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Frontiers in Pharmacology 2023: Sarcopenia is defined as a loss of muscle mass and strength. ATP homeostasis is crucial during myogenesis. We determined how the purinergic system modulates myogenesis...
: Sarcopenia is defined as a loss of muscle mass and strength. ATP homeostasis is crucial during myogenesis. We determined how the purinergic system modulates myogenesis using dipyridamole (blocks adenosine taken up by the cells) and tenofovir (inhibits ATP release) in a myoblast cell line. C2C12 cells were differentiated in the presence/absence of tenofovir/dipyridamole, with/without the A2B selective inhibitor PSB-603. Extra-/intracellular nucleotides were examined via HPLC. The expression of muscle differentiation proteins (Pax7, Mif5, MyoD, MyoG, and MHC), PKA/CREB, adenosine receptors (A1, A2A, A2B, and A3), ATP-channel pannexin-1 and the P2X7 receptor was analyzed via WB and RT-PCR. cAMP and AMPK activation was measured. Tenofovir increased intracellular ATP and reduced extracellular adenosine, decreasing Pax7 expression and increasing MHC expression prematurely. Dipyridamole increased intracellular AMP and extracellular adenosine, counteracting the premature myogenesis promoted by tenofovir. All adenosine receptors were expressed during differentiation with dipyridamole, increasing A2B expression. Tenofovir maintained inactive AMPK and decreased cAMP levels, as well as PKAα and pCREB expression, which were recovered with dipyridamole. Adenosine and ATP act as mediators in muscle myogenesis. The blockade of ATP release by tenofovir promotes premature myogenesis, with dipyridamole counteracting the premature differentiation promoted by tenofovir via the adenosine A2B receptor and cAMP/AMPK pathways. Therefore, dipyridamole might be of interest as a therapeutic approach in sarcopenia.
PubMed: 37771723
DOI: 10.3389/fphar.2023.1247664 -
Frontiers in Cardiovascular Medicine 2023Patients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue...
INTRODUCTION
Patients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue proliferation, a process in which smooth muscle cell (SMC) biology may play a central role. Dipyridamole (DP) is an approved therapeutic agent with data supporting improved vascular patency rates. Pre-clinical data supports that DP may enact its vasculoprotective effects via adenosine receptor-A2B (ADOR-A2B). We sought to evaluate the efficacy of DP to mitigate ISR in a pre-clinical rabbit stent model.
METHODS & RESULTS
24 New Zealand White Rabbits were divided into two cohorts-non-atherosclerosis and atherosclerosis ( = 12/cohort, 6 male and 6 female). Following stent implantation, rabbits were randomized 1:1 to control or oral dipyridamole therapy for 6 weeks followed by optical coherence tomography (OCT) and histology assessment of NI burden and stent strut healing. Compared to control, DP demonstrated a 16.6% relative reduction in NI volume (14.7 ± 0.8% vs. 12.5 ± 0.4%, = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, = 0.02). DP treated rabbits had a 44.6% ( = 0.045) relative reduction in NI SMC content. assessment of DP and coronary artery SMCs yielded dose-dependent reduction in SMC migration and proliferation. Selective small molecule antagonism of ADOR-A2B abrogated the effects of DP on SMC proliferation. DP modulated SMC phenotypic switching with ADOR-A2B siRNA knockdown supporting its role in the observed effects.
CONCLUSION
Dipyridamole reduces NI proliferation and improves stent healing in a preclinical model of stent implantation with conventional antiplatelets. Atherosclerosis attenuates the observed effect. Clinical trials of DP as an adjunctive agent may be warranted to evaluate for clinical efficacy in stent outcomes.
PubMed: 37745122
DOI: 10.3389/fcvm.2023.1130304 -
Frontiers in Cardiovascular Medicine 2023Stress echocardiography is a diagnostic cardiovascular exam that is commonly utilized for multiple indications, including but not limited to the assessment of... (Review)
Review
Stress echocardiography is a diagnostic cardiovascular exam that is commonly utilized for multiple indications, including but not limited to the assessment of obstructive coronary artery disease, valvular disease, obstructive hypertrophic cardiomyopathy, and diastolic function. Stress echocardiography can be performed via both exercise and pharmacologic modalities. Exercise stress is performed with either treadmill or bicycle-based exercise. Pharmacologic stress is performed via either dobutamine or vasodilator-mediated (i.e., dipyridamole, adenosine) stress testing. Each of these modalities is associated with a low overall prevalence of major, life-threatening adverse outcomes, though adverse events are most common with dobutamine stress echocardiography. In light of the recent COVID-19 pandemic, the risk of infectious complications to both the patient and stress personnel cannot be negated; however, when certain precautions are taken, the risk of infectious complications appears minimal. In this article, we review each of the stress echocardiographic modalities, examine major potential adverse outcomes and contraindications, assess the risks of stress testing in the setting of a global pandemic, and examine the utilization and safety of stress testing in special patient populations (i.e., language barriers, pediatric patients, pregnancy).
PubMed: 37600036
DOI: 10.3389/fcvm.2023.1228613 -
Scientific Reports Jul 2023Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets... (Randomized Controlled Trial)
Randomized Controlled Trial
Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24-3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8-35 day period but not in the 0-7 or 36-90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains.Trial registration ISRCTN47823388 .
Topics: Female; Humans; Platelet Aggregation Inhibitors; Brain Ischemia; Ischemic Attack, Transient; Clopidogrel; Stroke; Prospective Studies; Quality of Life; Aspirin; Hemorrhage; Dipyridamole; Drug Therapy, Combination; Ischemic Stroke; Acute Disease
PubMed: 37474599
DOI: 10.1038/s41598-023-38474-2 -
Molecular Imaging and Radionuclide... Jun 2023The pharmacological stress test with vasodilator agents is an alternative cardiological diagnostic tool for patients with contraindications to the classical stress test...
OBJECTIVES
The pharmacological stress test with vasodilator agents is an alternative cardiological diagnostic tool for patients with contraindications to the classical stress test provided by physical activity during single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The study compared the frequency of the side effects of regadenoson and dipyridamole during a SPECT MPI.
METHODS
This retrospective study included data of 283 consecutive patients who underwent pharmacological stress tests in years 2015-2020. The study group consisted of 240 patients who had received dipyridamole and 43 patients who had received regadenoson. The collected data included the patients' characteristics, the occurrence of side effects (divided into mild: headache, vertigo, nausea, vomiting, dyspnea, chest discomfort, hot flushes, general weakness and severe: bradycardia, hypotension, loss of consciousness), and blood pressure values/measurements.
RESULTS
Overall, complications occurred relatively often (regadenoson: 23.2%, dipirydamol: 26.7%, p=0.639). Procedure discontinuation was necessary in 0.7% of examinations, whereas pharmacological support was necessary in 4.7%. There was no difference in the prevalence of mild (regadenoson: 16.2%, dipirydamol: 18.3%, p=0.747) and severe complications (regadenoson: 11.6%, dipyridamole: 15.0%, p=0.563). However, regadenoson has been found to cause a significantly smaller mean decrease of systolic blood pressure (SBP) (regadenoson: -2.6±10.0 mmHg, dipyridamole: -8.7±9.6 mmHg, p=0.002), diastolic blood pressure (DBP) (regadenoson: -0.9±5.4 mmHg, dipyridamole: -3.6±6.2 mmHg, p=0.032), as well as mean arterial pressure (MAP) (regadenoson: -1.5±5.6 mmHg, dipyridamole: -5.4±6.5 mmHg, p=0.001).
CONCLUSION
Regadenoson and dipyridamole presented a similar safety profile during SPECT MPI. However, regadenoson has been found to cause significantly smaller decreases in SBP, DBP, and MAP.
PubMed: 37337782
DOI: 10.4274/mirt.galenos.2022.72593