protein), and other features. The enzyme can be activated by well-known neurohumoral or humoral agents, catecholamines, glycoprotein hormones produced by the hypothalamic pituitary axis, and other related compounds, including placental gonadotropin, organic fluorides, and forskolin, a diterpene. These compounds cause the ciliary epithelia to produce cyclic AMP at an accelerated rate. Cyclic AMP, as a second messenger, causes, either directly or indirectly, a decrease in the net rate of aqueous humor inflow that may be modulated by cofactors. Clinical syndromes fit the experimental data so that an integrated explanation can be given for the reduced intraocular pressure witnessed under certain central nervous system and adrenergic influences. The molecular biology of this concept provides important leads for future investigations that bear directly both upon the regulation of intraocular pressure and upon glaucoma.
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PMID:The adenylate cyclase receptor complex and aqueous humor formation. 609 93

The intracellular pathway by which beta-adrenergic agonists and antagonists affect aqueous humor dynamics involves the intracellular mediator, cyclic AMP. We have therefore tested the activity of forskolin, a direct activator of adenylate cyclase, in rabbits. Following a 15 min in vitro incubation in the presence of forskolin (15 microM) and isobutylmethylxanthine, a 10 fold increase in cyclic AMP was found in both rabbit iris-ciliary body and scleral-trabecular rings relative to controls. Following an intracameral injection of forskolin (10 micrograms) a time-dependent decrease in intraocular pressure was observed, which reached a mean decrease of 5 mm Hg at 4 hr in unanesthetized rabbits. Outflow facility was measured in anesthetized rabbits by constant pressure perfusion before injection and 1 hr after injection of either forskolin (10 micrograms) or control vehicle. Forskolin caused an approximate doubling of outflow facility (0.41 microliter/min/mm Hg) compared to the preinjection mean value. Control vehicle, ethyl alcohol, caused a statistically insignificant increase in outflow facility. At this concentration of forskolin, the integrity of the blood-aqueous barrier was normal as measured by protein and fluorescein entry into the aqueous humor. These results indicate that agents which directly activate adenylate cyclase are effective at increasing outflow facility and decreasing IOP.
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PMID:Forskolin stimulates cyclic AMP synthesis, lowers intraocular pressure and increases outflow facility in rabbits. 613 23

In unanesthetized rabbits the topical application of vanadate lowered intraocular pressure. Tonographic outflow facility and episcleral venous pressure were unaltered by topical vanadate. As estimated from the tonographic data, aqueous humor flow was reduced by approximately 30%. Posterior chamber aqueous humor ascorbate increased in the eye receiving topical vanadate, and this was compatible with a decreased rate of aqueous humor flow. Topical vanadate did not alter anterior chamber aqueous humor protein or cyclic AMP. In five monkeys intraocular pressure was also significantly reduced by topical vanadate.
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PMID:Topical vanadate lowers intraocular pressure in rabbits. 625 11

The effects of topical 0.5% timolol maleate and 1% or 2% levo-epinephrine hydrochloride on aqueous humor cyclic-AMP and intraocular pressure were assessed in 97 normotensive New Zealand white rabbits in vivo. The study was conducted using three experimental protocols: (A) timolol and epinephrine individually, (B) timolol and epinephrine in coadministration, and (C) timolol and epinephrine in crossover, applied either in a single dose, twice a day for two days, and/or twice a day for six days. These studies demonstrated that timolol has complex biochemical actions, one of which is beta-adrenergic antagonism. By itself, timolol had no effect on cyclic-AMP levels. However, when used in both single-dose coadministration and in pretreatment in six-day crossover with epinephrine, it significantly diminished the cyclic-AMP elevation produced by a single dose of epinephrine. In the six-day crossover protocol, pretreatment with timolol also significantly reduced the ocular hypotensive effect of a single dose of epinephrine, thereby correlating biochemical cause with clinical effect. Yet, timolol alone had no ocular hypotensive effect. Therefore, timolol's biochemical actions in this animal model cannot explain its marked clinical efficacy in man, which appears to depend on more complex pharmacologic actions.
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PMID:Topical timolol and epinephrine: biochemical actions and interactions in the rabbit eye in vivo. 630 42

There has been a suspicion on the part of many clinicians and research scientists that intraocular pressure can be regulated by neural and/or humoral influences upon the rate of aqueous humor formation. It has been difficult, if not impossible, to separate specific influences of the central nervous system upon intraocular pressure from vascular induced or other secondary alterations. The past two decades have witnesses a great deal of study of the role of the adrenergic nervous system upon the regulation of intraocular pressure. From the investigations it is possible to formulate an integrated concept that can place years of work and speculation on a firm molecular foundation. The secretory tissue of the eye, the ciliary processes, contain an enzyme receptor complex, comprised by receptor complex, comprised by receptor bound membrane proteins, the catalytic moiety of the enzyme, a guanyl nucleotide regulatory protein (or N protein) and other features. The enzyme can be activated by well known neurohumoral or humoral agents that consist of catecholamines, glycoprotein hormones produced by the hypothalamic pituitary axis, and other related compounds, including placental gonadotropin. These compounds cause the ciliary epithelia to produce cyclic AMP at an accelerated rate. Cyclic AMP, as a second messenger, causes, either directly or indirectly, a decrease in the rate of aqueous humor formation that may be modulated by cofactors. Clinical syndromes fit the experimental data so that an integrated explanation can be given for the reduced intraocular pressure witnessed under certain central nervous system and adrenergic influences. The molecular biology of this concept provides important leads for future investigations that bear directly both upon the regulation of intraocular pressure and upon glaucoma.
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PMID:A major pathway for the regulation of intraocular pressure. 630 89

Topical 2% l- or d-timolol reduced the elevation of intraocular pressure induced by water-loading in conscious rabbits. This drug effect appeared on the peak elevation (in pigmented eyes) and on the down-phase (in albino and pigmented eyes) of elevated intraocular pressure. The contralateral eye and the treated eye responded similarly. In urethane anesthetized, water-loaded rabbits, a greater inhibitory effect of l-timolol was observed in pigmented eyes than in albino eyes. Two per cent l-timolol caused alterations of heart rate and arterial blood pressure in water-loaded anesthetized rabbits, but time courses of these alterations did not correlate with the inhibitory effect on the elevation of intraocular pressure. The beta-adrenergic antagonistic activity of l-timolol and d-timolol were compared by their ability to inhibit l-isoproterenol-stimulated cyclic AMP synthesis in the rabbit iris-ciliary body preparation in vitro. The I50S for l- and d-timolol differ by about 1.5 log units. In our studies, d-timolol has little of the intraocular pressure lowering and the beta-adrenergic antagonistic activity of l-timolol. Thus, the conscious, water-loaded, pigmented rabbit can be used as a model for studying the effects of beta-adrenergic antagonists on intraocular pressure.
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PMID:Effects of l- and d-timolol on cyclic AMP synthesis and intraocular pressure in water-loaded, albino and pigmented rabbits. 630 96

We have studied the effects of terbutaline, timolol, forskolin and 8-bromo cyclic AMP on aqueous humour formation, intraocular pressure and on ciliary epithelial cyclic AMP levels, either in presence or in absence of IBMX, using the bovine isolated arterially perfused eye, excised ciliary processes and cultured ciliary epithelium. Both terbutaline, a beta-adrenoceptor agonist, and timolol, a beta-adrenoceptor antagonist, caused significant reduction in aqueous humour formation and intraocular pressure but produced no effect on ciliary epithelial cyclic AMP content in the absence of IBMX. Even a three times higher dose of terbutaline was entirely ineffective in producing any effect on ciliary cyclic AMP in the perfused eye. On the other hand, terbutaline at the IOP-reducing dose, produced a significant increase in cyclic AMP when injected after 30 min perfusion with IBMX. Incubation of excised ciliary processes or cultured ciliary epithelial cells with terbutaline (10(-6) to 10(-4) M) produced concentration-dependent increases in cyclic AMP, in both tissues, even in the absence of IBMX. Forskolin, which stimulates cyclic AMP synthesis without interacting with cell surface receptors, was found to produce highly significant increases in ciliary cyclic AMP content both in presence and in absence of IBMX but had no effect on aqueous humour formation in the isolated eye. IBMX perfused at concentrations of 1 mM or 10 microM had no effect on basal levels of ciliary cyclic AMP but the 1 mM concentration produced a marked and significant reduction in IOP. Direct application of 8-bromo cyclic AMP, a cell permeable analogue, more resistant to hydrolysis by phosphodiesterases, had also no effect on aqueous humour formation in the perfused eye. It is concluded that in the bovine arterially perfused eye, the correlation between the aqueous humour formation rate and ciliary epithelial cyclic AMP content is unclear.
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PMID:Effects of timolol, terbutaline and forskolin on IOP, aqueous humour formation and ciliary cyclic AMP levels in the bovine eye. 758 97

Moxonidine (MOX, 4-chloro-N-[4,5 dihydro-1H-imidazol-2-yl]-6-methoxy-2- methyl-5-pyridinamine), a relatively selective alpha-2 agonist, was investigated for effects on: 1) aqueous humor dynamics in normal and unilaterally sympathectomized rabbits; 2) noradrenergic functions in cat nictitating membrane (CNM); 3) [3H]norepinephrine overflow in rabbit iris-ciliary bodies (ICBs) and 4) cyclic AMP (cAMP) accumulation in rabbit ICBs and nonpigmented ciliary epithelial (NPE) cells. Unilateral, topical administration of MOX to the normal rabbit eyes produced decreases in intraocular pressure, aqueous humor flow rate and ipsilateral increases in pupil diameter. Ocular hypotensive response to MOX was inhibited by bilateral, topical pretreatment with idazoxan, an alpha-2/imidazoline antagonist, and efaroxan, an imidazoline antagonist. In sympathectically denervated rabbit eyes, MOX did not lower intraocular pressure or decrease aqueous humor flow rate. MOX suppressed, dose dependently, contractions of the CNM elicited by electrically stimulating the preganglionic sympathetic trunk, an effect antagonized by rauwolscine, an alpha-2 antagonist. In other experiments, MOX caused a dose-related inhibition of [3H]norepinephrine release from field-stimulated ICBs, an effect antagonized by efaroxan. MOX antagonized isoproterenol-induced cAMP accumulation in rabbit ICBs and NPE cells, an effect inhibited by rauwolscine. These results demonstrate that MOX: 1) produces ocular hypotension in rabbits by suppressing aqueous humor flow; 2) antagonizes electrically induced contractions of the CNM by inhibiting sympathetic neuronal function; 3) suppresses norepinephrine release of rabbit ICBs, an effect that was inhibited by efaroxan and 4) prevents isoproterenol-induced cAMP accumulation in the rabbit ICBs and NPE cells via action on alpha-2 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ocular actions of moxonidine: a possible role for imidazoline receptors. 791 82


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