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)

The effect of the domestic Forskolin on lowering the intraocular pressure (IOP) of rabbits was studied. The results showed that the Forskolin significantly lowered the normal IOP of rabbits and blocked the ocular hypertension induced by water load in rabbits (p < 0.01). The maximum decrease value of 2%, 1% and 0.5% of the Forskolin was 0.59. 0.36 and 0.19 kPa (1 kPa = 7.5 mmHg), which showed the noticeable dose-effect relationship. Topical ocular application of Forskolin lowered IOP in 1/2 hour, reached to a peak in 2-3 hours and remained significantly for 10 hours. The pupillary diameter did not change when IOP were reduced. Furthermore, the Forskolin had potent stimulative properties to adenylate cyclase (AC). The greater the ability of the Forskolin to stimulate AC, the stronger the effect of IOP lowering.
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PMID:[The experimental studies of the effect of Forskolin on the lowering of intraocular pressure]. 130 93

We have examined the effect of venom sac extract (VSE), prepared from two hymenopteran species, on intracellular cyclic AMP (cAMP) accumulation in a cultured human cell line. VSE prepared from the oriental hornet (Vespa orientalis) and from the paper wasp (Polistes carolina) induced an increase in accumulation of cAMP in human, transformed, non-pigmented, ciliary epithelial cells. The effect of V. orientalis VSE on intracellular cAMP was dose-dependent. Blocking the response of adenylate cyclase-linked beta-adrenergic receptors was without effect on this cellular response to VSE. On the other hand, the response to VSE prepared from both species was suppressed almost totally by the H2-histamine receptor-specific antagonist, cimetidine. The findings are discussed in the light of earlier observations that described a significant reduction in intraocular pressure in vertebrate animals treated with V. orientalis VSE.
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PMID:Hymenopteran venom stimulates adenylate cyclase in cultured human cells through a histamine receptor. 131 17

Fenoldopam mesylate stimulates adenyl cyclase in porcine ocular trabecular meshwork and raises intraocular pressure in humans. To clarify whether this results from direct activation of the dopamine-1 receptor or indirectly from baroreflex sympathetic stimulation after blood pressure reduction, intraocular pressure was measured in 14 patients with accelerated/malignant hypertension, randomized between intravenous fenoldopam or sodium nitroprusside. Intraocular pressure was measured with a Perkins tonometer, before and at the twentieth minute of each dose increment. In seven patients with a mean blood pressure of 232/131 mm Hg treated with fenoldopam, intraocular pressure increased in a dose-dependent fashion, from 16 +/- 1 to 20 +/- 2 mm Hg (p less than 0.005). In contrast, seven patients with a mean blood pressure of 225/134 mm Hg treated with sodium nitroprusside exhibited no change in intraocular pressure (15 +/- 1 versus 14 +/- 1 mm Hg) despite similar blood pressure reduction. Increases in heart rate were not significantly different. Rates of urinary excretion of norepinephrine plus epinephrine increased significantly relative to baseline (p less than 0.05) but were not different between groups. These data suggest that the increase in intraocular pressure with fenoldopam results from specific activation of the dopamine-1 receptor and is not caused by baroreflex sympathetic stimulation. Because dopamine-1 receptors may modulate intraocular pressure, dopamine-1 receptor blockers might be useful therapy for glaucoma.
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PMID:Intraocular pressure increases with fenoldopam, but not nitroprusside, in hypertensive humans. 167 12

In the normal heart the ratio of beta 1/beta 2-receptors in both atria and ventricles is about 75:25; in the failing heart the ratio is about 60:40. Stimulation of either beta 1- or beta 2-receptors results in a positive chronotropic and inotropic response. In the periphery, with the exception of lipolysis, renin release, control of intraocular pressure and intestinal relaxation, beta 2-related activity predominates. The nature of the beta 2-receptor is being unravelled and it has now been cloned. The beta-receptor antagonist is 'anchored' via disulfide bonding. Subsequent events involve the regulatory protein guanine nucleotide which couples the receptor to adenylate cyclase. beta-receptor density may by up- or down-regulated. beta-stimulation down-regulates (uncouples and internalizes or sequestrates) and beta-antagonism up-regulates beta-receptor numbers, but the functional implications of such changes are not always clear. A partial agonist occupies a receptor site and competitively inhibits the full agonist (e.g. noradrenaline). A partial agonist differs from a full agonist in that maximal response of a tissue is less. When background sympathetic activity is absent or very low a partial agonist will act as an agonist, e.g. increase heart rate, but when background tone is high the partial agonist will behave functionally as an antagonist, e.g. decrease heart rate. In animals partial agonist activity (PAA) can be assessed in many ways. In the catecholamine-depleted (reserpine or syrosingopine), vagotomized or pithed, intact animal beta-activity can be assessed via changes in heart rate, cardiac contractility and atrioventricular conduction. Isolated organs can also be used such as atria, papillary muscle, tracheal, mesenteric artery and uterine preparations. The choice of animal is important as marked species differences in response can occur. In man assessing PAA is difficult due to the presence of an intact sympathetic system: the problem can be overcome by autonomic blockade of constrictor and vagal reflexes with prazosin, clonidine and atropine but leaving the beta-receptor mediated responses unimpaired. beta 1- and beta 2-selective PAA can also be gauged via an increased sleeping heart rate (basal sympathetic tone) in the presence and absence of a beta 1- and beta 2-selective antagonist. beta 1-selective PAA can also cause an increase in resting systolic blood pressure, beta 2-selective PAA may be further assessed by a fall in DBP, increased blood flow, fall in peripheral resistance or increased finger tremor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Measurement and cardiovascular relevance of partial agonist activity (PAA) involving beta 1- and beta 2-adrenoceptors. 196 43

Alpha-2 (alpha 2) and DA2 agonists lower intraocular pressure (IOP) in laboratory animals and man. Like beta-blockers, alpha 2 and DA2 agonists appear to lower IOP by reducing aqueous inflow. These agents share a common mode of action on sympathetic nerve terminals, where they modulate the release of neurotransmitters. However, one can demonstrate that peripheral prejunctional alpha 2 and DA2 receptors on sympathetic neurons are separate entities by utilizing selective agonists and antagonists. In addition to their prejunctional actions, alpha 2 agonists act postjunctionally in the iris root/ciliary body (IRCB). Moreover, utilizing selective postjunctional alpha 2 adrenoceptor antagonists, heterogeneity can be demonstrated between ocular pre- and postjunctional adrenoceptors. Stimulation of postjunctional alpha 2 adrenoceptors in the IRCB can inhibit the cellular responses to endogenous neurotransmitters and hormones that are coupled positively to adenylate cyclase. Based upon these observations, one can predict that alpha 2 agonists should have a broader spectrum of action in the eye than beta-receptor antagonists. Three bioassays were used in the activity analysis of alpha 2 and DA2 agonists. Prejunctional (neuronal) activity was determined in the cat nictitating membrane preparation in which frequency-related (2-8 Hz), neuronally induced contractions were inhibited by these compounds. Postjunctional activity was assayed on isolated rabbit IRCB tissue where cAMP levels were stimulated by either isoproterenol or VIP in the absence and presence of the test agonist (alpha 2 or DA2). In this system, it has been demonstrated that alpha 2 agonists have inhibitory properties, but DA2 agonists are inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Review: alpha 2 and DA2 agonists as antiglaucoma agents: comparative pharmacology and clinical potential. 198 Dec 21

Effects of prostaglandin (PG) D2 analogues on the adenylate cyclase activity in membrane fractions of the iris-ciliary body complex were studied. PGD2 dose-dependently activated the adenylate cyclase with a maximal activity increase of about 60%. The concentration required to cause a half-maximal stimulation (EC50) was about 5 x 10(-7) M. The stimulatory effect of PGD2 was totally dependent on GTP with EC50 for GTP at about 10(-7) M. The rank order of potency of PGD2 analogues for stimulating the adenylate cyclase and BW245C (a selective PGD2 agonist) greater than PGD3 greater than PGD2 greater than 9 beta-PGD2. PGD2 metabolites and PGD2 analogues which have little hypotensive activity were essentially ineffective in stimulating the adenylate cyclase. This rank order was strikingly similar to that reported previously for their intraocular pressure-lowering effects. One exception was PGD2 methylester. This compound, though reportedly effective in reducing IOP, failed to activate the adenylate cyclase by itself, presumably because its hypotensive effect is due to its hydrolyzed product, PGD2. These results indicate that the abilities of PGD2 analogues to stimulate the adenylate cyclase of the iris-ciliary body complex in GTP-dependent manner are highly correlated with their ocular hypotensive activities, and suggest that a PGD2 receptor-stimulatory GTP-binding protein-adenylate cyclase complex is involved in the PGD2-induced ocular hypotension.
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PMID:Stimulatory effects of prostaglandin D2 analogues on adenylate cyclase in rabbit iris-ciliary body membrane fractions. 224 31

The inhibitory effect of neuropeptide Y (NPY) was studied on the adenylate cyclase (AC) activity in homogenates of rabbit ciliary processes and compared with that of the alpha 2-adrenergic agonist clonidine (CLN). NPY inhibited basal AC activity as well as AC activity stimulated by isoproterenol (ISO), vasoactive intestinal polypeptide (VIP) or forskolin (FSK). The extent of this inhibition corresponded well to the inhibition elicited by CLN. The inhibitory effects of NPY and CLN appeared to be nonadditive. AC activity stimulated by ISO was considerably more sensitive to the effects of either NPY or CLN than basal, VIP- or FSK-stimulated AC activity. It was inferred that NPY inhibitory effects were mediated by the activation of NPY receptors coupled negatively to the catalytic unit of AC via the inhibitory Gi protein. Moreover, involvement of NPY in physiological modulation of AC activity in ciliary processes and in the regulation of aqueous humor formation and intraocular pressure is suggested.
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PMID:Inhibitory effects of neuropeptide Y on adenylate cyclase of rabbit ciliary processes. 233 9

Intravitreal injection of purified human chorionic gonadotropin (hCG) in rabbits decreased intraocular pressure (IOP). A dose-dependent decrease in IOP was observed with intravitreal hCG concentrations at 30 nM and 100 nM. The onset of this effect was later than 10 hr following the injection and it lasted for more than 24 hrs. The purified beta-subunit of hCG caused a similar decrease in IOP with a short duration. The threshold intravitreal concentration was 10 nM. Unlike the intact hCG, the hCG beta-subunit was inactive as a gonadotropic agent to activate the adenylate cyclase in the rat testis. Intravitreal injection of rabbit luteinizing hormone, which was active as a gonadotropic agent, had no effect on IOP in 4 intravitreal concentrations ranging from 1 nM to 30 nM. These observations indicate that the mechanism of IOP decrease by intravitreal hCG is not related to its gonadotropic action. The IOP decrease in rabbits due to intravitreal hCG or its beta-subunit is probably related to a contaminant or an immune reaction.
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PMID:Intravitreal human chorionic gonadotropin decreases intraocular pressure in rabbits: mechanism of action. 246 70

Forskolin and 18 chemical analogs of forskolin were assayed for stimulation of adenylate cyclase activity in vitro and for their effects on intraocular pressure (IOP) in vivo. Adenylate cyclase activity was determined with a preparation of corpora striata from male Wistar rats and test drug concentrations of 0.3 to 300 microM. IOP effect was monitored after a single topical ocular application of a 1% suspension of the test drug to male New Zealand albino rabbits. Significant reductions in IOP occurred with compounds which had potent cyclase stimulatory properties. Most compounds with little cyclase stimulatory effect produced little or no decrease in IOP. A 1-substituted morpholino-acetoxy derivative, which may be a prodrug metabolized to active form by corneal esterases, showed little cyclase stimulation in vitro but produced significant reductions in IOP.
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PMID:Adenylate cyclase stimulation and intraocular pressure reduction by forskolin analogs. 262 15

Pirbuterol and nylidrin, both purported sympathomimetic amines, reduced intraocular pressure (IOP) when given topically (50 microliter, 0.1%) to albino rabbits. Pirbuterol increased the cyclic-AMP concentration in aqueous humor by a factor of 3.25, while nylidrin had no effect on aqueous cyclic-AMP nor on adenylate cyclase activity of iris-ciliary body membranes assayed in vitro. Studies of the receptor affinity of pirbuterol, timolol and nylidrin were carried out on iris-ciliary body membranes by competition binding with radioactive ligands. Four ligands were used that appear to label separate subpopulations of adrenergic receptors; dihydroalprenolol (beta-receptors), WB-4101 (alpha 1-receptors) prazosin (alpha 1-receptor subpopulation) and yohimbine (alpha 2-receptors). Pirbuterol and timolol showed exclusive selectivity for beta-receptors with high affinities (Kd 12.6 and 0.48 nM, respectively) compared with other adrenergic receptor populations in iris-ciliary body. Nylidrin had high affinities for beta-receptors (Kd 22 nM) and for the subpopulation of alpha 1-receptors labelled by prazosin (Kd 6.5 nM), but showed 100-fold lower affinity and complex binding characteristics to the two other classes of alpha-adrenergic receptor sites labelled by WB-4101 and yohimbine, respectively. The results show that pirbuterol and timolol are highly beta-receptor selective and that hypotensive responses to these drugs are not mediated by the other classes of alpha-adrenergic receptor determined in this study. However, the hypotensive response to nylidrin may be related to its prazosin-like (alpha 1-receptor) antagonist properties with additional activity at beta-receptors.
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PMID:Ocular hypotension in the rabbit. Receptor mechanisms of pirbuterol and nylidrin. 285 89


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