Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Population excitatory postsynaptic potentials (EPSPs) and population spikes evoked in area CA1 of hippocampal slices from aged Fischer 344 rats were significantly smaller in amplitude than responses obtained in slices from young Fischer 344 rats. 2. The A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) produced a concentration-dependent increase in synaptic potentials in slices from both young and aged rats. Low concentrations (1 nM) of 8-CPT were effective in producing increases in both population spike amplitudes and population EPSP slopes in young and aged rat slices. Response increases were maximized by 100 nM 8-CPT in slices from rats of both age groups. 3. Adenosine antagonism produced greater average increases in synaptic responses in hippocampal slices from aged rats at all concentrations tested (1.0 nM-1.0 microM). A qualitative age-related difference in the response to 8-CPT was also observed; 8-CPT produced a late component, consisting of multiple population spikes, in evoked responses in slices obtained from aged but not young rats. 4. Adenosine antagonism significantly increased the maximum evocable response (both spike amplitude and EPSP slope) in slices from aged rats, relative to increases observed in slices from young rats. This suggested that smaller synaptic potentials seen in slices from aged rats were in part due to greater levels of "tonic" adenosinergic inhibition. 5. Slices from young and aged rats were incubated in the adenosine reuptake inhibitor soluflazine (R64719; 1.0, 10, and 100 microM) and the inhibition of population EPSPs was observed for 60 min. No difference was observed in the rate of inhibition or the maximal level of inhibition produced by soluflazine, in slices from rats of either age group. 6. Application of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten- 5,10-imine hydrogen maleate (MK-801) and 2-amino-5-phosphonopentanoic acid (2-AP5), antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors, reduced the late multiple population spike component in slices from aged rats incubated in 8-CPT. A smaller direct effect of the NMDA antagonists was observed in slices from aged rats in the absence of 8-CPT treatment at maximal response levels. No effect of NMDA receptor antagonism was observed in slices from young rats under either condition. 7. Hippocampal tissue, from young and old rats utilized in the electrophysiological experiments, was assayed for A1 adenosine binding site density with a saturating concentration of radiolabeled agonist and antagonist. Guanine nucleotide modulation of agonist binding was also measured.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Age-dependence of effects of A1 adenosine receptor antagonism in rat hippocampal slices. 138 1

Adenosine A1 agonists have been shown to induce a variety of pharmacological effects. In New Zealand White rabbits, the topical administration of 500 micrograms of the relatively selective adenosine A1 receptor agonist R(-) phenylisopropyladenosine (R-PIA) produced a biphasic response in IOP in the ipsilateral eye: an initial ocular hypertension (3.5 +/- 1.4 mm of Hg) at 0.5 hour, followed by significant reduction in IOP (5 to 8 mm of Hg) from 2 to 6 hours postadministration. The IOP response to 50 and 165 micrograms of R-PIA demonstrated that the ocular hypotensive response to R-PIA was dose-related; however, no initial hypertension was observed at these lower doses. The ocular response to R-PIA was primarily unilateral with only a small reduction in contralateral IOP at 1 hour observed in animals treated with 500 micrograms. No significant change in pupil diameter was observed with any dose of R-PIA. Pretreatment with the adenosine antagonist CPT (10 mg/kg; i.p.) significantly inhibited the ocular hypotensive response to R-PIA. However, pretreatment with the cyclooxygenase inhibitor indomethacin (50 mg/kg; i.p.) did not alter the change in IOP induced by R-PIA. The administration of R-PIA once a day for five days demonstrated that tolerance does not develop in rabbits with repeated administration. These data demonstrate that the adenosine A1 agonist R-PIA can lower IOP. The unilateral nature and the inhibition by CPT supports the idea that this response is mediated by adenosine receptors located in the eye.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ocular hypotensive activity of the adenosine agonist (R)-phenylisopropyladenosine in rabbits. 160 41

The possible involvement of protein kinase C and/or a lipoxygenase product in the mechanism by which adenosine inhibits release of [3H]acetylcholine evoked by electrical pulses from [3H]choline-labelled hippocampal slices was examined. For comparison, the muscarinic autoreceptors were examined using carbachol. The order of potency of adenosine analogues (CHA = R-PIA greater than NECA much greater than CGS 21680, CV 1808) indicates that the adenosine receptor responsible is of the A1 subtype. Adenosine (10 microM) and R-PIA (0.1 microM) were virtually equiactive as inhibitors and were antagonized to an equal extent by 8-CPT with a potency (IC50 approximately 25 nM) which is also compatible with A1-receptor mediation. The effects of carbachol and of R-PIA were not antagonized by the lipoxygenase inhibitor NDGA (10 or 50 microM). Stimulation of protein kinase C by the phorbol ester 4 beta-phorbol 12,13-dibutyrate caused a concentration-dependent increase in stimulation-evoked 3H overflow, but did not antagonize the presynaptic inhibitory effect of R-PIA or carbachol (0.01-1 microM). Staurosporine (0.1 microM), which inhibited the stimulating effect of phorbol dibutyrate, did not alter the effects of carbachol or R-PIA. The presynaptic effects of phorbol dibutyrate, R-PIA and adenosine were reduced by pretreatment with N-ethylmaleimide (100 microM for 10 min), which inactivates G-proteins. The evoked transmitter release was unaffected by nifedipine (1 microM) in the presence and in the absence of phorbol dibutyrate. These results indicate that adenosine, by acting at presynaptic A1-receptors, reduces transmitter release by a mechanism that involves neither an NDGA-sensitive lipoxygenase nor protein kinase C. The results also indicate that the enhancement of transmitter release by phorbol esters is due to protein kinase C activation and that a G-protein may be involved in the effect but a dihydropyridine-sensitive L-type Ca2+ channel probably is not.
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PMID:Adenosine A1-receptor-mediated inhibition of evoked acetylcholine release in the rat hippocampus does not depend on protein kinase C. 226 53

Adenosine is thought to act as an endogenous anticonvulsant and neuroprotective substance in the brain. In the present study we compared neuronal death following status epilepticus (SE) induced in the presence of 8-cyclopentyl-1,3-dimethylxanthine (8-CPT), an A1-adenosine receptor antagonist, with that following SE induced by continuous hippocampal stimulation. Hippocampal damage was characterized using selective nerve and nonnerve cell markers. Six days after SE, both models produced similar patterns of CA1 and CA3 cell loss and selective loss of parvalbumin and hilar somatostatin-immunoreactive interneurons. Calbindin D28K-immunoreactive interneuron numbers and calbindin D28K immunoreactivity in dentate granule cells remained unchanged although calbindin D28K staining was lost in damaged CA1 neurons. Neuronal injury in these areas was also accompanied by reactive gliosis and microglial proliferation, as well as the production of basic fibroblast growth factor and insulin-like growth factor-1 by astrocytes. Although hippocampal damage appeared to be more severe after SE induced in the presence of 8-CPT, this may be due to the increased severity of SE generated in this model.
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PMID:Neuronal injury following electrically induced status epilepticus with and without adenosine receptor antagonism. 764 19

1. Conventional intracellular microelectrode techniques were used to subclassify P1 purinoceptors linked to reduction of cell input resistance, steady-state hyperpolarization of the membrane potential, or inhibition of fast e.p.s.ps, in neurones of microdissected myenteric plexus preparations from guinea-pig ileum. The potencies of P1 purinoceptor agonists were estimated in neurones that were current clamped to a fixed membrane potential. 2. In AH/Type 2 neurones, the A2 agonist, CGS 21680, the A1 agonist, CCPA or the mixed A1-A2 agonist, NECA, suppressed excitability by reducing input resistance (40-50% max.) and causing hyperpolarization (20-25 mV max.). CGS 21680 (0.1-1 microM) enhanced the after-hyperpolarizing potential. 3. From cumulative dose-response data, the potency order for reducing input resistance was CCPA (IC50 = 5.1 +/- 2.2 nM) >>> CGS 21680 (IC50 = 5.6 +/- 2.5 microM). This effect was reversed by the A1 antagonist, CPT (EC50 = 65 +/- 11 nM). 4. In contrast, the potency order for membrane hyperpolarization was CCPA (IC50 = 61 +/- 23 nM) = CGS 21680 (IC50 = 290 +/- 90 nM) > or = NECA (IC50 = 450 +/- 100 nM). Hyperpolarization elicited by CCPA was sensitive to the A1-A2 antagonist, DPSPX. 5. Agonists suppressed fast e.p.s.ps, but not DMPP responses, with an order of CCPA (IC50 = 8.1 +/- 3.0 nM) >>> CGS 21680 (IC30 = 10 +/- 2.9 microM). 6. In conclusion, the excitability of AH/Type 2 neurones is suppressed by activation of high affinity A l receptors that may be linked to a cyclic AMP-dependent pathway, leading to increase in calcium dependent potassium conductance and enhancement of the after-hyperpolarizing potential. Activation of lower affinity non A1 receptors linked to a cyclic AMP-independent pathway reduces excitability and leads mainly to a steady-state hyperpolarization. Adenosine also suppresses nicotinic cholinergic transmission by activating presynaptic high affinity Al receptors.
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PMID:Electrophysiological subtypes of inhibitory P1 purinoceptors on myenteric neurones of guinea-pig small bowel. 785 58

Adenosine has excitatory actions on neurotransmission in the superior colliculus. To investigate whether adenosine A1 or A2 receptors are involved in mediating these excitatory actions, the effect of A1 and A2 receptor agonists and antagonists on the evoked postsynaptic potentials (PSP) in the superficial grey layer were tested using slices of the superior colliculus. Application of both A1 agonists, such as CHA, R-PIA, and the A2 agonist, CGS-21680 increased the amplitude of the PSP. The increase in PSP amplitude occurred gradually over 20-30 min after application of these adenosine agonists. Application of the A1 antagonist 8-CPT, and the A2 antagonists, DMPX and CGS-15943, increased the amplitude of the PSP and could not antagonize the excitatory effect of adenosine. These results suggest that the mechanism of the excitatory effect of adenosine cannot be explained by the classical concept of A1 and A2 adenosine receptor subtypes which were identified by their effect on adenylate cyclase activity.
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PMID:Excitatory effects of adenosine receptor agonists and antagonists on neurotransmission in guinea pig superior collicular slices. 808 72

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

In order to define the purinergic receptors subtype involved in the control of cardiovascular activity, the effects of intracerebroventricular (icv 3rd ventricle) or intravenous (i.v.) injection of purinergic agonists and antagonists were evaluated on arterial blood pressure and heart rate of anaesthetized normotensive adult male rats. Adenosine (Ado) an A1 and A2 purinergic receptors agonist, N6-cyclohexyladenosine (CHA), an A1 receptor agonist and 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), an A2 purinergic receptor agonist, were administered in rats by icv (0.01-0.05-0.1 microgram) and i.v. (0.1-0.5-1 microgram/kg) injections. The animals treated with adenosine were either pretreated with an A1 (8-cyclopenthyl-1,3-dimethylxanthine, CPT) an A2 (3,7dimethyl-1-propargylxanthine, DMPX) or an A1-A2 (aminophylline, APH) purinergic receptor antagonist by icv (0.05 microgram) or i.v. (0.5 microgram/kg) injected or not at all pretreated. Ado, CPCA and CHA produced a dose-dependent decrease in arterial blood pressure and heart rate. The effects of CHA were less marked than those caused by Ado and CPCA. The icv and i.v. pretreatment with aminophylline, CPT and DMPX inhibited arterial hypotension and bradycardia induced by Ado, CHA and CPCA. The inhibitor effects of aminophylline and DMPX were stronger than those caused by CPT. These results showed that in the cerebral areas near the 3rd ventricle the purinergic system plays an important role in the control of cardiovascular function. The involvement of A2 purinergic receptors after administration of adenosine or its analogs on central and peripheral cardiovascular activity was also confirmed.
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PMID:Cardiovascular effects of adenosine and its analogs in anaesthetized rats. 835 64

The effect of endogenous adenosine on the delay to hypoxic depolarization (HD) was examined utilizing in vitro slices of gerbil hippocampus. Adenosine receptor antagonists were used to block the actions of adenosine during hypoxia, and the delay to HD was measured in the CA1 region. Both a broad spectrum antagonist (theophylline) and an A1 receptor-specific antagonist (8-cyclopentyl-1,3-dimethylxanthine; CPT) shortened the delay to HD. These findings indicate that endogenous adenosine working through A1 receptors prolongs the delay to HD. This effect may contribute to the neuroprotective influence of adenosine and its analogs.
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PMID:Endogenous adenosine delays the onset of hypoxic depolarization in the rat hippocampus in vitro via an action at A1 receptors. 850 12

1. Left ventricular interstitial adenosine and cardiac function were studied in open chest rats during adrenaline stimulation and P1-purinoceptor antagonism with 8-cyclopentyl-1,3-dimethylxanthine (8-CPT). 2. Cardiac microdialysate adenosine concentration was 0.10 +/- 0.01 mumol/L (n = 24) under basal conditions, giving an estimated interstitial adenosine concentration of 0.27 mumol/L. Stimulation with 3.2 and 8.0 micrograms/kg per min adrenaline increased the rate-pressure product (heart rate x systolic blood pressure) by 72 and 157%, respectively, and increased dialysate adenosine to 0.26 +/- 0.04 and 0.65 +/- 0.11 mumol/L (n = 12), respectively (interstitial concentrations of approximately 0.70 and 1.76 mumol/L). 3. Treatment with 60 micrograms/kg per min 8-CPT did not alter basal adenosine concentrations, but potentiated elevations in dialysate adenosine during infusion of 3.2 and 8.0 micrograms/kg per min adrenaline to 0.54 +/- 0.10 and 1.30 +/- 0.22 mumol/L, respectively (n = 12). Basal function and the response to 8.0 micrograms/kg per min adrenaline were unaltered by 8-CPT, whereas elevations in heart rate and rate-pressure product during stimulation with 3.2 micrograms/kg per min adrenaline were enhanced by 8-CPT (by up to 30%). 4. Studies in isolated hearts confirmed the inhibitory potency of 8-CPT at A1 vs A2 P1-purinoceptors (e.g. pK(B) of 7.7 +/- 0.2 and 6.4 +/- 0.1 for 5'-N-ethyl carboxamidoadenosine-mediated bradycardia and vasodilatation, respectively; n = 6). Studies in intact animals verified effective A1 blockade by 60 micrograms/kg per min 8-CPT, but also revealed some inhibition of A2-mediated responses. 5. In conclusion, the data show that cardiac interstitial adenosine levels exist within a physiologically active range in vivo and increase dose-dependently during graded adrenaline stimulation. Adenosine receptor antagonism enhances elevations in interstitial adenosine and modifies functional responses to moderate, but not high, doses of adrenaline. Whether 8-CPT-dependent elevations in interstitial adenosine are due to A1 inhibition vs inhibition of A2-mediated vasodilatation requires further investigation.
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PMID:Interstitial adenosine and function in rat heart in vivo: effects of adrenaline and 8-cyclopentyl-1,3-dimethylxanthine. 871 76


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