Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuromodulator adenosine is known to decrease neurotransmitter release at the neuromuscular junction by activation of an A1 adenosine receptor coupled to a pertussis toxin-sensitive G protein. Among the mechanisms that could contribute to the depression of neurotransmitter release is reduced entry of calcium through channels located in the presynaptic terminal. In the present study, we have examined the effects of adenosine on high-voltage-activated (HVA) calcium currents in motoneurons, the presynaptic cells of the neuromuscular junction. The motoneurons were isolated from embryonic mice, placed in primary tissue culture for 16 hr, and analyzed by means of the whole-cell patch-clamp technique. Adenosine (40 microM) reduced both transient and sustained components of HVA calcium current. This effect was blocked by the A1 antagonist 8-cyclopentyltheophylline (CPT; 100 nM) and was mimicked by the A1 agonist N6-cyclohexyladenosine (CHA; 50 nM to 10 microM) but not by the A2a agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS-21680; 1 micron). Pretreatment with pertussis toxin (200 ng/ml, > 16 hr) abolished the depression of HVA calcium current by adenosine receptor activation. Brief (3 min) exposure of the cells to 10 microM omega-conotoxin GVIA irreversibly blocked a part of the HVA current, which can therefore be attributed to N-type channels; the remaining current was unaffected by adenosine receptor activation. Hence, it appears that adenosine decreases only the N-current portion of HVA current and that this inhibition occurs via an A1 receptor linked to a pertussis toxin-sensitive G protein. Other investigators have shown that N-type channels do not play a primary role in eliciting transmitter release at the mammalian neuromuscular junction. Thus, it is uncertain what motoneuronal functions are influenced by adenosine modulation of N-type channels.
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PMID:Adenosine acting at an A1 receptor decreases N-type calcium current in mouse motoneurons. 820 77

We compared the effects of isoflurane, enflurane, and halothane on myocardial blood flow, function, and metabolism in normally perfused and ischemic regions of the swine heart. A model of single vessel incomplete occlusion was used so that the capacity of these anesthetics to cause transmural coronary steal could be tested. After median sternotomy, the left anterior descending coronary artery (LAD) was cannulated and autoperfused from the carotid artery. Systolic segment shortening was measured in the regions of the heart perfused by the LAD and left circumflex arteries. Regional myocardial blood flow was measured with radioactive microspheres. Blood was obtained from the anterior cardiac vein for measurement of lactate. Measurements were made during imposition of a stenosis on the perfusion circuit sufficient to decrease resting flow by 25%. The same stenosis was imposed during three treatment periods in a randomized and balanced cross-over design. In one group of 12 swine, treatments were two doses of intracoronary adenosine and a control period. A second group of 12 were given 1.5% isoflurane, 2.18% enflurane, and 0.98% halothane. Heart rate, mean aortic pressure, and left atrial pressure were matched during the three treatments in each animal. Adenosine caused transmural steal resulting in diminished systolic segment shortening in the ischemic LAD region. During isoflurane, compared to halothane, the first derivative of left ventricular pressure with respect to time was greater by 28%, and systolic segment shortening in the normal left circumflex artery and ischemic LAD regions was greater by 27% and 31%, respectively. Subepicardial flow in the ischemic region was greater with isoflurane but subendocardial flow was unchanged. Lactate production during isoflurane was 52% and 76% greater than during halothane and enflurane, respectively. Our results indicate that isoflurane is not a sufficiently potent arteriolar vasodilator in swine to cause transmural steal. Although myocardial performance was superior with isoflurane in both ischemic and normally perfused regions, lactate production also increased, suggesting worsened ischemic metabolism. It is likely that the myocardial oxygen supply/demand ratio worsened with isoflurane because it caused less myocardial depression than the other anesthetics.
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PMID:Isoflurane, compared to halothane or enflurane, causes increased lactate production but no transmural coronary steal during myocardial ischemia in swine. 834 17

Adenosine has recently been shown to play a potentially important role in the regulation of synaptic excitability during experimental hypoxia in the hippocampus of the rat. Endogenous adenosine, rapidly released at the initiation of a hypoxic episode, produced synaptic depression, which could protect sensitive neurons. In the present experiments, an inhibitor of the reuptake of adenosine, soluflazine (R64719) was employed to increase the levels of endogenous adenosine under normoxic and hypoxic conditions in slices of the hippocampus of the rat. Soluflazine produced a slow-onset, concentration-dependent depression of population excitatory postsynaptic potentials, which was reversed by the specific A1 adenosine receptor antagonist, 8-cyclopentyltheophylline. During severe N2-induced hypoxia, soluflazine significantly delayed hypoxic depolarization. These results suggest that inhibition of the reuptake of adenosine may have therapeutic potential in the amelioration of hypoxic/ischemic neuronal damage, particularly in the hippocampus.
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PMID:The effects of the adenosine reuptake inhibitor soluflazine on synaptic potentials and population hypoxic depolarizations in area CA1 of rat hippocampus in vitro. 838 14

Conditioning stimulation of afferent fibers in hippocampal area CA1 produced heterosynaptic, posttetanic depression (PTD) of responses evoked by stimulation of an independent set of afferent fibers. PTD was present within 5 s of conditioning stimulation, amounted to a 60-80% reduction of excitatory postsynaptic potentials (EPSPs), and required a period of 3-5 min for recovery. Antagonists of A1 adenosine receptors substantially reduced PTD. Adenosine released into, or formed in, the extracellular space during conditioning stimulation may diffuse within the slice to depress evoked release of glutamate.
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PMID:Role of adenosine in heterosynaptic, posttetanic depression in area CA1 of hippocampus. 839 68

Adenosine is a purine nucleoside with a rapid onset and brief duration of action after intravenous bolus administration. Its most prominent cardiac effect is impairment or blockade of atrioventricular nodal conduction, but other effects are depression of automaticity of the sinus node and attenuation of catecholamine-related ventricular after-depolarizations. The cardiac cell surface receptor is the A1 purinoceptor. The therapeutic value of adenosine is predominantly in those arrhythmias in which the atrioventricular node forms part of a reentry circuit, as clearly demonstrated by the high success rate for termination of atrioventricular nodal reentry tachycardia and of atrioventricular reentry tachycardia involving an accessory pathway in the Wolff-Parkinson-White syndrome. Ventricular tachycardias are generally unresponsive, with the exception of right ventricular outflow tract tachycardia. A diagnostic role has emerged for adenosine. The transient blockade of the atrioventricular node that it causes can reveal important electrocardiographic features in arrhythmias, such as atrial flutter, or can unmask latent preexcitation. In wide-QRS tachycardias, adenosine can help to distinguish ventricular tachycardia from supraventricular tachycardia with QRS aberration. Unlike verapamil, adenosine is safe in ventricular tachycardia. A suggested dosing scheme is to give incremental doses at 1-minute intervals, starting at 0.05 mg/kg and continuing until complete atrioventricular block is induced or a maximum of 0.25 mg/kg is reached. Side effects are transient, sometimes uncomfortable, and not hazardous; dyspnea and chest discomfort are most frequent. A history of asthma is a relative contraindication. Aminophylline antagonizes and dipyridamole potentiates the effects of adenosine.
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PMID:The therapeutic and diagnostic cardiac electrophysiological uses of adenosine. 848 69

The molecular layer of the dentate gyrus exhibits extensive circuit and receptor reorganization after entorhinal lesions and in Alzheimer's disease, including decreased adenosine (A1) receptor binding in the terminal zone of damaged perforant path fibers. We examined the adenosine-sensitivity of evoked synaptic activity recorded from the rat dentate gyrus molecular layer in hippocampal slices prepared after electrolytic lesions were placed in approximately the middle third of the entorhinal cortex. Extracellular field potentials (EFPs) recorded in slices prepared from animals two days post-lesion were small, upward-going, and exhibited paired-pulse potentiation, but by two weeks post-lesion EFPs had recovered to large, downward-going responses that exhibited paired-pulsed depression. EFPs recorded from two week post-lesion slices were about 2-fold more sensitive (P < or = 0.05) to exposure to adenosine when compared to EFPs recorded from slices from unlesioned animals. Adenosine-induced reduction of paired-pulse depression was similar between unlesioned and post-lesion slices. AChE histochemistry performed after recording revealed dense staining in the dentate gyrus molecular layer of post-lesion slices as compared to slices from unlesioned animals, confirming that sprouting of cholinergic fibers occurred as expected from previous entorhinal lesion studies. Autoradiography performed on adjacent slices showed a decrease in binding to A1-adenosine receptors in the dentate gyrus molecular layer in post-lesion slices as compared to slices from unlesioned animals, indicating that there was a loss of presynaptically located A1-adenosine receptors on damaged perforant pathway terminals. These results indicate that, in addition to the recovery of the major excitatory signal to the hippocampus after entorhinal cell loss, this signal is more sensitive to modulation by adenosine, suggesting an increase in A1-adenosine receptor efficacy in the reinnervated region.
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PMID:Increased sensitivity to adenosine in the rat dentate gyrus molecular layer two weeks after partial entorhinal lesions. 850 4

1. Using an extracellular recording technique, we have investigated the site of action of adenosine and muscarine on the rat superior cervical ganglion (SCG). The adenosine-induced hyperpolarization and muscarine-induced depolarization of ganglia were localized to the cell bodies of the ganglia. Responses to muscarine and adenosine were larger when recorded via the internal carotid nerve (ICN) compared with the external carotid nerve. Depression of the response to muscarine by adenosine was similar for both nerve trunks. 2. The effects of adenosine and cyclic nucleotides on the d.c. potential and the depolarization to muscarine were examined by recording via the ICN. Adenosine at concentrations up to 1 mM produced concentration-dependent hyperpolarizations. Hyperpolarization induced by 100 microM adenosine was unaffected by 1 microM tetrodotoxin or the muscarinic M1-receptor antagonist pirenzepine (0.3 microM). In contrast, hyperpolarizations to 100 microM adenosine were significantly reduced by 10 microM 8-phenytheophylline (55 +/- 7 microV vs 15 +/- 9 microV, P < 0.01, n = 4). Two agents known to increase intracellular cAMP, i.e. 8-bromo-cyclic-adenosine-3'-5' monophosphate (8BrcAMP) and isoprenaline, depolarized ganglia. Depolarizations to 100 nM mucarine were significantly depressed by adenosine (100 microM) by 26 +/- 2% (n = 61), but unaltered by 8BrcAMP or cyclic guanosine-3'-5' monophosphate. 3. Dipyridamole and hydroxy-nitro-benzylthioguanosine (inhibitors of adenosine transport) and erythro-6-amino-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase), potentiated the depression by adenosine of the response to muscarine, and the hyperpolarization to adenosine respectively. However, there was no evidence to support the hypothesis that there was spontaneous release of endogenous adenosine under the conditions of study, as dipyridamole or EHNA did not alter the control d.c. potential or the depolarization to muscarine. 4. It is concluded that the ability of adenosine to hyperpolarize and depress the response of the rat SCG to muscarine is due to the direct activation of postsynaptic somatodendritic P1-purinoceptors and unlikely to be mediated by an increase in intracellular cAMP. In addition the rat SCG has mechanisms for both the uptake and inactivation of adenosine.
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PMID:On the site of action and inactivation of adenosine by the rat superior cervical ganglion. 851 24

The aim of this study was to examine the effect of initial hyperkalemic reperfusion (HKR), with and without added adenosine, on coronary flow, myocardial function, and endothelium-dependent and endothelium-independent coronary vascular function. Cardioplegic arrest was induced in 40 isolated guinea pig hearts by infusing oxygenated cardioplegic (high in potassium ion) Krebs solution for 5 minutes. Hearts were then stored at room temperature for 3.5 hours. On reperfusion, hearts were divided into four groups of 10 hearts each: control, reperfusion with regular Krebs solution (4.6 mmol/L potassium chloride); base hyperkalemic reperfusion, initial reperfusion with 37 degrees C oxygenated, cardioplegic Krebs solution for 5 minutes; hyperkalemic reperfusion with addition of 1 mmol/L adenosine during HKR; and hyperkalemic reperfusion with addition of 5 mmol/L adenosine. Coronary reserve (adenosine bolus 2 mmol/L) and responses to acetylcholine (1 mumol/L) and nitroprusside (100 mumol/L) were examined before and after ischemia and reperfusion. Flow did not return to preischemic values in any group after reperfusion. Adenosine treatment during initial reperfusion increased coronary flow (percentage of baseline +/- standard error of the mean) from 57% +/- 4% in control and 45% +/- 3% in hearts with hyperkalemic reperfusion to 79% +/- 3% and 83% +/- 5% in hearts with hyperkalemic reperfusion also treated with, respectively, 1 mmol/L adenosine and 5 mmol/L adenosine (p < 0.05). At 30 and 60 minutes of reperfusion, however, flow remained elevated only in the group treated with 5 mmol/L adenosine. Coronary reserve and responses to acetylcholine and nitroprusside were equivalently depressed in all groups after reperfusion. Recovery of left ventricular systolic and diastolic function was improved in all groups after hyperkalemic reperfusion (54% +/- 4% of preischemic value) compared with control (39% +/- 3%), and recovery was further enhanced in the group treated with 5 mmol/L adenosine (60% +/- 4%). In this ex vivo model, hyperkalemic reperfusion improved myocardial function after cardioplegic arrest and the addition of 5 mmol/L adenosine improved coronary flow. Adenosine may counteract the potassium chloride-induced vasoconstriction that occurs during hyperkalemic reperfusion and may thus improve coronary flow and myocardial function. Postischemic depression of endothelium-dependent or endothelium-independent vascular functions, however, was not alleviated by hyperkalemic reperfusion with or without adenosine.
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PMID:Improvement in functional recovery of the isolated guinea pig heart after hyperkalemic reperfusion with adenosine. 855 91

Adenosine is a potent inhibitory modulator in the brain. It suppresses glutamatergic synaptic transmission and possibly acts as a brain endogenous neuroprotective agent. In this study we have examined the effects of a clinically used porcine brain tissue hydrolysate, Cerebrolysin, on synaptic transmission in the CA1 area of rat hippocampal slices. A major effect of the drug at doses approximating those administered clinically to demented patients was a depression of synaptic transmission at the Schaffer collateral-commissural pathway in CA1. Detailed analysis showed that the inhibition is presynaptic and can be reduced by low doses of a specific blocker of adenosine A1 receptors, 8-cyclopentyltheophylline. Because Cerebrolysin does not contain a detectable amount of adenosine, the effect on adenosine A1 receptors must be indirect, perhaps by release of the endogenous agonist. This action of Cerebrolysin is consistent with a putative neuroprotective action underlying its clinical usage.
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PMID:Brain tissue hydrolysate acts on presynaptic adenosine receptors in the rat hippocampus. 856 89

1. Within the hypothalamus, adenosine has been reported to influence temperature regulation, sleep homeostasis, and endocrine secretions. The effects of adenosine on hypothalamic neurons have not been studied at the cellular level. Adenosine (5 nM-30 microM) showed no influence on intracellular Ca2+ or electrical activity in the presence of glutamate receptor antagonists D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione; consequently, we examined the role of adenosine in modulating the activity of glutamate in cultured hypothalamic neurons (n > 1,700) with fura-2 Ca2+ digital imaging and whole cell patch-clamp electrophysiology in the absence of glutamate receptor block. 2. When glutamate receptors were not blocked, adenosine (1-30 microM) and the selective adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA; 5 nM-1 microM) caused a large reduction in intracellular Ca2+ and electrical activity, suggesting that glutamate neurotransmission was critical for an effect of adenosine to be detected. Neuronal Ca2+ levels were reversibly depressed by CPA (50 nM), with a maximum depression of 90%, and these effects were blocked by coadministration of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 3. Ca2+ levels in immature neurons before the time of synaptogenesis were not affected by adenosine. Adenosine A1 receptor activation suppressed glutamate-mediated Ca2+ activity in neurons in vitro 8 to 73 days. 4. Adenosine (1 or 10 microM) caused a hyperpolarization of membrane potential and a reduction of large postsynaptic potentials arising from endogenously released glutamate. The administration of low concentrations of CPA (5 nM) decreased the frequency of glutamate-mediated, neuronally synchronized Ca2+ transients and the frequency of postsynaptic potentials. 5. To compare the relative effects of adenosine on hypothalamic neurons with cells from other brain regions, we assayed the effects of CPA on glutamate-mediated Ca2+ in hippocampal and cortical cultures. CPA (50 nM) reversibly depressed glutamate-mediated Ca2+ rises in hypothalamic neurons by 35%, compared with 54% in hippocampal neurons and 46% in cortical neurons. 6. If it does play a functional role, adenosine should be released by hypothalamic cells. In some neurons the adenosine A1 receptor antagonists cyclopentyltheophylline or DPCPX caused an increase in intracellular Ca2+, suggesting that adenosine was secreted by hypothalamic cells, tonically depressing glutamate-enhanced neuronal Ca2+. 7. To determine whether adenosine could exert a postsynaptic effect, we coapplied it with glutamate agonists in the presence of tetrodotoxin. Within subpopulations of hypothalamic neurons, adenosine and CPA either inhibited (18% of total neurons) or potentiated (6% of total neurons) responses to glutamate, N-methyl-D-aspartate, and kainate by > or = 20%. 8. In contrast to the modest effects found in neurons, responses of hypothalamic astrocytes to the application of glutamate or the metabotropic glutamate receptor agonist (+/-)-trans-1-amino-1,3-cyclopentanedicarboxylic acid were strongly potentiated by adenosine (mean +225%) and CPA. 9. Together, these findings suggest that adenosine exerts a major presynaptic effect and a minor postsynaptic effect in the modulation of glutamate neurotransmission in the hypothalamus, where it can play a significant role in blocking a large part of the glutamate-induced Ca2+ rise. In the absence of glutamate transmission, adenosine has relatively little effect on either neuronal intracellular Ca2+ or electrical activity.
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PMID:Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons. 859 3


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