Adenosine Modulation of Calcium Currents and Presynaptic Inhibition of GABA Release in Suprachiasmatic and Arcuate Nucleus Neurons

1997 ◽  
Vol 77 (6) ◽  
pp. 3035-3047 ◽  
Author(s):  
Gong Chen ◽  
Anthony N. van den Pol
Keyword(s):  
Presynaptic Inhibition ◽  
Receptor Agonist ◽  
Arcuate Nucleus ◽  
Gaba Release ◽  
Calcium Currents ◽  
Whole Cell ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Arcuate Neurons ◽  
A2 Receptors

Chen, Gong and Anthony N. van den Pol. Adenosine modulation of calcium currents and presynaptic inhibition of GABA release in suprachiasmatic and arcuate nucleus neurons. J. Neurophysiol. 77: 3035–3047, 1997. Adenosine modulation of calcium channel currents and synaptic γ-aminobutyrate (GABA) release was investigated with whole cell voltage-clamp recordings in rat suprachiasmatic nucleus (SCN) and arcuate nucleus cultures ( n = 94). In SCN cultures, ∼70% of the neurons showed a reversible inhibition of whole cell barium currents on the application of adenosine or its analogues. Adenosine at 1 μM reduced the amplitude of the barium currents by ∼27%. In contrast to the significant reduction in the amplitude, the rising and decaying phases of the barium currents, and the inverted bell shape of the current-voltage curve of the barium currents, were not changed by adenosine. The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 100 nM) and the adenosine A2 receptor agonist N6-[2-(3,5-dimethoxyphenyl)-ethyl]adenosine (DPMA; 100 nM) inhibited the barium currents by 21% and 16%, respectively, in SCN neurons, indicating both A1 and A2 receptor actions. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM) significantly reduced the effect of CPA but did not change the effect of DPMA on the barium currents. In the presence of tetrodotoxin to block action potentials, the frequency, but not the amplitude, of miniature inhibitory postsynaptic currents was significantly reduced (46%) by 1 μM adenosine, suggesting a presynaptic mechanism of adenosine action. In support of this suggestion, the postsynaptic GABA receptor responses were not influenced by 1 μM adenosine in the majority of SCN neurons. Most solitary self-innervating SCN neurons in microisland cultures were GABAergic. In these cells, the evoked autaptic GABA release (inhibitory postsynaptic current) was significantly inhibited by adenosine (37%), CPA (27%), and DPMA (28%), indicating that both A1 and A2 receptors were present in presynaptic axons. Similar to the effect in SCN neurons, adenosine inhibited both barium currents and GABA release in arcuate neurons. The reduction of whole cell barium currents by adenosine (1 μM), CPA (100 nM), and DPMA (100 nM) was 24, 17, and 19%, respectively. In solitary self-innervating arcuate neurons, adenosine inhibited the evoked GABA release (inhibitory postsynaptic current) by ∼48%. We conclude that both adenosine A1 and A2 receptors are present in the SCN and arcuate nucleus of the hypothalamus. Adenosine inhibits calcium currents and presynaptically reduces inhibitory GABA neurotransmission.

Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism

1992 ◽  
Vol 263 (5) ◽  
pp. H1460-H1465 ◽  
Author(s):  
R. D. Lasley ◽  
R. M. Mentzer
Keyword(s):  
Receptor Agonist ◽  
Myocardial Function ◽  
Left Ventricular ◽  
Adenosine A1 Receptor ◽  
Extracellular Adenosine ◽  
Adenosine A2 Receptor ◽  
Rat Hearts ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
A2 Receptors

The effects of adenosine in the nonischemic heart have been shown to be mediated via its binding to extracellular adenosine A1 and A2 receptors located predominantly on myocytes and endothelial cells, respectively. We tested the hypothesis that the beneficial effect of adenosine on postischemic myocardial function is mediated via an adenosine A1 receptor mechanism. Isolated rat hearts perfused at constant pressure (85 cmH2O) were subjected to 30 min of global no-flow ischemia (37 degrees C) and 45 min of reperfusion. Hearts treated with adenosine (100 microM) and the adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 0.25 microM) recovered 72 +/- 4 and 70 +/- 4% of preischemic left ventricular developed pressures (LVDP), respectively, after 45 min of reperfusion compared with untreated hearts (54 +/- 3% of preischemic LVDP). Adenosine and CHA hearts exhibited greater myocardial ATP contents than control hearts after 10 min of ischemia, but there were no differences in tissue ATP levels after 30 min of ischemia. In contrast, hearts treated with the adenosine A2 receptor agonist phenylaminoadenosine (0.25 microM) failed to demonstrate improved postischemic function (52 +/- 5%). The addition of the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the cardioprotective effect of adenosine (57 +/- 4%). These results suggest that adenosine enhances postischemic myocardial function via an A1 receptor mechanism.

Adenosine A1 and A2 receptors mediate tone-dependent responses in feline pulmonary vascular bed

1996 ◽  
Vol 270 (1) ◽  
pp. H200-H207 ◽  
Author(s):  
D. Y. Cheng ◽  
B. J. DeWitt ◽  
F. Suzuki ◽  
C. F. Neely ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Receptor Agonist ◽  
Adenosine A1 Receptor ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Alpha Beta ◽  
Low Tone ◽  
A2 Receptors

Adenosine produces tone-dependent pulmonary vascular responses; however, the adenosine receptor subtype mediating these responses is unknown. In the present study, the adenosine receptor subtypes mediating tone-dependent responses were investigated, Intralobar injections of adenosine,ATP, and analogues under low-tone conditions caused dose-related increases in lobar arterial pressure; the order of potency was alpha,beta-methylene ATP (alpha,beta-metATP) > N6-cyclopentyladenosine (CPA) > ATP > adenosine. Under low-tone conditions, pressor responses to adenosine, ATP, and CPA, an adenosine A1-receptor agonist, were reduced by KW-3902, an adenosine A1-receptor antagonist, whereas KW-3902 and meclofenamate had no effect on responses to alpha,beta-metATP, norepinephrine, serotonin, or angiotensin II. Under elevated-tone conditions, injections of adenosine, ATP, and analogues caused dose-related decreases in lobar arterial pressure, and adenosine was 10-fold less potent than 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), an A2-receptor agonist, and ATP. KF-17837, an A2-receptor antagonist, reduced vasodilator responses to adenosine and CPCA, whereas responses to ATP, isoproterenol, diethylamine-NO, lemakalim, and bradykinin were not changed. The vasodilator responses to adenosine were not attenuated by Nw-nitro-L-arginine benzyl ester, methylene blue, or U-37883A. These results suggest that vasoconstrictor responses to adenosine are mediated by A1 receptors and the release of vasoconstrictor prostanoids, and that, under elevated-tone conditions, vasodilator responses are mediated by A2 receptors but not the release of nitric oxide or the activation of guanylate cyclase or K+ATP channels.

Contribution of adenosine to isoproterenol-stimulated prostacyclin production in rabbit heart

1992 ◽  
Vol 263 (1) ◽  
pp. H218-H225
Author(s):  
C. Cano ◽  
Z. Qureshi ◽  
S. Carter ◽  
K. U. Malik
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Rabbit Heart ◽  
Mechanical Function ◽  
Cgs 21680 ◽  
A1 Receptor ◽  
Prostacyclin Production ◽  
Prostacyclin Synthesis ◽  
A2 Receptors ◽  
Krebs Henseleit Buffer

This study investigated adenosine's contribution to isoproterenol-stimulated prostacyclin production, measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) output, and mechanical function in the isolated rabbit heart perfused with Krebs-Henseleit buffer. The isoproterenol-induced increase in 6-keto-PGF1 alpha was diminished by adenosine (10 microM), the A1 receptor antagonist 1,3-dipropyl, 8-cyclopentylxanthine (DPCPX 0.06 microM), and the A2 receptor agonist CGS-21680 (0.6 microM); CGS-21680 did not decrease heart rate (HR) or myocardial contractility (dP/dt(max)). The isoproterenol-induced increase in 6-keto-PGF1 alpha was potentiated by the A1 receptor agonist 1-deaza,2-chloro,N6-cyclopentyladenosine (DCCA, 0.6 microM) and the A2 receptor antagonist 3,7-dimethyl,1-propargylxanthine (DMPX, 6 microM). The isoproterenol-induced increase in dP/dt(max) and HR was diminished by adenosine, DCCA, and DMPX. DPCPX enhanced dP/dt(max) and HR and prevented the decrease by adenosine and DCCA of the isoproterenol-induced increase in HR and dP/dt(max); the increase by DCCA but not the decrease by adenosine in 6-keto-PGF1 alpha output was abolished. DMPX abolished the effect of adenosine and CGS-21680 to reduce isoproterenol-stimulated 6-keto-PGF1 alpha. These data suggest that adenosine generated in response to isoproterenol attenuates its effect on HR and dP/dt(max) through A1 receptors and on prostacyclin synthesis via A2 receptors.

Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons

1995 ◽  
Vol 74 (5) ◽  
pp. 2150-2162 ◽  
Author(s):  
K. Obrietan ◽  
A. B. Belousov ◽  
H. C. Heller ◽  
A. N. van den Pol
Keyword(s):  
Electrical Activity ◽  
Glutamate Receptor ◽  
Receptor Agonist ◽  
Adenosine A1 Receptor ◽  
Receptor Antagonists ◽  
Hypothalamic Neurons ◽  
Postsynaptic Potentials ◽  
Adenosine A1 ◽  
Hypothalamic Cells ◽  
A1 Receptor

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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