Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prazosin hydrochloride, an oral antihypertensive, is reported to inhibit phosphodiesterase and block postsynaptic alpha-adrenergic receptors, intraocular pressure (IOP) in rabbits was reduced in a dose-related manner following topical ocular application of concentrations of 0.0001% to 0.1%. The ocular hypotensive response lasted six to eight hours with a maximum effect at approximately two hours. The IOP of unilaterally sympathectomized rabbits treated in both eyes with prazosin decreased more in the normal eyes than in the sympathectomized eyes. Treatment of only the unsympathectomized eyes of these rabbits elicited a similar response. Normal rabbits elicited a similar response. Normal rabbits treated in only one eye also showed a slight response in the contralateral eye. Preliminary experiments did not support the hypothesis that these effects were due to a decrease of systemic blood pressure. No substantial ocular toxicity or pupillary changes were observed.
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PMID:Influence of topically applied prazosin on the intraocular pressure of experimental animals. 48 19

The mechanism by which pivaloyloxymethyl (POM) ester of griseolic acid (GA), a potent cyclic AMP-phosphodiesterase inhibitor, lowers intraocular pressure (IOP) in albino rabbits was studied. The rate of aqueous flow, measured by fluorophotometry, was significantly lower in GA POM ester-treated eyes (2.36 +/- 0.24 microliters/min) than in control eyes (3.02 +/- 0.24 microliters/min). Topically applied GA POM ester did not alter tonographic outflow or uveoscleral outflow. No differences in aqueous humor protein concentrations between GA POM ester-treated and control eyes were observed. It was thought that the GA POM ester lowered the IOP by decreasing the aqueous inflow. Topical application of this compound caused no inflammatory response in the eye or changes in the blood aqueous barrier.
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PMID:Effects of a cyclic AMP phosphodiesterase inhibitor, 8'-pivaloyloxymethyl ester of griseolic acid, on aqueous humor dynamics in rabbits. 165 74

The effects of griseolic acid (GA), a cyclic-AMP phosphodiesterase (PDE) inhibitor, and its 8'-pivaloyloxymethyl (POM) ester on intraocular pressure (IOP) in rabbits were investigated. When 50 microliters of 1 and 2% GA POM ester solutions were topically applied to one eye in normal rabbits, significant IOP decreases were detected at 2 hrs and at 1 to 5 hrs, respectively. Other than ocular hypotension, no other ocular effects were detected locally even after administration of 2% GA POM ester. A more marked reduction in IOP occurred after the intravitreal injection of the GA POM ester. IOP was also reduced when GA was used in an intravitreal injection but not when it was topically applied. The difference in permeability between GA and GA POM ester across the corneal epithelium may explain why GA failed to reduced IOP following topical administration. GA and the GA POM ester inhibited cAMP PDE in rabbit ciliary body at low concentrations, the I50 being 0.075 microM and 2.4 microM, respectively, with 0.25 microM cAMP as substrate. GA and the GA POM ester markedly increased cAMP levels in vitro in iris-ciliary body specimens. Possibly, GA POM ester or its analogues may represent a new mechanistic class of ocular hypotensive agents.
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PMID:A cyclic AMP phosphodiesterase inhibitor, 8'-pivaloyloxymethyl ester (POM-ester) of griseolic acid, lowers rabbit intraocular pressure. 166 21

Isobutylmethylxanthine (IBMX), a phosphodiesterase/adenosine receptor inhibitor, was combined with norepinephrine (nE), epinephrine (Epi) and isoproterenol, respectively, to evaluate their effect on intraocular pressure (IOP). Application of topical IBMX alone had no measurable effect on IOP. When IBMX was combined with nE or Epi the ocular hypotension in rabbits and beagles increased. The Emax for nE alone was 2.9 +/- 0.4 mmHg, for Epi alone 7.3 +/- 0.5 mmHg and for isoproterenol alone 5.1 +/- 0.3 mmHg. The EC50 was 0.2 +/- 0.05% (nE), 0.05 +/- 0.01% (Epi) and 0.003 +/- 0.001% for isoproterenol. When given in combination with 1% IBMX the Emax for nE was 7.4 +/- 1.7 mmHg, for Epi 9.0 +/- 0.8 mmHg and for isoproterenol 6.1 +/- 0.3 mmHg. The corresponding values for EC50 were 0.07 +/- 0.03% (nE), 0.02 +/- 0.006% (Epi) and 0.002 +/- 0.001% for isoproterenol. Combining 1% IBMX with 0.1% Epi increased the aqueous humour cyclic AMP-levels at 1, 3 and 5 hr in rabbits. The results of this study demonstrate that a phosphodiesterase/adenosine receptor inhibitor such as IBMX enhances the reduction in IOP induced by adrenergic agonists.
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PMID:Isobutylmethylxanthine enhances adrenergic-induced ocular hypotension in rabbits and beagles. 171 10

Griseolic acid-ester (GA-ester), one of the strongest cAMP phosphodiesterase inhibitors, was combined with isoproterenol and timolol in this study to evaluate the effect on intraocular pressure (IOP). Furthermore, the ocular hypotensive effect of GA-ester in pigmented and albino rabbits was compared, and the binding ability of GA-ester to synthetic melanin was examined. GA-ester markedly enhanced the hypotensive effect of isoproterenol, and the combination of GA-ester with timolol resulted in an additional fall in IOP. No differences in the hypotensive effect of GA-ester between pigmented and albino rabbits were observed. GA-ester did not bind to synthetic melanin. GA-ester has unique characteristics as an ocular hypotensive agent.
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PMID:[Changes in ocular hypotensive effect of griseolic acid with isoproterenol, timolol and melanin]. 217 7

Synthetic rat atrial natriuretic peptide (ANP) was examined for effects on guanylate-and on adenylate cyclase activity in ciliary process homogenates and for effects on intraocular pressure in the albino rabbit eye. Ciliary process guanylate cyclase was associated predominantly with the particulate fraction and was partially activated by ANP (EC50, approximately 1 nM) relative to a maximal dose of Na Nitroprusside (2 uM), whereas particulate adenylate cyclase (basal as well as forskolin-stimulated activity) showed no responses to ANP at doses up to 0.3 uM. Particulate cAMP phosphodiesterase activity was stimulated by low doses of cGMP (1-5 uM) in ciliary processes. Thus, ANP, acting via guanylate cyclase, has the potential to regulate phosphodiesterase activity and indirectly decrease cAMP levels in membranes derived from ciliary processes. Intravitreous injection of ANP (2-4 ug/eye) caused a small decrease (1-1.5 mm Hg) in intraocular pressure measured 16-24 hours after injection but the pressure had returned to normal by 40 hours. The findings demonstrate regulation of biochemical and pharmacological responses by ANP in the albino rabbit eye suggesting that this peptide may play a physiological role in secretory functions of ciliary processes.
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PMID:Atrial natriuretic peptide (ANP), guanylate cyclase, and intraocular pressure in the rabbit eye. 289 Apr 98

Forskolin has been reported to stimulate cAMP formation and reduce intraocular pressure in rabbit and primate eyes. In view of recent evidence for the involvement of cAMP in modulation of transmitter release at adrenergic synapses, we have investigated the presynaptic effects of forskolin and other cAMP activators on field-stimulated secretion of 3H-norepinephrine (3H-NE) in the isolated, perfused rabbit iris-ciliary body. Forskolin (10(-7)-10(-5) M) was found to markedly enhance stimulation-evoked 3H-NE release without affecting basal (spontaneous) release. The response to forskolin was potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 0.5 mM) and was mimicked by the cell-permeant cyclic nucleotide analog 8-bromo-cAMP. 8-bromo-cGMP also produce a small enhancement of stimulus-evoked 3H-NE secretion, whereas IBMX alone had little effect on either stimulated or basal secretion. These results suggest that cAMP may play an important neuromodulatory role in regulation of norepinephrine release at intraocular synapses, and raise the possibility that the ocular hypotensive response to forskolin in rabbit eyes may be mediated, in part, by enhanced adrenergic neurosecretion.
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PMID:Potentiation of sympathetic neurosecretion by forskolin and cyclic AMP in the rabbit iris-ciliary body. 301 36

Alterations in either cyclic AMP (cAMP) or cyclic GMP (cGMP) may modulate the production of aqueous humor by the ciliary epithelium of the eye, thereby affecting intraocular pressure. We have found distinct profiles of phosphodiesterase (PDE) isozyme activity in cultured cells derived from bovine pigmented ciliary epithelium (PE) and cells derived from human nonpigmented ciliary epithelium (NPE), as well as corresponding differences in the effects of selective PDE inhibitors on the accumulation of cAMP and cGMP. In NPE cells, but not in PE cells, the major peak of PDE activity was stimulated by Ca++/calmodulin-stimulated (PDE I), and hydrolyzed both cAMP and cGMP. In contrast, PE cells contained a cGMP-specific PDE V not found in NPE cells. Rolipram, a selective inhibitor of PDE IV, was more potent and effective than the selective PDE III inhibitor CI-930 at potentiating intracellular cAMP accumulation in both cell types. Zaprinast, a selective inhibitor of PDE V, potentiated cGMP accumulation in PE but not in NPE cells. The results suggest that selective PDE inhibitors may modulate aqueous humor production by pigmented and nonpigmented ciliary epithelium, the two cell types may have different functional roles, and selective modulation of their functions may be possible. Furthermore, there may be distinct roles for intracellular calcium in regulating cGMP and cAMP in pigmented vs. nonpigmented ciliary epithelial cells.
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PMID:Distinct profiles of phosphodiesterase isozymes in cultured cells derived from nonpigmented and pigmented ocular ciliary epithelium. 826 91

The purpose of this work is to investigate the effect of prostaglandins (PGs) on the contraction of ciliary muscle cells. It has been proposed that PGs induce relaxation of ciliary muscle and facilitate uveoscleral outflow, and reduce intraocular pressure (IOP). The ocular response to PGs is complicated because the relative contributions of uveoscleral flow and the conventional outflow to lowering IOP and the type of PG receptors associated with ciliary muscle may vary depending on animal species. In order to obtain insights into prostaglandin receptors of ciliary muscle, ciliary muscle cells from porcine eye were grown in culture and characterized immunocytochemically with antibodies against smooth muscle-alpha-actin and PGE2 receptor subtypes. As in ciliary muscle tissues, positive immunostaining for alpha-actin and EP2 and EP3 subtypes was observed in cultured cells. Time-dependent contraction of cultured cells induced by 10(-4) M carbachol was recorded by taking sequential photographs and analyzed. Using this assay method, the effect of prostaglandins E2 and F2 alpha to inhibit the carbachol-induced contraction was studied. PGE2 showed potent inhibition of cell contraction; 10(-7) approximately 10(-8) M PGE2 inhibited 50% of full contraction in 15 min. PGF2 alpha at 10(-4) M neither caused cell contraction by itself nor blocked carbachol-induced contraction. The EP2 agonist 11-deoxy-16, 16-dimethyl PGE2 at 10(-4) M inhibited cell contraction but the EP3 agonist sulprostone had no effect. Dibutyryl cAMP at 3 x 10(-5) M inhibited contraction by 50%. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), less than 10(-7) M dibutyryl cAMP caused 50% inhibition. In support of the cAMP effect, the addition of 10(-4) M PGE2 to cultured cells in the presence of indomethacin and IBMX was shown to cause an 80% increase in intracellular cAMP concentration compared with the basal (i.e. unstimulated) level of cAMP. Stimulation of cells with 10(-4) M PGF2 alpha caused no increase in cellular cAMP. These results indicate that PGE2 receptor EP2 subtype, but not PGF2 alpha receptor, is involved in the inhibition (hence relaxation by inference) of carbachol-induced porcine ciliary muscle cell contraction. It awaits further studies to determine whether cultured ciliary muscle cells of other species respond similarly to different PGs.
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PMID:The effects of prostaglandins E2 and F2 alpha on porcine ciliary muscle cells in culture. 897 45

It has been shown that inhibition of phosphodiesterase (PDE) or an increase in intracellular cyclic adenosine monophosphate (cAMP) can lower the intraocular pressure in mammalian eyes. The PDE inhibitor rolipram binds with high affinity to a cAMP-dependent PDE. In the following study, receptors for rolipram in the mammalian eye are determined by autoradiography. About 1050 histological sections of rabbit (albino and pigmented), rat, monkey (baboon and marmoset) and human eyes were examined concerning rolipram-binding sites in different structures. The highest specific binding of rolipram to the ciliary body epithelium was seen in human, rabbit and baboon eyes. Marmoset eyes showed the highest specific binding in the ciliary body muscle, rat eyes in the retina. Specific binding was consistently high in the ciliary body epithelium and therefore at the site of aqueous humor formation. Because of these results and the known mode of action of rolipram, one can assume a close connection between rolipram-binding sites and the regulation of intraocular pressure.
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PMID:[Localization of cAMP-selective phosphodiesterase in the mammalian eye by (3H)-rolipram]. 900 85


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