Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The influence of compound IS-35 on intraocular pressure of unanesthetized rabbits was studied. In some cases intraocular pressure was measured with either the tonometer of Schiotz and was calculated in mmHg according to Leydhecker's scale (1973), or with the tonometer of Maclakov. Intraocular pressure was measured before and at 30, 60, 120, 180, 240 and 360 min after topical application of IS-35, timolol and trimetoquinol. It was established that IS-35 applied locally in the eye as 0.5% solution or collyrium decreases statistically significantly intraocular pressure. This effect was similar to that of timolol and exceeded significantly the effect of trimetoquinol. The experimental study on the beta-adrenergic adenylate cyclase showed that the mechanism of action of IS-35 on ophthalmotonus most probably is similar to the effect of timolol and is due to the suppression of aqueous humor formation.
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PMID:Effects of compound IS-35 on intraocular pressure. 341 49

Protein kinase C was identified as a major protein kinase enzyme activity in rabbit ciliary processes. Phorbol myristate acetate (4 beta-PMA) in the presence of Ca2+ activated protein kinase C but did not directly affect the cyclic AMP-dependent protein kinase enzyme isolated from ciliary processes. To elucidate possible roles of protein kinase C, PMA was injected intravitreally into rabbit eyes. Fifty pmoles of PMA produced approximately a 40% decrease of the intraocular pressure relative to the control eye lasting for more than 72 hr. A reduction of intraocular pressure was still elicited by this dose of PMA in animals pretreated with systemic indomethacin given to suppress a possible inflammatory response. The biologically inactive analogue, 4 alpha-phorbol didecanoate (100 pmoles/eye) had no significant effect on intraocular pressure. In vivo and in vitro treatment with PMA had no significant effect on adenylate cyclase in ciliary process membranes assayed in vitro. However, protein kinase C isolated from rat brain, when added together with cofactors to membranes in vitro, augmented adenylate cyclase activation by isoproterenol, vasoactive intestinal peptide and aluminum fluoride. A slight increase in the basal activity and in the forskolin response was not statistically significant. The effect of protein kinase C to increase responsiveness of ciliary process adenylate cyclase was totally dependent on the presence of Ca2+ and was augmented by addition of PMA. These findings indicate modulation of adenylate cyclase activity by protein kinase C acting at the level of the G-proteins and suggest a possible role for this enzyme in water and electrolyte transport in the ciliary processes.
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PMID:Phorbol ester: effect on intraocular pressure, adenylate cyclase, and protein kinase in the rabbit eye. 367 53

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

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

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

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

Topical ocular application of forskolin, a diterpene that increases intracellular cyclic adenosine monophosphate by stimulating adenylate cyclase directly without cell surface mediation, lowered intraocular pressure (IOP) in rabbits, monkeys, and volunteers who were free from eye disease. In man 50 microliters of a topical suspension of 1% forskolin significantly lowered IOP in 1 h, the effect reaching a peak at 2 h but remaining significant for at least 5 h. Outflow pressure fell by 70% on average. Forskolin and its analogues represent a new class of drugs active against glaucoma which differ in their molecular actions from any previously used drug.
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PMID:Forskolin lowers intraocular pressure in rabbits, monkeys, and man. 613 71

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

Prior biochemical studies have shown that the ciliary process epithelium, which is involved in the secretion of aqueous humour, is rich in beta-adrenoceptors with pharmacological characteristics similar to those of the beta 2 subclass. The present experiments demonstrate that the beta-adrenoceptor antagonist, ICI 118,551, is a potent inhibitor of isoprenaline-stimulated adenylate cyclase activity measured in broken cell preparations of rabbit ciliary process. In rabbit cardiac muscle, however, ICI 118,551 is a relatively weak antagonist of isoprenaline-stimulated adenylate cyclase, being approximately 100 fold less potent than the non-selective beta-adrenoceptor antagonist, timolol. ICI 118,551 is also less potent than timolol in inhibiting isoprenaline-sensitive adenylate cyclase of rabbit lung. ICI 118,551 applied topically to eyes of unanaesthetized rabbits causes a dose-dependent decrease in intraocular pressure. Furthermore, in a blind crossover study in rabbits, topically applied ICI 118,551 decreased intraocular pressure for more than 6 h and was more effective than an identical dose of the clinically effective anti-glaucoma agent, timolol. Systemic absorption from topically-applied timolol, but not ICI 118,551, is sufficient to alter cardiac response to subcutaneous administration of isoprenaline. Furthermore, dose-response studies, using direct systemic administration of the two beta-adrenoceptor antagonists, revealed that ICI 118,551 is about 60 times less potent than timolol in blocking isoprenaline-induced cardio-acceleration. ICI 118,551, applied to one eye, causes a decrease in intraocular pressure in the contralateral eye, and systemic administration of ICI 118,551 results in decreased intraocular pressure in both eyes, data indicating that at least part of the ocular hypotensive effect of topical ICI 118,551 is mediated through systemic absorption. 8 These findings provide biochemical and physiological evidence that selective beta 2-adrenoceptor blockers such as ICI 118,551, used topically or systemically, may be useful as ocular hypotensive agents with decreased cardiac side-effects.
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PMID:ICI 118,551: an effective ocular hypotensive agent with selectivity for the ciliary process beta 2-adrenoceptor and with minimal cardiac side effects. 615 Jul 44


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