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

A2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer' s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A2B adenosine receptor antagonists and their interactions with A2B adenosine receptor were reviewed.
Adenosine ; pharmacology ; Adenosine A2 Receptor Antagonists ; Adenosine A3 Receptor Antagonists ; Adenosine-5'-(N-ethylcarboxamide) ; pharmacology ; therapeutic use ; Animals ; Anti-Asthmatic Agents ; therapeutic use ; Asthma ; drug therapy ; Humans ; Pulmonary Artery ; drug effects ; Structure-Activity Relationship ; 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

OBJECTIVETo observe whether adenosine Al receptor (Al R) mediated neuroprotection of Shenmai Injection (SI) on rat cerebral ischemia/reperfusion (I/R) injury.

METHODSThe focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). Totally 60 successfully modeled rats was divided into 5 groups according to randomized block principle, i.e., the model group, the SI group, the SI + AlR antagonist (1,3-dipropyl-8-cyclopentylxanthine, DPCPX) group, the AlR antagonist control group, and the dimethyl sulfoxide (DMSO) control group, 12 in each group. Besides, a sham-operation group was set up (n =12). SI at 15 mL/kg was peritoneally injected to mice in the SI group immediately after cerebral I/R. Equal volume of normal saline was injected to mice in the model group and the sham-operation group. DPCPX at 1 mg/mL was peritoneally injected to mice in the Al R antagonist control group 30 min before peritoneal injecting SI. DPCPX at 1 mg/kg and DMSO at 1 mL/kg were peritoneally injected to mice in the AlR antagonist control group and the DMSO control group 30 min immediately before cerebral I/R. Rats' neurobehavioral scores were assessed after 24 h reperfusion. The volume of cerebral infarction and Bcl-2 protein expression of cerebral infarction penumbra were also detected. Results Compared with the sham-operation group, neurobehavioral scores, the volume of cerebral infarction, and Bcl-2 protein expression increased (all P <0. 05). Compared with the model group, neurobehavioral scores and the volume of cerebral infarction obviously decreased, but Bcl-2 protein expression increased in the SI group (all P <0. 05). Compared with the SI group, neurobehavioral scores increased, the volume of cerebral infarction was obviously enlarged, and Bcl-2 protein expression was obviously reduced in the A1R antagonist control group (all P <0. 05).

CONCLUSIONSSI's neurobehavioral scores could be partially reversed in the Al R antagonist control group, the volume of cerebral infarction and Bcl-2 protein expression improved. AlR might possibly meditate neuroprotection of SI on MACO mire

Adenosine ; Animals ; Brain Ischemia ; drug therapy ; Drug Combinations ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Infarction, Middle Cerebral Artery ; Mice ; Neuroprotection ; physiology ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptor, Adenosine A1 ; metabolism ; Reperfusion Injury ; drug therapy ; Xanthines

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

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

OBJECTIVETo investigate the effects of propentofylline on the expressions of glial fibrillary acidic protein (GFAP) and TNF-alpha and its action mechanism in the rat model of chronic prostatitis pain (CPP).

METHODSWe equally randomized 30 male SD rats to groups A (sham operation), B (CPP model) and C (propentofylline intervention). After modelling, the rats in group C received intraperitoneal injection of propentofylline at 2 mg/kg, while those in groups A and B were injected intrathecally with the same dose of normal saline. At 15 days after the treatment, we examined the expressions of GFAP in the spinal cord and TNF-alpha in the prostate by immunohistochemistry.

RESULTSThe levels of GFAP and TNF-alpha were obviously lower in group A (2.56 +/- 0.16 and 1.34 +/- 0.05) than in B (16.79 +/- 0.72 and 3.46 +/- 0.05) and C (8.83 +/- 0.63 and 2.25 +/- 0.05), significantly increased in B as compared with A (P < 0.05). And the increase was markedly less in group C than in B (P < 0.05).

CONCLUSIONPropentofylline inhibits chronic prostatitis pain in the rat model by suppressing the activation of astroglia and the release of inflammatory mediators.

Animals ; Astrocytes ; metabolism ; Chronic Disease ; Chronic Pain ; drug therapy ; metabolism ; Glial Fibrillary Acidic Protein ; metabolism ; Male ; Prostatitis ; drug therapy ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; Xanthines ; pharmacology ; therapeutic use

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

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

We examined the antiallodynic interaction between gabapentin and adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation for drug administration. Mechanical allodynia was measured by applying von Frey filaments. Gabapentin and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED50). Fractions of ED50s were administered concurrently to establish the ED50 of the drug combination. The drug interaction between gabapentin and R-PIA was analyzed using the isobolographic method. Adenosine A1 receptor antagonist was administered intrathecally to examine the reversal of the antiallodynic effect. Locomotor function changes were evaluated by rotarod testing. Intrathecal gabapentin and R-PIA and their combination produced a dose-dependent antagonism against mechanical allodynia without severe side effects. Intrathecal gabapentin synergistically enhanced the antiallodynic effect of R-PIA when coadministered. There were no significant changes in rotarod performance time, except gabapentin 300 microgram. In the combination group, the maximal antiallodynic effect was reversed by A1 adenosine receptor antagonist. These results suggest that activation of adenosine A1 receptors at the spinal level is required for the synergistic interaction on the mechanical allodynia.
Adenosine/administration & dosage/*analogs & derivatives ; Amines/*administration & dosage ; Animals ; Cyclohexanecarboxylic Acids/*administration & dosage ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Injections, Spinal ; Ligation ; Male ; Pain/*drug therapy ; Rats ; Rats, Sprague-Dawley ; Receptor, Adenosine A1/drug effects/physiology ; Spinal Nerves/*injuries ; Xanthines/pharmacology ; gamma-Aminobutyric Acid/*administration & dosage