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)

In the isolated superior cervical ganglion of the rat, activation of either DA1 or DA2 receptors leads to inhibition of ganglionic transmission. Using dopamine as well as relatively selective dopamine receptor agonists and antagonists we have performed electrophysiological as well as biochemical experiments to study the nature of dopamine receptors in this sympathetic ganglion. Fenoldopam, a selective DA1 receptor agonist caused marked inhibition of the compound postganglionic action potential evoked by stimulation of preganglionic nerve. The inhibitory effect of fenoldopam was antagonized by the DA1 receptor antagonist R-sulpiride but not by the DA2 receptor antagonist S-sulpiride. However, the more potent and selective DA1 receptor antagonist SCH-23390 failed to antagonize ganglion blocking effect of fenoldopam indicating that DA1 receptor in sympathetic ganglia is different from that in blood vessels. The superior cervical ganglion also contains DA2 receptors inasmuch as quinpirole, a DA2 receptor agonist, caused inhibition of ganglionic transmission which was antagonized by S-sulpiride but not by R-sulpiride. The existence of both subtypes of dopamine receptor in the superior cervical ganglion was ascertained further as dopamine itself caused inhibition of ganglionic transmission which was antagonized by either S- or R-sulpiride. Again, however, the DA1 receptor antagonist SCH-23390 failed to antagonize the ganglion blocking effect of dopamine. To characterize further the ganglionic DA1 receptor we sought to demonstrate whether or not ganglionic DA1 receptor is linked to the enzyme adenylate cyclase as is known to be the case for peripheral DA1 or central D1 dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of DA1 receptors by dopamine or fenoldopam increases cyclic AMP levels in the renal artery but not in the superior cervical ganglion of the rat. 287 13

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.
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PMID:Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism. 287 16

The effects of dopamine (DA) and of two selective DA DA1 agonists (SKF 38393 and SKF 82526) on adenylate cyclase activity were studied with human kidney cortex membrane preparations. DA elicited a dose-related stimulation of adenylate cyclase activity with an EC50 of 60 microM. The selective DA DA1 antagonist SCH 23390 behaved as a competitive antagonist, shifting the dose-response curve to the right. The non-selective beta-adrenoceptor antagonist (-)-propranolol did not affect the EC50 of the dose-response curve to DA but attenuated the maximal stimulatory effect of DA at concentrations higher than 100 microM. (+)-Sulpiride inhibited DA-induced adenylate cyclase stimulation in a dose-dependent manner with an IC50 of 4.6 X 10(-8) M but (-)-sulpiride was without effect. Both SKF 38393 and SKF 82526 stimulated the adenylate cyclase activity of human kidney cortex; this effect was completely antagonized by SCH 23390. Our results, demonstrating the presence of DA-sensitive adenylate cyclase activity, strongly suggest the presence of a DA receptor of the DA1 subtype in human kidney cortex.
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PMID:Presence of dopamine-dependent adenylate cyclase activity in human renal cortex. 290 Jul 70

The title compounds were prepared and examined to elucidate further the structure-activity relationships of dopamine agonists related to nomifensine. Two of the compounds, 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydrothieno[2,3-c]pyridine, have been reported in the patent literature. In stimulation of rat retinal adenylate cyclase, a measure of dopamine D-1 agonist activity, the tetrahydroisoquinoline was about equipotent to dopamine. The thienyl isostere had nearly twice the potency. Both compounds were potent vasodilators in the canine renal artery, producing dilation through stimulation of DA1 type peripheral dopamine receptors. A monohydroxy analogue, 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline, had only slight activity in the cyclase assay and was inactive in the canine renal artery. These results, combined with those from an earlier study, demonstrate that N-alkylation decreases both dopamine D-1 and DA-1 agonist potency, with activity ordered as H greater than methyl greater than ethyl greater than propyl. The results also demonstrate the necessity for the catechol function in this series.
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PMID:Specific dopamine D-1 and DA1 properties of 4-(mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and its tetrahydrothieno[2,3-c]pyridine analogue. 295 23

Dopamine DA1 receptors were transferred from rat striatal membranes to Friend erythroleukemia cells (Fc) by membrane fusion. The Fc cells lack DA1 receptors but have a functional adenylate cyclase system. The striatal membranes bearing DA1 receptors were treated with N-ethylmaleimide (NEM) prior to fusion to inactivate their intrinsic adenylate cyclase activity. Fusion of the NEM-treated membranes and the Fc cells was induced by polyethylene glycol treatment to form a functional system de novo, which could be demonstrated by measuring the increase in cAMP production after addition of dopamine. This method provides a possibility to study the functional competence of receptors in neural tissue in more detail.
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PMID:Fusion transfer of dopamine DA1 receptors to Friend erythroleukemia cells. 315 74

Dopamine (DA) caused a significant activation of striatal adenylate cyclase in neonatal and adult but not in senescent rats. GTP activated cyclase at the adult stage but not at both neonatal and senescent stages. NaF and forskolin activated cyclase at every stage. The coupling mechanism between DA1 receptors and catalytic units of cyclase seems to become functional at the neonatal stage but GTP recognition and/or binding sites lack in stimulatory GTP binding protein in neonatal and senescent membranes.
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PMID:Activation of adenylate cyclase by dopamine, GTP, NaF and forskolin in striatal membranes of neonatal, adult and senescent rats. 654 37

Dopamine-4-O-sulfate (DA-4-S), a major metabolite of dopamine, was examined for pharmacologic activity both in vivo and in vitro. Intravenous doses of DA-4-S ranging from 1.3-34.3 micrograms/kg had no effect on renal blood flow or blood pressure in the anesthetized dog, demonstrating lack of agonist activity at vascular DA1 receptor sites. These data also suggest that DA-4-S is not metabolically converted to an active dopamine agonist in the dog. No beta-adrenoceptor agonist activity of DA-4-S could be detected in the isolated guinea-pig left atrium, and no alpha 1-agonist activity of DA-4-S could be detected in the perfused rabbit ear artery, although sympathetic neurotransmission was inhibited in this tissue at high concentrations (EC50 = 3.9 X 10(-6) M). This latter response was competitively inhibited by S-sulpiride. This lack of affinity for dopaminergic and adrenergic receptors was confirmed by biochemical assays (striatal adenylate cyclase stimulation; 3H-spiroperidol, 3H-clonidine, and 3H-WB 4101 binding using brain tissue preparations). In all the above tests, the activity of DA-4-S was much weaker than dopamine, showing this metabolite has little intrinsic dopaminergic or adrenergic pharmacological activity.
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PMID:Pharmacological characterization of dopamine-4-O-sulfate. 671 57

The modulation of dopamine DA1 receptors of cultured rat renal arterial smooth muscle cells by glucocorticoid and sodium chloride was studied. At a concentration of 10 nM, the synthetic glucocorticoid dexamethasone increased maximum receptor binding but had no effect on the dissociation constant. However, the maximum binding of [3H]Sch-23390 in cells treated with 100 mM sodium chloride did not change. However, the dissociation constant for DA1 receptor was increased by adding sodium chloride. The glucocorticoid effect on DA1 of arterial smooth muscle cells became apparent after hours of incubation in the presence of the steroid and was significantly inhibited by cycloheximide (10 micrograms/ml) or by the glucocorticoid receptor antagonist RU-38486, indicating that the effect required protein synthesis through glucocorticoid receptors. Treatment of cells with 1 microM dexamethasone for 24 h increased basal and DA1-stimulated adenylate cyclase activity. Basal adenylate cyclase was decreased by sodium chloride in a dose-dependent manner. These results suggest differential control of DA1 receptors on vascular smooth muscle cells by glucocorticoid or sodium chloride.
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PMID:Dopamine DA1 receptors on vascular smooth muscle cells are regulated by glucocorticoid and sodium chloride. 809 5

The interaction between dopamine DA1 receptors and a phorbol ester was studied to elucidate the role of protein kinase C in the response of this receptor. The in vitro binding of [3H]Sch 23390 to DA1 receptor sites on vascular smooth muscle cells was saturable. The extent of [3H]Sch 23390 binding to phorbol ester-treated cells was increased without any change in the dissociation constant. The production of adenosine 3',5'-cyclic monophosphate (cAMP) in response to DA1 receptor stimulation was enhanced by preincubation of vascular smooth muscle cells with the phorbol ester for 4 h. However, no enhancement was observed when the medium used for preincubation was supplemented with a protein kinase C inhibitor. Direct stimulation of stimulatory guanine nucleotide-binding regulatory protein with 5-guanylylimidodiphosphate and direct stimulation of adenylate cyclase with forskolin produced no significant differences in cyclase levels between phorbol ester-treated and untreated cells. These results suggest that activation of protein kinase C triggers an increase in the membrane expression of DA1 receptors, thereby enhancing receptor-coupled cAMP generation.
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PMID:Interaction between a phorbol ester and dopamine DA1 receptors on vascular smooth muscle. 838 2

The effect of dopamine on the arterioles (50.8-95.2 microns) in the cremaster muscle was examined to determine its effect on microcirculation. Anesthetized rats were used under a light microscope connected to a videocamera. Drugs were applied using small round filter paper (370 microns in diameter) containing the drug and placed in the immediate vicinity of the arteriole on the cremaster with a micromanipulator. The dose of the drug applied was represented by concentration of the drug solution in which the filter paper was immersed. Dopamine (10(-6)-10(-4)M) induced neither constriction nor dilation of the arteriole in the cremaster. Papaverine (10(-2)M) did not dilate the arteriole. However, the arterioles were constricted by noradrenaline (10(-6)-10(-4)M) and vasopressin (10(-7)M) in a dose-dependent manner. Noradrenaline (10(-4)M)-induced constriction was blocked by concomitant application of dopamine (10(-4)M). This effect of dopamine was antagonized by SCH23390 (10(-3)M). However, isoproterenol (10(-3)M) did not affect the arteriole, nor inhibit noradrenaline (10(-4)M)-induced constriction of the arterioles. While forskolin (10(-2)M) alone did not produce constriction or dilation of the arterioles, it inhibited noradrenaline (10(-4)M)-induced constriction of the arteriole. These results suggest that dopamine prevents the constriction of the arteriole induced by noradrenaline, by activation of DA1 receptors, which activates adenylate cyclase.
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PMID:Inhibitory effects of dopamine on noradrenaline-induced constriction of arterioles in vivo in the striated cremaster muscle. 848 19


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