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:4.1.1.6 (CAD)
4,420 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was an attempt to characterize the adenosine receptor in human coronary arteries, and to establish the dependence of the relaxations mediated by this receptor on a functional endothelium. Human coronary arteries were obtained from organ donors. Adenosine and its analogs (5'-N-ethyl-carboxamido-adenosine, NECA; N6-L-phenylisopropyladenosine, L-PIA; 2-chloroadenosine, CAD), all inhibited the contraction induced by 25 mmol/l KCl in a concentration-dependent manner and the order of potency was found to be: NECA greater than CAD greater than L-PIA greater than adenosine. These relaxations were antagonized by 8-phenyltheophylline (8PT). At higher concentrations of KCl, the relaxations were attenuated. In rings which relaxed in response to endothelium-dependent relaxing agents (bradykinin and A23187), NECA and CAD produced relaxations similar to those produced in rings which did not show endothelium-dependent responses. The results suggest that the coronary adenosine receptor (probably A2) mediates relaxations which may not be dependent on the relaxing function of the endothelium.
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PMID:Relaxation by adenosine and its analogs of potassium-contracted human coronary arteries. 233 4

Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative chronotropic and inotropic responses to adenosine in the isolated, blood-perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6-cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 5'-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not chronotropic responses to CAD and adenosine were dose-dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E-4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart.
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PMID:Are negative chronotropic and inotropic responses to adenosine differentiated at the receptor or postreceptor levels in isolated dog hearts? 785 2

The present study further examined the functional presence and the signal transduction mechanism(s) for adenosine A(2A) and A(2B) receptors through nitric oxide (NO) and the guanosine 3', 5'-cyclic monophosphate (cGMP) pathway in cultured porcine coronary artery endothelial cells (PCAEC). The application of adenosine receptor agonists, NECA, CGS-21680 and CAD between 10(-7) and 10(-4) M, enhanced the production of NO (measured as nitrite) in a dose-dependent manner. On the basis of EC(50) values, these agonists showed the following order of potency: NECA>CGS-21680>CAD. This order appears to be of the A(2) adenosine receptor subtype. Similarly, the same concentrations of adenosine agonists evoked the production of cGMP in a dose-dependent manner, exhibiting a rank order that is similar to that of NO production. NO synthase inhibitor, N-nitro-L-arginine methylester (L-NAME, 10(-5) M), inhibited the production of NO and cGMP, which was reversed by L-arginine (10(-4) M). Selective A(2A) adenosine receptor antagonists, ZM-241385 and SCH-58261, at 10(-7) M, significantly inhibited the effects of CGS-21680, but only partly inhibited the effect of NECA on NO and cGMP production. Along with the earlier molecular evidence from this laboratory [Am. J. Physiol. 279 (2000) H650], the present data further support the presence of both A(2A) and A(2B) receptors in PCAEC. These results further support that coronary endothelial cells express functional A(2A) and A(2B) adenosine receptors, leading to GMP production through the NO-synthase-linked mechanism. This is the first direct evidence where an A(2B) adenosine receptor has been linked to NO production in cultured endothelial cells and could play a role in coronary artery physiology and pathophysiology.
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PMID:Adenosine A(2A) and A(2B) receptors mediated nitric oxide production in coronary artery endothelial cells. 1174 40

Acute activation of Galpha(i/o)-coupled D2 dopamine receptors inhibits A2A adenosine receptor stimulation of adenylate cyclase. This antagonistic interaction between D2 dopamine and A2A adenosine receptors has been well documented; however, the effects of persistent activation of D2 dopamine receptors on subsequent A2A adenosine receptor signaling have not been explored. The present study investigated the effects of short-term (3-h) and long-term (18-h) activation of D2L dopamine receptors on subsequent A2A adenosine receptor stimulation of adenylate cyclase in CAD-D2L and NS20Y-D2L neuroblastoma cells. Short- and long-term activation of D2L dopamine receptors markedly increased 5'-N-methylcarboxamidoadenosine (MECA)-stimulated cyclic AMP accumulation 1.4-fold and 1.7-fold, respectively. D2L receptor-induced sensitization of A2A-stimulated cyclic AMP accumulation was blocked by the D2 antagonist spiperone and pertussis toxin pretreatment. In addition, persistent activation of A2A adenosine receptors resulted in 50% desensitization of subsequent MECA-stimulated cyclic AMP accumulation; however, MECA-induced desensitization of A2A adenosine receptors did not prevent completely quinpirole-induced sensitization of adenylate cyclase. These studies revealed a novel mode of regulation between D2L dopamine and A2A adenosine receptors and suggest a cooperative interaction in the regulation of cyclic AMP signaling.
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PMID:Sensitization of neuronal A2A adenosine receptors after persistent D2 dopamine receptor activation. 1456 8

Functional regulation and expression of the adenosine A2A receptor and associated G-protein were investigated in porcine coronary artery exposed to an A2A receptor antagonist, ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol). The arteries were incubated for 3 days in culture medium in the absence (control) and presence (treated) of 10 microM ZM 241385. Changes in isometric tension by adenosine receptor agonists were evaluated in endothelium-free tissues. ZM 241385-treatment produced a statistically significant rightward displacement of CGS-21680, NECA, and CAD concentration-response curves compared with the respective controls (P < 0.05). The EC50, expressed in nM, values in treated and control tissues were: 617.3 +/- 23 versus 24.9 +/- 1.5 for CGS-21680 (2-(p-(2-carboxyethyl)phenethylamino)-5'N-ethylcarboxamidoadenosine), 27.4 +/- 6.3 versus 3.06 +/- 0.8 for NECA (5'-N-ethylcarboxamidoadenosine), and 5786.2 +/- 160 versus 89.2 +/- 24.1 for CAD (chloroadenosine). However, the relaxing effect of forskolin remained unchanged in treated and control tissues. The concentration-response curves for NECA, CAD, and CGS-21680 were also displaced to the right when cAMP levels were measured in treated and control smooth muscle cells while no differences were observed with forskolin. Quantitative Western blot analysis demonstrated that the density of A2A receptors increased in ZM 241385-treated artery. We also showed a significant decrease in Galphas protein levels after ZM 241385 treatment compared with control. Taken together, these data indicate that prolonged blockade of A2A receptors in the coronary artery leads to desensitization of the functional effects of adenosine agonists by a mechanism that involves decreases in cAMP production. This was associated with an up-regulation of A2A receptors and a decrease in Galphas protein expression.
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PMID:Modulation of A2A adenosine receptors and associated Galphas proteins by ZM 241385 treatment of porcine coronary artery. 1463 95

1. The present study was carried out to characterize the effect of adenosine on calcium dynamics in the rat portal vein. Isolated portal vein of male albino rats was used as the experimental model as it exhibits autorhythmicity. 2. Adenosine and its analogues 2-CAD, N6-CHA and NECA were used to characterize the type of adenosine receptor involved and 2-CAD was used along with adenosine throughout the other part of study to characterize the effect of adenosine on Ca2+ dynamics. Adenosine and its analogues were found to inhibit the spontaneous contractions of rat portal vein in a concentration-related manner. The order of potency was NECA > 2-CAD > N6-CHA > adenosine. Incubation of the tissue with CGS-15943A, an adenosine receptor antagonist, had a per se enhancing effect on autorhythmicity. Adenosine and 2-CAD failed to reverse the contractile response produced by hypertonic KCl (80 or 30 mM). Whereas adenosine and 2-CAD effectively relaxed the tissues contracted with phenylephrine (10(-5) m). 3. Preincubation of the tissue with 2-CAD (10(-4), 10(-5) or 10(-6) m) for 5 min raised the threshold concentration of CaCl2 to evoke contractile response and also significantly increased the mean EC50 values of CaCl2. Nifedipine was found to be more potent than 2-CAD on Ca2+ channels. 4. The results of the present study suggest that the endogenous adenosine plays a significant role in producing vascular relaxation through the participation of A2 receptor subtype. This effect may be due to its inhibitory effect on release of Ca2+ from the intracellular stores. Further to this effect, 2-CAD had a major inhibitory effect on voltage-operated Ca2+ channels compared with receptor-operated Ca2+ channels. 5. It can be concluded that adenosine through its A2 receptor produces vasorelaxant effect by interfering with the release of Ca2+ from the intracellular stores coupled with influx of Ca2+ from the extracellular sources.
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PMID:Adenosine affects the calcium dynamics of rat portal vein. 1469 Apr 93

In neural crest (NC) cultures cAMP signaling is an instructive signal in catecholaminergic, sympathoadrenal cell development. However, the extracellular signals activating the cAMP pathway during NC cell development have not been identified. We demonstrate that in avian NC cultures, evidenced by tyrosine hydroxylase expression and catecholamine biosynthesis, adenosine and not adrenergic signaling, together with BMP2, promotes sympathoadrenal cell development. In NC cultures, addition of the adenosine receptor agonist NECA in the presence of BMP2 promotes sympathoadrenal cell development, whereas the antagonist CGS 15943 or the adenosine degrading enzyme adenosine deaminase (ADA) suppresses TH expression. Importantly, NC cells express A2A and A2B receptors which couple with Gsalpha increasing intracellular cAMP. Employing the CNS-derived catecholaminergic CAD cell line, we also demonstrate that neuronal differentiation mediated by serum withdrawal is further enhanced by treatment with IBMX, a cAMP-elevating agent, or the adenosine receptor agonist NECA, acting via cAMP. By contrast, the adenosine receptor antagonist CGS 15943 or the adenosine degrading enzyme ADA inhibits CAD cell neuronal differentiation mediated by serum withdrawal. These results support that adenosine is a physiological signal in neuronal differentiation of the CNS-derived catecholaminergic CAD cell line and suggest that adenosine signaling is involved in NC cell development in vivo.
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PMID:Adenosine signaling promotes neuronal, catecholaminergic differentiation of primary neural crest cells and CNS-derived CAD cells. 1588 17

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