Although the A1 adenosine receptor (A1 receptor), the main adenosine receptor type in cardiac muscle, is involved in powerful cardioprotective processes such as ischemic preconditioning, the atrial A1 receptor reserve has not yet been quantified for the direct negative inotropic effect of adenosine. In the present study, adenosine concentration-effect (E/c) curves were constructed before and after pretreatment with FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 receptor antagonist, in isolated guinea pig atria. To prevent the intracellular elimination of the administered adenosine, NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, was used. As expected, NBTI alone and FSCPX-pretreatment alone shifted the adenosine E/c curve to the left and right, respectively. However, in the presence of NBTI, FSCPX-pretreatment appeared to increase the maximal response to adenosine. By means of the receptorial responsiveness method (RRM), our recently developed procedure, adenosine E/c curves generated in the presence of NBTI were corrected for the bias caused by the endogenous adenosine accumulated by NBTI. The corrected curves indicate a substantial A1 receptor reserve for the direct negative inotropy evoked by adenosine. In addition, our results suggest that accumulation of an endogenous agonist may bias the E/c curve constructed with the same or similar agonist that can lead to seemingly paradoxical results.
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http://dx.doi.org/10.4149/gpb_2013041 | DOI Listing |
Invest Ophthalmol Vis Sci
January 2025
Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.
Purpose: To investigate the effect of Rho-associated protein kinase (ROCK) inhibitor Y27632 on bioenergetic capacity and resilience of corneal endothelial cells (CECs) under metabolic stress.
Methods: Bovine CECs (BCECs) were treated with Y27632 and subjected to bioenergetic profiling using the Seahorse XFp Analyzer. The effects on adenosine triphosphate (ATP) production through oxidative phosphorylation and glycolysis were measured.
Ann Surg Oncol
January 2025
Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Background: Three dimensional (3D) cell cultures can be effectively used for drug discovery and development but there are still challenges in their general application to high-throughput screening. In this study, we developed a novel high-throughput chemotherapeutic 3D drug screening system for gastric cancer, named 'Cure-GA', to discover clinically applicable anticancer drugs and predict therapeutic responses.
Methods: Primary cancer cells were isolated from 143 fresh surgical specimens by enzymatic treatment.
Am J Cardiovasc Drugs
January 2025
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Oral bempedoic acid (NEXLETOL in the USA; Nilemdo in the EU) and the fixed dose combination (FDC) of bempedoic acid/ezetimibe (NEXLIZET in the USA; Nustendi in the EU) are approved to reduce cardiovascular (CV) risk in statin-intolerant patients who are at high risk for, or have, CV disease. A first-in-class therapy, bempedoic acid inhibits the adenosine triphosphate-citrate lyase enzyme in the cholesterol biosynthesis pathway. In the multinational phase III CLEAR Outcomes trial in statin-intolerant patients, once-daily bempedoic acid 180 mg significantly reduced the risk of the primary endpoint (a four-component major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) compared with placebo.
View Article and Find Full Text PDFImmunohorizons
January 2025
Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
CD73 is ubiquitously expressed and regulates critical functions across multiple organ systems. The sequential actions of CD39 and CD73 accomplish the conversion of adenosine triphosphate to adenosine and shift the adenosine triphosphate-driven proinflammatory immune cell milieu toward an anti-inflammatory state. This immunological switch is a major mechanism by which regulatory T (Treg) cells control inflammation.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2025
Sichuan University, College of Biomass Science and Engineering, College of Biomass Science and Engineering, Healthy Food Evaluation Research Cen, 610065, Chengdu, CHINA.
RNA modifications, such as N6-methylation of adenosine (m6A), serve as key regulators of cellular behaviors, and are highly dynamic; however, tools for dynamic monitoring of RNA modifications in live cells are lacking. Here, we develop a genetically encoded live-cell RNA methylation sensor that can dynamically monitor RNA m6A level at single-cell resolution. The sensor senses RNA m6A in cells via affinity-induced cytoplasmic retention using a nuclear location sequence-fused m6A reader.
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