Levels Of Adenosine Receptors Research Articles

Adenosine plasma levels and adenosine receptor levels determine the outcome of adenosine test and head-up tilt test in syncopal patients with a normal heart

Abstract Background/Introduction The neurohumoral profile underlying the manifestation of reflex syncope remains incompletely understood. Adenosine plasma (ADP) and adenosine receptor (ADR) levels may differentiate the outcomes of head-up tilt table test (HUTT) and adenosine test (ADT) but their role in the diagnostic evaluation of patients with syncope has yet to be determined. Purpose We sought to assess the ADP and ADR levels in patients without structural heart disease who underwent HUTT and ADT tests as part of the diagnostic workup of syncope. We specifically investigated differences in the outcomes of the HUTT and ADT tests as well as to the ADP levels during HUTT. Methods HUTT and ADT were performed as per the standard protocols. ADT was considered positive in the event of asystole >6 seconds or heart block for >10 seconds after intravenous Adenosine 0.15 mg/kg administration in the supine position. ADP levels were assessed at three timepoints during the HUTT: at baseline (supine), immediately after bed tilt and, in cases of a positive HUTT, at the time of syncope. Patients were categorized in quintiles of very low, low, intermediate, high and very high baseline ADP levels. We also assessed the A2A ADR levels of monocytes. Results We prospectively analyzed 124 patients (71 women, age 46.78±21.01 years). ADT was positive in 12.9% of patients and HUTT in 44.4% of patients. Patients with very low baseline ADP levels (lowest quintile) more frequently presented with a positive ADT (odds ratio [OR] 4.08, 95% Confidence Interval [CI] 1.40 to 13.13, p<0.05). Baseline ADP did not differ between patients with positive and negative HUTT. However, patients with vasodepressor response to HUTT exhibited increase in ADP from baseline to bed tilt (0.33±1.03 vs. 0.42±1.14 ppm/Um/L, p<0.05) and in syncope (0.70±1.89, P<0.05), while no difference was noted in patients with cardioinhibitory or mixed response. Patients with positive ADT and negative HUTT had higher ADR levels (221.5±88.56 MFI) as compared to patients with negative ADT and positive HUTT (59.78±83.65 MFI, p<0.05) and to patients with positive ADT and HUTT (33.29±35.77 MFI, p<0.05). Within patients with positive HUTT, those with onset of syncope in the Isoprenaline provocation phase (>20 min) had lower ADR levels (80.88±238.98 vs 89.43±96.08 MFI, p<0.05). Conclusion(s) Baseline ADP levels are related to the outcome of ADT while an ADP increase immediately after bed tilt and in syncope is evident in vasodepressor response to HUTT. Higher ADR levels are related to positive ADT and negative HUTT. Lower ADR levels are associated with more delayed onset of syncope during HUTT. ADP and ADR levels warrant further investigation as they may characterize a subset of patients with specific responses to ADT and HUTT and may be implicated in the pathophysiology of reflex syncope. Funding Acknowledgement Type of funding sources: None.

Baseline adenosine plasma levels indicate differential response to adenosine test and head-up tilt test in syncopal patients

Abstract Background/Introduction Head-up tilt table test (HUTT) and Adenosine test (ADT) can be useful in the diagnostic evaluation of syncope. Adenosine plasma (ADP) and Adenosine receptor (ADR) levels may differentiate the outcomes of HUTT and ADT but their precise role in the risk stratification of patients with syncope remains elusive. Purpose We sought to assess the ADP and ADR levels in patients without structural heart disease who underwent HUTT and ADT tests as part of the diagnostic workup of syncope. We specifically investigated differences in the outcomes of the HUTT and ADT tests as well as to the ADP levels during HUTT according to the baseline ADP levels. Methods HUTT and ADT were performed as per the standard protocols. ADT was considered positive in the event of asystole >6 seconds or heart block for >10 seconds after intravenous Adenosine 0.15 mg/kg administration in the supine position. ADP levels (ppm/Um/L) were assessed at three timepoints during the HUTT: at baseline (supine), immediately after bed tilt and, in cases of a positive HUTT, at the time of syncope. Patients were categorized in terciles of low, intermediate and high baseline ADP levels. We also assessed the A2A ADR levels of monocytes. Results We prospectively analyzed 106 patients (62 women, age 46.87±20.63 years). ADT was positive in 14.2% of patients and HUTT in 47.2% of patients. Females were more likely to have low ADP levels (odds ratio [OR] 2.70, 95% Confidence Interval [CI] 1.04 to 6.94, p<0.05). Patients with low baseline ADP levels showed a trend for positive ADT (OR 3.15, 95% CI 1.05 to 10.85, p=0.07), while patients with high baseline ADP levels showed a trend for negative HUTT (OR 2.35, 95% CI 0.94 to 5.90, p=0.075). Within patients with positive HUTT, those with low baseline ADP levels, showed an increase in ADP in the tilt phase (0.063 vs 0.027 ppm/Um/L, p<0.05) but not at the time of syncope (0.045 ppm/Um/L) while those with intermediate baseline ADP levels showed an increase in ADP in the tilt phase (0.16 vs 0.095 ppm/Um/L, p<0.05) which persisted during syncope (0.18 ppm/Um/L, p<0.05). Patients with high baseline ADP levels did not exhibit differences in ADP during positive HUTT. Higher baseline ADP levels were associated with smaller increases in the tilt phase (Pearson's r −0.621, p<0.001). ADR levels in patients with positive HUTT correlated positively with baseline ADP levels (Pearson's r 0.878, p<0.001). Conclusion(s) Baseline ADP levels may be related to the outcome of ADT and HUTT. ADP increases during HUTT except for patients with high baseline ADP. ADP and ADR levels warrant further investigation as they may characterize a subset of patients with specific responses to HUTT and may be implicated in the pathophysiology of reflex syncope. Funding Acknowledgement Type of funding source: None

Effect of pulsed electromagnetic field exposure on adenosine receptors in rat brain

Different effects of pulsed electromagnetic field (PEMF) exposure on brain tissue have been described in pre-clinical models and in clinical settings. Nevertheless, the mechanism of action and the possible interaction with membrane receptors such as adenosine receptors (ARs) has not been investigated. The present study focused on the effect of PEMFs on A1 and A2A ARs in the rat cerebral cortex and cortical neurons. Affinity and density of ARs were evaluated by means of saturation binding experiments while mRNA expression was investigated through retro-transcription polymerase chain reaction (RT-PCR). PEMF treatment of the intact rat cerebral cortex or cortical neurons at 1.5 mT mediated a transient and significant increase in A2A ARs after 4 h (2.0-fold increase) and 6 h (1.4- and 1.8-fold increase, respectively) of exposure. In addition, PEMF treatment of the rat cerebral cortex and rat cortical neurons at 3 mT upregulated A2A ARs after 2 h (2.0- and 2.2-fold increase, respectively) and 4 h (1.6- and 1.9-fold increase, respectively). The treatment of rat cortex membranes with PEMFs at 1.5 and 3 mT induced an increase in A2A AR density after 2 h (1.9- and 2.2-fold increase, respectively) and was constant at all incubation times investigated. In rat cortical neurons, mRNA levels of A1 and A2A ARs were not affected by PEMF exposure for the times and intensities used. These results suggest that PEMF treatment has different biological effects in whole organs or cells in comparison with isolated membranes.

Role of β-arrestin1/ERK MAP kinase pathway in regulating adenosine A1 receptor desensitization and recovery

Exposure of cells to adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and downregulation of the A(1)AR. The receptor levels on the cell surface generally recover on withdrawal of the agonist, because of either translocation of the sequestered A(1)AR back to plasma membrane or de novo synthesis of A(1)AR. To examine the mechanism(s) underlying A(1)AR downregulation and recovery, we treated ductus deferens tumor (DDT(1) MF-2) cells with the agonist R-phenylisopropyladenosine (R-PIA) and showed a decrease in membrane A(1)AR levels by 24 h, which was associated with an unexpected 11-fold increase in A(1)AR mRNA. Acute exposure of these cells to R-PIA resulted in a rapid translocation of beta-arrestin1 to the plasma membrane. Knockdown of beta-arrestin1 by short interfering RNA (siRNA) blocked R-PIA-mediated downregulation of the A(1)AR, suppressed R-PIA-dependent ERK1/2 and activator protein-1 (AP-1) activity, and reduced the induction of A(1)AR mRNA. Withdrawal of the agonist after a 24-h exposure resulted in rapid recovery of plasma membrane A(1)AR. This was dependent on the de novo protein synthesis and on the activity of ERK1/2 but independent of beta-arrestin1 and nuclear factor-kappaB. Together, these data suggest that exposure to A(1)AR agonist stimulates ERK1/2 activity via beta-arrestin1, which subserves receptor uncoupling and downregulation, in addition to the induction of A(1)AR expression. We propose that such a pathway ensures both the termination of the agonist signal and recovery by priming the cell for rapid de novo synthesis of A(1)AR once the drug is terminated.

Diabetes-induced alterations of adenosine receptors expression level in rat liver

Diabetes mellitus is associated with metabolic, functional, and structural changes in the liver. Adenosine has been demonstrated to play an important regulatory role in the liver, and its action has been associated with all four adenosine receptors (ARs) subtypes. The goal of this study was to evaluate the impact of streptozotocin-induced diabetes on expression level of ARs in rat liver. Performed analyses (real-time PCR, Western blots) revealed detectable levels of mRNA and protein of A 1-AR, A 2A-AR, A 2B-AR, and A 3-AR in the rat liver. Development of diabetes resulted in a significant increase of A 2A-AR and A 3-AR mRNA levels. This was associated with elevated ARs protein content. The level of A 2B-AR mRNA in diabetic liver decreased ∼ 40% and was accompanied by 60% drop in A 2B-AR protein in liver membranes. Diabetes did not affect the expression level of A 1-AR in the liver. Administration of insulin for four days to diabetic rats resulted in returning of the ARs expression to the levels observed in liver of normal rat. The changes in ARs genes expression and receptors protein content could be related to some pathological changes taking place in diabetic liver. This might suggest involvement of ARs in pathogenesis of liver disease.