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.

Abstract P300: A Novel Highly Selective Adenosine A 1 Receptor Agonist (VCP28) Reduces Ischemia/Reperfusion Injury at Concentrations that Do Not Affect Heart Rate

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Paul J White ◽  
Vijay Urmaliya ◽  
Colin W Pouton ◽  
Shane Devine ◽  
Peter Scammells
Keyword(s):  
Heart Rate ◽  
Receptor Agonist ◽  
Left Ventricular ◽  
Adenosine A1 Receptor ◽  
Rat Hearts ◽  
Adenosine A1 ◽  
Si Model ◽  
A1 Receptor ◽  
Cardioprotective Effects ◽  
Isolated Rat

Whilst adenosine A1 receptor agonists have repeatedly been shown to protect the ischaemic myocardium, the clinical use of these agents is limited by strong cardiodepressant effects. The cardioprotective effects of a novel adenosine A1 receptor agonist N6-(2,2,5,5-tetramethylpyrrolidin-1-yloxyl-3-ylmethyl) adenosine (VCP28) were compared with the selective adenosine A1receptor agonist N6-cyclopentyladenosine (CPA) in a H9c2(2–1) cardiac cell line-simulated ischemia (SI) model (12 hours) and a global ischemia (30 minutes) and reperfusion (60 minutes) model in isolated rat heart model. H9c2(2–1) cells were treated with CPA and VCP28 at the start of ischemia for entire ischemic duration, whereas isolated rat hearts were treated at the onset of reperfusion for 15 minutes. In a H9c2(2–1) cell SI model, CPA and VCP28 (100 nM) significantly (P , 0.05, n = 5–6) reduced the proportion of nonviable cells (30.88% 6 2.49% and 16.17% 6 3.77% of SI group, respectively) and lactate dehydrogenase efflux. In isolated rat hearts, CPA and VCP28 significantly (n = 6–8, P , 0.05) improved postischemic contractility (dP/dtmax, 81.69% 6 10.96%, 91.07% 6 19.87% of baseline, respectively), left ventricular developed pressure, and end diastolic pressure and reduced infarct size. The adenosine A1 receptor antagonist DPCPX abolished the cardioprotective effects of CPA and VCP28 in both models. At the concentrations used in the ischaemia models, VCP28 had no effect on heart rate, unlike CPA. In conclusion, the adenosine A1 receptor agonist VCP28 has cardioprotective equal effects to the prototype A1 agonist CPA at concentrations that have no effect on heart rate.

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.

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.

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