Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Glutamate inhibits the electrically evoked release of noradrenaline in rabbit brain cortex slices; the inhibition is mediated by adenyl compounds, presumably adenosine. The aim of the present study was to identify the receptors involved in this indirect inhibitory effect of glutamate. Slices of the occipitoparietal cortex were preincubated with [3H]-noradrenaline and then superfused and stimulated by trains of 6 pulses, 100 Hz. 2. The ionotropic glutamate receptor agonists alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AM-PA; 10-100 microM), kainate (10-100 microM) and N-methyl-D-aspartate (NMDA; 30-300 microM) but not the metabotropic glutamate receptor agonist, 1-amino-1,3-cyclopentanedicarboxylate (ACPD; 10-100 microM) reduced the electrically evoked overflow of tritium. 3. The effects of AMPA, kainate and NMDA were attenuated or abolished by the adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as well as by adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as well as by adenosine deaminase but not by the alpha 2-adrenoceptor antagonist yohimbine, the gamma-aminobutyric acid (GABA) receptor antagonists, bicuculline and 2-hydroxysaclofen and the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). 4. The NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5) blocked the inhibitory effect of NMDA but not that of AMPA and kainate. The non-NMDA-receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked the effect of AMPA but not of kainate and NMDA. 5. In addition to decreasing the electrically evoked overflow of tritium, AMPA, kainate and NMDA but not ACPD caused a steep but transient rise of basal tritium efflux. This immediate releasing effect was not significantly changed by DPCPX, adenosine deaminase, yohimbine, bicuculline, 2-hydroxysaclofen and L-NAME (except that L-NAME enhanced the effect of kainate). AP5 and CNQX antagonized the immediate releasing effects in the same way that they antagonized the inhibition by AMPA, kainate and NMDA of the electrically evoked overflow of tritium.6. It is concluded that AMPA, kainate and NMDA, like glutamate, reduce the electrically evoked release of noradrenaline by releasing adenosine or an adenine nucleotide which is then degraded to adenosine. Activation of each of the three ionotropic glutamate receptors, AMPA, kainate and NMDA receptors, but not activation of metabotropic glutamate receptors can initiate this indirect inhibitory effect on the release of noradrenaline (as well as the known noradrenaline releasing effect).
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PMID:Ionotropic glutamate receptor types leading to adenosine-mediated inhibition of electrically evoked [3H]-noradrenaline release in rabbit brain cortex slices. 750 27

1. The possibility that prostacyclin (IP-) receptor agonists inhibit spontaneous contractions of the rat isolated colon by activating enteric neurones has been investigated. Cicaprost was used as the test agonist because of its high stability, selectivity and potency (IC50 = 3.8 nM). 2. The Na+ channel blockers saxitoxin (STX, 1 nM) and tetrodotoxin (TTX, 1 microM), whilst having little effect on resting spontaneous activity, virtually abolished the inhibitory actions of cicaprost (10 nM) and nicotine (3 microM); inhibitory responses to isoprenaline (20 nM) were not affected. Phentolamine (1 microM), propranolol (1 microM) and atropine (1 microM) had no effect on cicaprost inhibition. These data are compatible with release of inhibitory NANC transmitter(s) by cicaprost. 3. A transmitter role for nitric oxide was investigated. The nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM) inhibited the actions of both cicaprost (10 nM) and nicotine (3 microM) by 50-60%, but did not affect responses to isoprenaline (20 nM) or sodium nitroprusside (1-5 microM). The enantiomeric D-NAME (100 microM), which has negligible NOS inhibitory activity, had no effect on the action of cicaprost. 4. The involvement of purinergic transmitters was also investigated. Desensitization to the inhibitory action of ATP did not affect cicaprost responses. The P2x/P2y-receptor antagonist, suramin, at 300 microM blocked ATP responses, but not those due to adenosine; it did not affect cicaprost inhibition. The selective adenosine A1-receptor antagonist, DPCPX, used at a sufficiently high concentration (5 microM) to block adenosine A2-receptors, did not affect cicaprost inhibition. Apamin (25 nM), a blocker of calcium activated K+ channels on smooth muscle, abolished or markedly reduced the inhibitory actions of ATP and adenosine, and partially inhibited cicaprost and nicotine responses. The combination of L-NAME(100 microM) and apamin (25 nM) abolished cicaprost and nicotine responses.5. Investigation of vasoactive intestinal peptide (VIP) as a potential transmitter showed that its inhibitory action on the colon (IC50 = 50 nM) was partially inhibited by TTX (1 microM). alpha-Chymotrypsin abolished the effect of VIP but had no effect on cicaprost inhibition. Attempts to inhibit VIP responses using peptide antagonists and by agonist desensitization were unsuccessful.6. KCI (40 mM) contracted the colon and abolished spontaneous activity. Under these conditions,isoprenaline, sodium nitroprusside and ATP induced relaxation, whereas cicaprost (10-3 10 nM) had no effect. Cicaprost inhibited both the tone and the spontaneous activity induced by the EP1/EP3-receptor agonist, sulprostone (8.6 nM) but not when either TTX (1 microM) or KC1 (40 mM) was also present. On KCl-treated preparations, the prostacyclin analogue, iloprost (10-500 nM), induced contraction,presumably due to activation of EP-receptors.7. It is concluded that IP-receptor agonists inhibit the contractility of rat colon by stimulating the release of at least two transmitters from NANC enteric neurones. Nitric oxide appears to be one of the transmitters. The second transmitter mechanism is apamin-sensitive; the experimental results do not support ATP, adenosine or VIP as transmitter candidates. However, further studies using more potent and selective receptor antagonists are required.
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PMID:Inhibition of rat colon contractility by prostacyclin (IP-) receptor agonists: involvement of NANC neurotransmission. 754 96

The purpose of this study was to evaluate potential mechanisms of ischemia-evoked amino acid transmitter release. Changes in extracellular levels of transmitter amino acids and lactic acid dehydrogenase (LDH) in rat cerebral cortex during and following four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked release of glutamate, aspartate and gamma-amino-butyric acid (GABA) was compared in control vs. drug-treated animals. Tetrodotoxin and antagonists of glutamate receptors (DNQX, MK-801, and AP-3) depressed the initial rate of increase in extracellular glutamate and aspartate without altering the total amount of these amino acids collected in the cortical superfusates. Cobalt, a calcium channel antagonist, failed to alter efflux. Acidic amino acid transport inhibitors (dihydrokainate, L-trans-PDC) depressed the rate of onset of glutamate and aspartate release and dihydrokainate depressed total release by 44%. PD 81723, an allosteric enhancer at the A1 adenosine receptor, depressed glutamate efflux, as did L-NAME, an inhibitor of nitric oxide synthase. Extracellular increases in GABA levels were depressed by tetrodotoxin and L-trans-PDC. The GABA transport inhibitor, nipecotic acid, increased the initial rate of onset of GABA release. Increases in LDH levels in the extracellular fluid became apparent during the period of ischemia and continued to increase during the subsequent 90 min of reperfusion. These results suggest that ischemia evokes a release of neurotransmitter amino acids that is only partially dependent upon Ca2+ influx activation or the reversal of amino acid transporters. Nonselective mechanisms, resulting from the disruption of plasma membrane integrity, may contribute significantly to the total ischemia-evoked release of excitatory amino acids.
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PMID:Characterization of glutamate, aspartate, and GABA release from ischemic rat cerebral cortex. 791 62

To evaluate therapeutic options for the prevention of radiocontrast media (RCM)-induced nephropathy, a model was developed in which rats received NG-nitro-L-arginine methyl ester (L-NAME) for 10 wk in order to inhibit nitric oxide (NO) synthetase. This study tests the hypothesis that infusion of an adenosine antagonist before RCM application may avoid the vasoconstrictive response in NO-depleted rats. Rats received L-NAME for 10 wk orally (50 mg/L drinking water) to achieve NO depletion. Renal function was determined by [3H]inulin clearance for analysis of the GFR and by flowmetry for assessing renal blood flow (RBF). After a control clearance period (baseline clearance period), the renal response to RCM application (sodium diatrizoate, 2 ml/kg body wt) was measured two times every 30 min starting 30 min after RCM application (clearance periods 1 and 2). L-NAME rats and control rats received two adenosine antagonists. The nonselective adenosine antagonist theophylline was given as an initial bolus of 50 mumol/kg body wt within 10 min, followed by continuous infusion of 100 mumol/kg body wt per h, and the specific adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was given as a bolus of 100 micrograms/kg body wt before RCM application. Results were compared with vehicle infusion. In the control group, no significant change of GFR or RBF could be detected after application of RCM with or without prior infusion of DPCPX or theophylline. In L-NAME rats, RBF decreased significantly after RCM application (baseline, 5.6 +/- 0.2 ml/min; first clearance period, 4.6 +/- 0.3 ml/min [P < 0.05]; second clearance period, 4.3 +/- 0.3 [P < 0.01]). GFR was also reduced in L-NAME rats without previous infusion of theophylline or DPCPX (baseline, 0.95 +/- 0.1 ml/min; first clearance period, 0.83 +/- 0.1 ml/min; second clearance period, 0.69 +/- 0.1 ml/min [P = 0.058]). Prior treatment with either theophylline or DPCPX resulted in complete protection against a decline of RBF and GFR induced by RCM in L-NAME rats. Rats with chronic NO blockade showed a significant increase of the renal vasoconstrictive effect of contrast media. Application of L-NAME in rats seems to constitute a suitable animal model to study the pathophysiology of radiocontrast media-induced nephropathy. In this animal model, administration of adenosine antagonists prevented the decline of GFR and RBF.
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PMID:Prevention of radiocontrast-induced nephropathy by adenosine antagonists in rats with chronic nitric oxide deficiency. 921 62

The ionic mechanisms underlying the negative dromotropic effect of adenosine were studied in calcium-tolerant myocytes isolated from the region of the rabbit atrioventricular (AV) node. Action potentials and membrane currents were recorded by using the whole cell patch clamp technique. Adenosine (1 to 50 microM) abolished the spontaneous activity of AV node myocytes with hyperpolarization of the membrane potential. Voltage clamp experiments showed that adenosine induced an inwardly rectifying, time-independent potassium current. These effects were antagonized by 8-cyclopentyl-1,3-dipropylxanthine and produced by ribose 5-phosphate isomerase A, indicating that they were mediated by the A1 adenosine receptor. Adenosine also had a small direct inhibitory action on the inward calcium current (ICa) but had a more marked indirect action following stimulation of the calcium current by isoprenaline. The isoprenaline-induced increase in ICa was abolished in the presence of adenosine 10 microM. In cells pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the isoprenaline-induced increase in ICa was not reduced by the addition of adenosine. Coincubation of the cells with L-NAME plus L-arginine (the endogenous substrate of nitric oxide synthase) restored the adenosine-induced attenuation of ICa. A membrane permeable analogue of cGMP, 8Br cGMP, an inhibitor of cGMP-stimulated phosphodiesterase, prevented the antiadrenergic effect of adenosine. These results suggest that adenosine activates guanylyl cyclase following the production of nitric oxide, and the subsequent stimulation of phosphodiesterase enhances the breakdown of isoprenaline-elevated cAMP leading to a reduction in the stimulated ICa. In conclusion, the important ionic mechanisms of the actions of adenosine on AV nodal cells are a direct effect, with activation of a potassium conductance and an indirect antiadrenergic effect on ICa, which is mediated by nitric oxide production and phosphodiesterase stimulation.
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PMID:Ionic mechanisms of the effect of adenosine on single rabbit atrioventricular node myocytes. 944

Renal hemodynamic changes could play a key role in radiocontrast media-induced nephropathy (RCIN), although the pathophysiological mechanisms are unclear. We investigated the role of adenosine in RCIN caused by sodium diatrizoate (Urografin, 3 ml/kg) in nitro-L-Arg methyl ester (L-NAME)-hypertensive rats in different hydration states [eight weeks of L-NAME (50 mg/liter) in drinking water; high or low sodium intake for the last two weeks]. In clearance experiments under thiobutabarbital anesthesia in these previously mentioned animals, glomerular filtration rate (GFR), renal blood flow (RBF), and mean arterial pressure (MAP) were measured in the presence or absence of the adenosine A1-receptor antagonist 8-cyclopropyl-1,3-dipropylxanthine (DPCPX, 100 microg/kg bolus plus 10 microg/kg/hr). DPCPX or pretreatment did not change control hemodynamics. Contrast medium caused GFR and RBF to fall significantly in volume-depleted rats (from 0.29 +/- 0.02 to 0.21 +/- 0.02 ml/min/100 g and 5.4 +/- 0.3 to 4.0 +/- 0.4 ml/min, respectively) without change in MAP. In volume-expanded rats, changes were not significant (0.25 +/- 0.01 to 0.24 +/- 0.02 ml/min/100 g and 5.6 +/- 0.3 to 5.3 +/- 0.4 ml/min, respectively). In the volume-depleted rats, changes were prevented by DPCPX (0.27 +/- 0.02 to 0.24 +/- 0.02 ml/min/100 g and 4.8 +/- 0.1 to 5.0 +/- 0.1 ml/min, respectively). The acute hemodynamic effects elicited by contrast medium in L-NAME hypertensive rats thus can be prevented by volume expansion. Adenosine, via A1-receptors, contributes to the adverse effects of contrast media.
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PMID:Adenosine and extracellular volume in radiocontrast media-induced nephropathy. 973 87

The role of adenosine and ATP-sensitive potassium channels (KATP) in the mechanism of ischemic preconditioning (IPC)-induced protection against the post-ischemic endothelial dysfunction was studied. Langendorff-perfused guinea-pig hearts were subjected either to 40 min of global ischemia and 40 min reperfusion or were preconditioned prior to the ischemia/reperfusion with three cycles of either 5 min ischemia/5 min reperfusion (IPC) or 5 min infusion/5 min wash-out of adenosine, adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) or KATP opener, pinacidil. The magnitude of coronary flow reduction caused by NO-synthase inhibitor, Nomega-nitro-l-arginine methyl ester (l-NAME), served as an index of a basal endothelium-dependent vasodilator tone. Coronary overflows produced by a bolus of acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of agonist-induced endothelium-dependent and endothelium-independent vascular function, respectively. The coronary flow, LVDP, ACh response and l-NAME response were reduced by 8, 32, 41 and 54%, respectively, while SNP response was not changed in the hearts subjected to ischemia/reperfusion. ACh response was fully restored, l-NAME response was partially restored, and SNP response was not affected in the hearts subjected to IPC. The post-ischemic recoveries of coronary flow and LVDP were not improved by IPC. The protective effect of IPC on the ACh response was mimicked by adenosine, CHA, and pinacidil. The protective effect of IPC, CHA and pinacidil was abolished by KATP antagonist, glibenclamide. The IPC protection was affected neither by a non-specific adenosine antagonist, 8-p-sulfophenyltheophylline, nor by a specific adenosine A1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). Our data indicate that: (1) IPC affords endothelial protection in the mechanism that involves activation of KATP, but not adenosine A1 receptors; (2) exogenous adenosine and A1 receptor agonist afford the protection, which might be of a potential clinical significance; (3) the endothelial dysfunction is not involved in the mechanism of myocardial stunning in guinea-pig hearts.
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PMID:The role of adenosine and ATP-sensitive potassium channels in the protection afforded by ischemic preconditioning against the post-ischemic endothelial dysfunction in guinea-pig hearts. 976 29

1. In anaesthetized rats, we recorded arterial blood pressure (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC). We tested the effects of the nitric oxide (NO) synthesis inhibitor L-NAME (nitro-L-arginine methyl ester), or the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, on responses evoked by systemic hypoxia (breathing 8% O2 for 5 min) or i.a. infusion for 5 min of adenosine, the NO donor sodium nitroprusside (SNP), the adenosine A1 receptor agonist CCPA (2-chloro-N6-cyclopentyladenosine) or the adenosine A2A receptor agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadeno sin e hydrochloride). 2. L-NAME (10 mg kg-1 i.v.) greatly reduced the increase in FVC induced by hypoxia or adenosine, as we have shown before, but had no effect on the increase in FVC evoked by SNP. In addition, L-NAME abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that muscle vasodilatation induced by systemic hypoxia and infused adenosine are largely NO dependent. They also indicate that muscle dilatation induced by A1 receptor stimulation is entirely NO dependent while that induced by A2A receptors is largely NO dependent; dilatation may also be induced by direct stimulation of A2A receptors on the vascular smooth muscle. 3. Glibenclamide (10 or 20 mg kg-1 i.v.) reduced the increase in FVC induced by hypoxia, preferentially affecting the early part (< 1 min). In addition, glibenclamide greatly reduced the increase in FVC induced by adenosine, but it had no effect on that evoked by SNP. Further, glibenclamide abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that hypoxia-induced muscle vasodilatation is initiated by KATP channel opening. They also indicate that NO does not induce muscle vasodilatation by opening KATP channels on the vascular smooth muscle, but indicate that the dilatation induced by adenosine and by A2A receptor stimulation is largely dependent on KATP channel opening, while that induced by A1 receptor stimulation is wholly dependent on KATP channel opening. 4. These results, together with previous evidence that hypoxia-induced vasodilatation in skeletal muscle is largely mediated by adenosine acting on A1 receptors, lead us to propose that adenosine is released from endothelium during systemic hypoxia and acts on endothelial A1 receptors to open KATP channels on the endothelial cells and cause synthesis of NO, which then acts on the vascular smooth muscle to cause dilatation. During severe systemic hypoxia we propose that adenosine may also act on A2A receptors on the endothelium to cause dilatation by a similar process and may act on A2A receptors on the vascular smooth muscle to cause dilatation by opening KATP channels.
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PMID:Cellular mechanisms by which adenosine induces vasodilatation in rat skeletal muscle: significance for systemic hypoxia. 983 24

Intravascular adenosine may exert its negative dromotropic effect via activation of luminal coronary endothelial receptors, which suggests the presence of transcellular dromotropic mediators of endothelial origin, perhaps nitric oxide (NO) and prostaglandins. We decided to test this hypothesis in isolated guinea pig hearts retrogradely perfused with Krebs-Henseleit solution. A pair of stimulating electrodes were placed in the right atria and the auricular-ventricular (A-V) delay recorded by means of a recording electrode placed on the left atria and an electrode placed on the tip of the ventricle. Hearts were paced at a rate of 3.8 +/- 0.2 Hz and perfused at a coronary flow of 9 +/- 0.25 ml/min. To obtain dose-response curves, single doses (as boluses) of different concentrations of adenosine were infused and the maximal increase in A-V delay induced by each dose was determined. Agents that inhibit NO accumulation, such as N(G)-nitro-L-arginine methyl ester (L-NAME) and oxyhemoglobin, diminished the effect of adenosine while NO-sparing agents, such as superoxide dismutase and dithiotreitol, enhanced the adenosine effect. Infusion of NO and the NO donor morpholinosydnonimine increased the A-V delay in a dose-dependent manner. In addition, the dose-response curve for adenosine was displaced downward and to the right by indomethacin, indicating also the involvement of prostaglandins. Infusion of L-NAME in addition to indomethacin further diminished the effects of adenosine, indicating that NO and prostaglandins acted simultaneously. To selectively activate intravascular endothelial adenosine receptors, adenosine amino congener (ADAC), an adenosine A1 receptor agonist, was covalently coupled to 2 X 10(6) Da dextran. When intracoronarily infused, the dextran-ADAC complex remains in the blood vessel lumen because it is too large to diffuse to the interstitium. On intracoronary administration, the dextran-ADAC complex caused a negative dromotropic effect which was diminished by L-NAME and indomethacin. Our data indicate that the dromotropic effect caused by intracoronarily administered adenosine is the result solely of activation of intravascular endothelial adenosine receptors, possibly type A , and that NO and prostaglandins are synergistic endothelial mediators of this effect.
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PMID:Intravascular adenosine: the endothelial mediators of its negative dromotropic effects. 1032 77

Several studies have recently suggested a principal role of adenosine in the pathogenesis of radiocontrast media-induced nephropathy. In the present experiments, we therefore investigated the renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a potent and selective adenosine A1 receptor antagonist, on radiocontrast media-induced nephropathy in the model of the N-pi-nitro-L-arginine methyl ester (L-NAME) hypertensive, chronic nitric oxide (NO)-depleted rat. Chronic NO depletion was induced by pretreatment with L-NAME, 50 mg/ml, added to drinking water for 8 weeks. Clearance experiments were performed in anesthetized rats and glomerular filtration rate was assessed prior to and following the application of high osmolar radiocontrast media (sodium diatrizoate, 3 ml/kg, i.v.) or an equivalent volume of isoosmolar mannitol to examine the role of hyperosmolarity in radiocontrast media-induced nephropathy. Subgroups received KW-3902 (0.1 mg/kg, i.v.), 20 min prior to radiocontrast media administration. Age-matched, untreated rats served as controls. Radiocontrast media application induced a significant decline in glomerular filtration rate in L-NAME hypertensive animals, whereas no effects were observed in control rats. KW-3902 fully prevented the drop in glomerular filtration rate in response to radiocontrast media in L-NAME hypertensive rats. No renal hemodynamic alterations were observed in mannitol-infused animals. The present experiments demonstrate that the decrease in glomerular filtration rate following radiocontrast media occurred independently of the osmotic load, and that KW-3902 effectively prevented the radiocontrast media-induced deterioration in renal function. KW-3902 may be especially beneficial in patients at high risk for developing acute renal failure following radiocontrast media application or in patients in which extracellular fluid volume expansion is limited by clinical conditions such as congestive heart failure.
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PMID:The selective adenosine A1 receptor antagonist KW-3902 prevents radiocontrast media-induced nephropathy in rats with chronic nitric oxide deficiency. 1123 Oct


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