No abstract available.
Korea* ; Myocardial Infarction* ; Purinergic P2Y Receptor Antagonists*

Purinergic P2Y Receptor Antagonists ; Consensus ; Cardiovascular System ; Cardiology ; Asia

The aim of this study is to investigate the effect of isosorbide-5-mononitrate (ISMN) on the electric field stimulation induced sympathetic purinergic vasoconstriction of the rabbit saphenous arterial rings. Isometric vasoconstrictive responses to electric field stimulation and to exogenous noradrenaline and adenosine triphosphate were recorded. We found that the vasoconstrictive responses to electric field stimulation (15 V, 1 ms pulse duration, 2 - 16 Hz) were frequency-dependant in the rabbit saphenous arterial rings, and abolished by tetrodotoxin (0.1 micromol x L(-1)). The alpha1-adrenoceptor antagonist prazosin (1 micromol x L(-1)) did not affect the vascular responses to the electric field stimulation (2 -8 Hz). After a combination treatment with both alpha,beta-meATP (3 micromol x L(-1), desensitizing P2X1 receptors) and prazosin (1 micromol x L(-1)), the vasoconstrictive responses to electric field stimulation were abolished. When the arterial preparation was treated with ISMN (one preparation was exposed to only one concentration of ISMN), ISMN at 0.1 mmol x L(-1) significantly inhibited the vasoconstriction induced by electric stimulation at 8 Hz, 0.3 and 1.0 mmol x L(-1) significantly inhibited the vasoconstrictive responses to electric stimulation at 2 - 16 Hz. The highest concentration of ISMN (1.0 mmol x L(-1)) reduced the vasoconstrictive responses by 46% (2 Hz), 47% (4 Hz), 34% (8 Hz) and 22% (16 Hz), separately. ISMN (0.3 and 1.0 mmol x L(-1)) did not affect the vascular responses to exogenous noradrenaline (0.01-100 micromol x L(-1)) and adenosine triphosphate (1 mmol x L(-1)). It is reasonable to suggest that ISMN inhibits the purinergic vasoconstriction induced by sympathetic nerve stimulation via a prejunctional mechanism.
Adenosine Triphosphate ; analogs & derivatives ; pharmacology ; Adrenergic alpha-Antagonists ; pharmacology ; Animals ; Arteries ; drug effects ; Delayed-Action Preparations ; Electric Stimulation ; Isosorbide Dinitrate ; administration & dosage ; analogs & derivatives ; pharmacology ; Male ; Norepinephrine ; pharmacology ; Prazosin ; pharmacology ; Purinergic P2 Receptor Agonists ; Rabbits ; Receptors, Purinergic P2X ; Vasoconstriction ; drug effects

P2X7 receptor is a member of ATP-gated non-selective cation channels. P2X7 receptor is widely distributed in vivo, and its expression is always observed to be up-regulated in the pathological inflammatory circumstances. P2X7 receptor has an unusual property of forming membrane pore during prolonged agonist exposure or high concentrations of agonist activation, different from other members of P2X receptors (P2X1-6). Because of this property, P2X7 receptor has been implicated in inflammatory cytokine release, and is closely related to inflammatory diseases. With the wide application of the P2X7-knockout animal model and specific P2X7 receptor antagonists in inflammatory disease research, P2X7 receptor is emerging as a new target for the treatment of inflammatory diseases. This article will review the recent progress regarding the effect of P2X7 receptor on inflammatory diseases and its mechanism.
Animals ; Cytokines ; metabolism ; Disease Models, Animal ; Inflammation ; metabolism ; Purinergic P2X Receptor Antagonists ; pharmacology ; Receptors, Purinergic P2X7 ; metabolism

BACKGROUND AND OBJECTIVES: Increased bleeding rates with standard dose prasugrel have led to increased questions about the effectiveness and safety of the lower maintenance dose. We compared platelet inhibitory efficacy between low dose prasugrel and standard dose clopidogrel in patients on maintenance dose dual antiplatelet therapy. SUBJECTS AND METHODS: Forty-three patients who underwent percutaneous coronary intervention were randomized to receive 75 mg clopidogrel (n=23) or 5 mg prasugrel (n=20). Another 20 patients were allocated to 10 mg prasugrel as a reference comparison group. All patients (weight, > or =60 kg; age, <75 years) had been receiving 100 mg aspirin and 75 mg clopidogrel daily. The platelet function test was performed at baseline and 30 days after randomization. The primary endpoint was P2Y12 reaction unit (PRU) at 30 days between 5 mg prasugrel and 75 mg clopidogrel. RESULTS: No differences in baseline PRU values were observed among the three groups. The prasugrel (5 mg) group had a significantly lower PRU value compared with that of 75 mg clopidogrel (174.6+/-60.2 vs. 223.4+/-72.9, p=0.022) group at 30 days, whereas the 10 mg prasugrel group showed a lower PRU value (71.9+/-34.4) compared with that of the 5 mg prasugrel (p<0.001). The rate of high on-treatment platelet reactivity (PRU >235) was significant lower in the 5 mg prasugrel group than that in the 75 mg clopidogrel group (15.0% vs. 56.5%, p=0.010). CONCLUSION: Prasugrel (5 mg) is more potent antiplatelet therapy than 75 mg clopidogrel in non-low body weight and non-elderly patients on a maintenance dose dual antiplatelet therapy.
Aspirin ; Body Weight ; Hemorrhage ; Humans ; Percutaneous Coronary Intervention* ; Platelet Function Tests ; Purinergic P2Y Receptor Antagonists ; Random Allocation ; Prasugrel Hydrochloride

BACKGROUNDThe mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known. The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves.

METHODSEight-week-old male C57BL/6 mice were used. For each exposure time point, eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression. Whereas in the 21 days-Brilliant Blue G (BBG, a selective P2X7R antagonist) study, 48 mice were randomly divided into CIH group, BBG-treated CIH group, RA group and BBG-treated RA group. The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR). The spatial learning was analyzed by Morris water maze. The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Western blotting. The expressions of tumor necrosis factor α, interleukin 1β (IL-β), IL-18, and IL-6 were measured by real-time PCR. The malondialdehyde and superoxide dismutase levels were detected by colorimetric method. Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method.

RESULTSThe P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure. In the BBG study, the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test. The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group. BBG alleviated CIH-induced neural injury and consequent functional deficits.

CONCLUSIONSThe P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

Animals ; Disease Models, Animal ; Hypoxia ; Male ; Metabolic Networks and Pathways ; Mice ; Mice, Inbred C57BL ; Purinergic P2 Receptor Antagonists ; pharmacology ; Receptors, Purinergic P2X7 ; analysis ; physiology ; Rosaniline Dyes ; pharmacology ; Sleep Apnea, Obstructive ; metabolism

PURPOSE: To simultaneously monitor electrical discharges in various bladder regions and the external urethral sphincter (EUS) during voiding contractions, and to assess the functional role of myogenic modulation of the lower urinary tract (LUT) by ionotropic purinergic receptors containing the P2X3 subunit. METHODS: Female Sprague-Dawley rats were anesthetized with urethane, and implanted with a suprapubic catheter for open cystometry. Flexible microelectrodes were placed ventrally in the bladder dome, upper bladder, lower bladder, and bladder base, along with the middle section of the exposed EUS. Intravesical P2X3-containing receptors were blocked with AF-323, a specific P2X3-P2X2/3 receptor antagonist. A digital electrophysiology amplifier was used to record electrical and cystometric signals throughout the LUT. RESULTS: Electrical activity in the LUT started before effective voiding contractions. Bladder pressure and electrical waveforms showed consistent out-of-phase activity when compared with the recordings made at the EUS. This pattern was also observed during voiding contractions in the presence of AF-353, supporting the hypothesis that during bladder distension, activation of P2X3-containing receptors is required for voiding contractions. Furthermore, the inhibition of P2X3-containing receptors significantly decreased the amplitude of electrical signals in the urinary bladder, but not the base or EUS. CONCLUSIONS: Our results provide novel information about the regulation of the micturition process by P2X3-containing receptors located in the inner layers of the bladder.
Animals ; Catheters ; Electrophysiology ; Female* ; Humans ; Lower Urinary Tract Symptoms ; Microelectrodes ; Purinergic P2X Receptor Antagonists ; Rats* ; Rats, Sprague-Dawley ; Receptors, Purinergic ; Urethane ; Urethra ; Urinary Bladder* ; Urinary Tract ; Urination*

BACKGROUND/AIMS: Platelet counts and characteristics can influence platelet reactivity during antiplatelet therapy. We compared the effects of both platelet count and indices on platelet reactivity between patients who were treated with either clopodogrel or ticagrelor. METHODS: Patients with coronary artery disease who underwent percutaneous coronary intervention were randomly assigned to either the clopidogrel (n = 63) or ticagrelor (n = 65) groups. Platelet count, platelet indices (including mean platelet volume, platelet distribution width, platelet large cell ratio, and immature platelet fraction), and platelet reactivity were measured before intervention, and 48 hours and 30 days post-intervention. High on-treatment platelet reactivity (HPR) was defined as ≥ 47 unit as assessed by multiple electrode platelet aggregometry. RESULTS: Baseline platelet reactivity was similar between the two groups; however, at 48 hours and 30 days, platelet reactivity was significantly lower in the ticagrelor group than in the clopidogrel group. Platelet count, mean platelet volume, platelet distribution width, platelet large cell ratio, and immature platelet fraction were significantly correlated with platelet reactivity in the clopidogrel group; however, these correlations were attenuated in the ticagrelor group. The use of clopodogrel (hazard ratio [HR] 4.1, 95% confidence interval [CI] 1.4–11.9; p = 0.010) and platelet count (HR 9.7, 95% CI 2.9–32.7; p = 0.001) were independent predictors for 30 day HPR. Platelet count was an independent predictor of HPR in the clopidogrel group but not in the ticagrelor group. CONCLUSIONS: Platelet count and indices are significantly correlated with platelet reactivity. However, antiplatelet treatment with ticagrelor could overcome these associations.
Blood Platelets* ; Coronary Artery Disease ; Electrodes ; Humans ; Mean Platelet Volume ; Percutaneous Coronary Intervention ; Platelet Count* ; Platelet Function Tests ; Purinergic P2Y Receptor Antagonists

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

To investigate the protective effects of P2X7 receptor (P2X7R) inhibitor against cerebral ischemia/reperfusion (I/R) injury in rats and the possible mechanisms.
 Methods: The neurological deficit of rats was evaluated by Longa score. The infarct volume was examined by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression levels of extracellular signal-regulated kinase (ERK), phosphorylation extracellular signal-regulated kinas p-ERK), connexin 43 (Cx43), Bax, Bcl-2 and cleaved caspase-3 were detected by Western blot.
 Results: Compared with sham group, the neurobehavioral score (P<0.05) and cerebral infarct volume (P<0.01) of rats in I/R group was increased. Compared with I/R group, brilliant blue G (BBG, the antagonist of P2X7R) or PD98059 (the inhibitor of EKR kinase) could reduce the neurobehavioral score (P<0.01) and cerebral infarct volume significantly (P<0.05). The neurobehavioral score and cerebral infarct volume was further decreased (P<0.05) when rats were treated with both BBG and PD98059. Compared with I/R group, the expression levels of p-ERK, Cx43, cleaved caspase-3 and the ratio of Bax/Bcl-2 were decreased by BBG or PD98059 pretreatment, and the protective effects were further enhanced when rats were treated with both BBG and PD98059 (P<0.05).
 Conclusion: Inhibition of P2X7R reduces the cerebral I/R injury of rats. ERK inhibition is probably involved in the protective effects of P2X7R inhibitor against cerebral I/R injury, which may be related to the reduction of Cx43 and cleaved caspase-3, and the ratio of Bax/Bcl-2.
Animals ; Brain Ischemia ; drug therapy ; prevention & control ; Gene Expression Regulation ; drug effects ; Phosphorylation ; drug effects ; Purinergic P2X Receptor Antagonists ; pharmacology ; therapeutic use ; Rats ; Receptors, Purinergic P2X7 ; Reperfusion Injury ; drug therapy ; prevention & control