Adenosine receptors (AR) play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline (a non-selective, blood-brain-barrier penetrably AR antagonist) could attenuate the effects of YZG-330 [(2R,3S,4R,5R)-2-(hydroxymethyl-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner: within the next 3 hour after intragastric administration (ig) of 0.25, 1 or 4 mg . kg-1 YZG-330, the extreme values on body temperature decreasing were (1.2 ± 0.3) °C, (3.6 ± 0.4) °C (P<0.001) and (7.4±0.5) °C (P<0.001), separately; whereas the duration that body temperature below 34 °C were 0, (10±5) and (153±4) min, separately. Adenosine A1 receptor (A1R) antagonist (DPCPX) could effectively reverse YZG-330's effect on decreasing body temperature, with intraperitoneal administration of DPCPX (5 mg . kg-1) 20 min prior than YZG-330 (4 mg.kg-1, ig), the extreme value on body temperature decreasing was (3.5 ± 0.7) °C (P<0.001), the duration that body temperature below 34 °C was (8±6) min (P<0.001). However, adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG-330 at all. Combined with the fact that 8-SPT (a non-selective, blood-brain-barrier impenetrably AR antagonist) did not reverse the effect of YZG-330, we come to the conclusion that central-adenosine A, receptor plays a significant role on the thermal regulation effect of YZG-330.
Adenosine ; analogs & derivatives ; pharmacology ; Adenosine A1 Receptor Antagonists ; pharmacology ; Animals ; Body Temperature Regulation ; drug effects ; Mice ; Pyrimidines ; pharmacology ; Receptor, Adenosine A1 ; physiology ; Triazoles ; pharmacology ; Xanthines ; pharmacology

Cardio-renal syndromes are disorders of the heart and kidney wherein acute or long-term dysfunction in one organ may induce acute or long-term dysfunction of the other. Because of this complex organ interaction, management of cardiorenal syndrome must be tailored to the underlying pathophysiology. Clinical guidelines exist for the treatment of heart failure or renal failure as separate conditions. Thus far, however, there has been no consensus about managing patients with cardio-renal and reno-cardiac syndromes. Pharmacologic treatment remains a controversial subject. Standard cardiac drugs such as diuretics and inotropes may have limited effect because resistance often develops after long-term use. Recent studies of patients with acute cardio-renal syndromes have focused on newer therapies, including phosphodiesterase inhibitors, vasopressin antagonists, adenosine A1 receptor antagonists, and renal protective dopamine. Initial clinical trials of these agents have shown encouraging results in some patients with heart failure, but have failed to demonstrate a clear superiority over more conventional treatments. Similarly, the benefits of diuretics, aspirin, erythropoietin agents, and iron supplements for management of chronic cardiorenal syndromes are unknown.
Adenosine A1 Receptor Antagonists ; Aspirin ; Cardio-Renal Syndrome ; Consensus ; Diuretics ; Dopamine ; Erythropoietin ; Heart ; Heart Failure ; Humans ; Iron ; Kidney ; Phosphodiesterase Inhibitors ; Renal Insufficiency ; Vasopressins

This study is to examine the sedative, hypnotic and anticonvulsive effects of an adenosine analogue, WS090501. The spontaneous locomotor activity was recorded by open field equipment, and the EEG of rats was recorded by polyphysiograph. Pentylenetetrazol (PTZ)-induced seizure model was used. The spontaneous locomotor activity was decreased by WS090501 at various doses (0.06, 0.13, and 0.25 mg x kg(-1)), and the decreasing rate was 28.4%, 47.1% and 61.2% respectively. Furthermore, the effect of WS090501 on spontaneous locomotor activity of mice can be antagonized by DPCPX, a selective adenosine A1R antagonist, but cannot be antagonized by SCH58261, a selective adenosine A2AR antagonist. The NREM sleep was significantly increased by WS090501 (0.05 and 0.2 mg x kg(-1)), and the increasing rate was 27.6% and 102.8%, respectively, at 6th hour after administration. The REM sleep decreased significantly at the higher dose. PTZ induced serious convulsion in mice. The latency of convulsion was prolonged, and the number of seizure and mortality decreased after administration of WS090501. These results show that WS090501 has potent sedative, hypnotic and anticonvulsive effects, which may be mediated through adenosine A1R.
Adenosine ; analogs & derivatives ; antagonists & inhibitors ; pharmacology ; Adenosine A1 Receptor Antagonists ; pharmacology ; Adenosine A2 Receptor Antagonists ; pharmacology ; Animals ; Anticonvulsants ; antagonists & inhibitors ; pharmacology ; Convulsants ; Electroencephalography ; Hypnotics and Sedatives ; antagonists & inhibitors ; pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Motor Activity ; drug effects ; Pentylenetetrazole ; Pyrimidines ; pharmacology ; Rats ; Rats, Wistar ; Seizures ; chemically induced ; prevention & control ; Sleep ; drug effects ; Triazoles ; pharmacology ; Xanthines ; pharmacology

The effects of injection of adenosine into the renal artery on multi- and single-unit spontaneous discharges of renal afferent nerve fibers were investigated in anesthetized rabbits. The results obtained are as follows: (1) injection of 50, 100, and 200 nmol/kg adenosine into the renal artery increased the renal afferent nerve activity (ARNA) in a dose-dependent manner with unchanged arterial pressure; (2) pretreatment with 8-cyclopenthl-1,3-dipropylxanthine (DPCPX, 160 nmol/kg), an adenosine A1 receptor antagonist, partly abolished the effect of adenosine; and (3) pretreatment with a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methylester (L-NAME, 0.1 mmol/kg) significantly enhanced the ARNA response to adenosine. The results suggest that injection of adenosine into the renal artery activates ARNA via adenosine receptors in anesthetized rabbits and that nitric oxide may be involved in regulating the activity of renal sensory nerve fibers as an inhibitory neurotransmitter.
Adenosine ; pharmacology ; Adenosine A1 Receptor Antagonists ; Afferent Pathways ; drug effects ; physiology ; Animals ; Dose-Response Relationship, Drug ; Electrophysiology ; Female ; Injections, Intra-Arterial ; Kidney ; innervation ; Male ; Nerve Fibers ; drug effects ; physiology ; Nitric Oxide ; physiology ; Rabbits ; Renal Artery ; Xanthines ; pharmacology

AIMTo observe the effect of adenosine A, receptor antagonist on synaptic transmission in the dentate gyrus of hippocampus and its relations with NMDA receptor.

METHODSUsing electrophysiological technique to record the long-term potentiation (LTP), the relation between selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and NMDA receptor agonist/antagonist, in both basic synaptic transmission and 200 Hz high-frequency stimulation (HFS) induced LTP of the dentate gyrus of hippocampus in anesthetized rats, was studied.

RESULTSDPCPX (6 mg x L(-1), 5 microL, icv) or NMDA (0.2 mg x L(-1), 5 microL, icv) was shown not to affect the synaptic transmission in the dentate gyrus in rats. DPCPX was found not to affect the keeping of LTP induced by HFS after icv NMDA. But the basic synaptic transmission and the magnitude of LTP induced by HFS in the dentate gyrus after icv NMDA could be enhanced significantly by icv DPCPX in advance. DPCPX could not affect the magnitude of LTP inhibited by AP5 (0.5 mg x L(-1), 5 microL) NMDA receptor antagonist, but the inhibitory effect of AP5 on LTP could be antagonized by icv DPCPX in advance.

CONCLUSIONThe selective adenosine A1 receptor antagonist DPCPX could not affect the synaptic transmission in the dentate gyrus of hippocampus, but could significantly enhance the effect of NMDA receptor in both basic synaptic transmission and HFS induced LTP in the dentate gyrus of hippocampus in anesthetized rats.

2-Amino-5-phosphonovalerate ; pharmacology ; Adenosine A1 Receptor Antagonists ; Animals ; Dentate Gyrus ; drug effects ; physiology ; Long-Term Potentiation ; drug effects ; Male ; N-Methylaspartate ; pharmacology ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Synaptic Transmission ; drug effects ; Xanthines ; pharmacology

AIMTo study the effect of AMP579 and adenosine on potassium ionic (K+) or sodium ionic (Na+) channels and to elucidate ionic mechanisms underlying negative inotropic and antiarrhythmic effects of AMP579 and adenosine.

METHODSIonic channel currents of rat and guinea pig ventricular myocytes were recorded by patch clamp technique in whole-cell configuration.

RESULTSAdenosine showed a stronger activating effect on transient outward K+ current (I(to)) than AMP579, EC50 of adenosine and AMP579 were 2.33 and 8. 32 micromol x L(-1), respectively (P < 0.05). An adenosine A1 receptor blocker, 1,3-dipropyl-8-cyclopentylxanthine (PD116948), can abolish the effects of AMP579 and adenosine on I(to), demonstrating that the effect is mediated by adenosine A1 receptor. Adenosine exerted a more obvious inhibitory effect on delayed rectifier K+ current (IK) than AMP579. IC50 of adenosine and AMP579 were 1.21 and 2.31 micromol x L(-1), respectively (P < 0.05). AMP579 had a more powerful inhibitory effect on inward rectifier K+ current (IK1) than adenosine. IC50 of AMP579 and adenosine were 4.15 and 20.7 micromol x L(-1), repectively (P < 0.01). AMP579 and adenosine exerted a similar inhibitory effect on fast inward Na+ current (INA), IC50 of AMP579 and adenosine were 9.46 and 6.23 micromol x L(-1), respectively (P > 0.05).

CONCLUSIONAdenosine showed a stronger activating effect on I(to) than AMP579, however, the mechanism of AMP579 and adenosine activating I(to) was mediated by adenosine A1 receptor. AMP579 has a more powerful inhibitory effect on IK1, and less inhibitory effect on IK than adenosine. Both drugs have a similar inhibitory effect on INa. The negative inotropic and antiarrhythmic effects are related to these ionic mechanisms.

Adenosine ; chemistry ; pharmacology ; Adenosine A1 Receptor Antagonists ; Adenosine A2 Receptor Antagonists ; Animals ; Dose-Response Relationship, Drug ; Electric Stimulation ; Guinea Pigs ; Heart Ventricles ; cytology ; Imidazoles ; chemistry ; pharmacology ; Male ; Membrane Potentials ; drug effects ; Molecular Structure ; Myocytes, Cardiac ; cytology ; drug effects ; physiology ; Potassium Channels ; physiology ; Potassium Channels, Inwardly Rectifying ; physiology ; Pyridines ; chemistry ; pharmacology ; Rats ; Rats, Wistar ; Sodium Channels ; physiology ; Theobromine ; analogs & derivatives ; pharmacology ; Xanthines ; pharmacology

High level of adenosine A1 receptor-like immunoreactivity has been found in the CA2/CA3a region of adult rat hippocampus, but its roles in the neuronal activity or signal propagation in hippocampus and its intracellular cascade remain to be studied. In this study, we examined the relation between adenosine-3',5'-cyclic monophosphate (cAMP) cascade and suppression of synaptic transmission by endogenous adenosine through adenosine A1 receptor in the CA2 area. In transverse hippocampal slice, maximal electrical stimulation of the hilus region (0.6 mA) only evoked small population spikes (PSs) in the CA2 area (0.5 mV). In the presence of forskolin (20 micromol/L), a direct adenylate cyclase activator, PSs in CA2 were increased to 1.1 mV. When 8-cyclopentyltheophylline (8CPT, 2 micromol/L), an adenosine A1 receptor antagonist, was added in the presence of 20 micromol/L forskolin, PSs with an average amplitude of 4.7 mV were recorded in the CA2 area, much higher than the sum of the amplitude of PSs in the presence of forskolin and 8CPT alone. To test whether this synergistic potentiation results from the additive activation of cAMP cascade, the cAMP content in hippocampal slices was measured with enzyme immunoassay (EIA). Results showed that 8CPT did not increase the cAMP content in CA2 with or without forskolin. Co-application of forskolin and Ro 20-1724, a cAMP-specific phosphodiesterase-IV inhibitor, only increased PSs in CA2 to 1.3 mV but increased cAMP content by 4.4 times. On the other hand, co-application of 8CPT and 1, 9-dideoxyforskolin, a forskolin analog which has no effect on adenylate cyclase, did not mimic the synergistic effect of 8CPT and forskolin on PSs in CA2. These results indicate that up-regulation of adenylate cyclase activity and inhibition of adenosine A1 receptor activity synergistically facilitate the neuronal activity in the CA2 area and the effect of adenosine A1 receptor antagonist is via non-cAMP cascade. These data also suggest that acting on adenosine A1 receptors, endogenous and extragenous adenosine/adenosine A1 agonist(s) inhibit neuronal activity through different pathways.
Adenosine A1 Receptor Antagonists ; Adenylyl Cyclases ; metabolism ; Animals ; Colforsin ; pharmacology ; Cyclic AMP ; physiology ; Drug Synergism ; Hippocampus ; drug effects ; physiology ; Long-Term Potentiation ; drug effects ; Male ; Neurons ; drug effects ; physiology ; Rats ; Rats, Wistar ; Theophylline ; analogs & derivatives ; pharmacology

AIMTo study the effect of blocking adenosine A1 receptors on learning and memory and the relation with cholinergic and aminoacidergic nerve.

METHODSUsing step through test, spectrophotometry and HPLC method, the effect of selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.3, 0.15, 0.075, 0.03, 0.015 microgram, icv) on memory impairment by scopolamine (Scop, 3 mg.kg-1 i.p.) or 2-amino-5-phosphonovaleric (AP5, 2.5 ng, icv), acetylcholinesterase (AChE) activity and aminoacid level in brain of mice was studied.

RESULTSDPCPX was shown to significantly improve scopolamine-induced memory impairment, but not AP5-induced. The activity of AChE in mouse brain was significantly inhibited by large doses of DPCPX in vitro and in vivo test. DPCPX(0.3 microgram, icv) was shown to significantly increase the content of glutamate and aspartic acid in brain of mice. DPCPX (0.3, 0.15 microgram, icv) significantly decrease GABA and increase Glu/GABA in brain of mice.

CONCLUSIONThe selective adenosine A1 receptor antagonist DPCPX was shown to significantly improve scopolamine but not AP5-induced memory impairment. Large doses of DPCPX was shown to influence the AChE activity and the changes in aminoacid level in brain, especially increase Glu/GABA.

2-Amino-5-phosphonovalerate ; metabolism ; Acetylcholine ; metabolism ; Adenosine A1 Receptor Antagonists ; Animals ; Brain ; drug effects ; metabolism ; Female ; Glutamic Acid ; metabolism ; Learning ; drug effects ; Male ; Mice ; Random Allocation ; Scopolamine Hydrobromide ; Xanthines ; pharmacology ; gamma-Aminobutyric Acid ; metabolism