### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

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Receptors for Purines and Pyrimidines

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer

Adenosine receptors as therapeutic targets

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000549

2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society

FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death

https://escholarship.org/content/qt65h088d5/qt65h088d5.pdf

Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.

The purpose of this review is to examine the role of the extracellular A1-adenosine (Ado) receptor in modulating membrane potential and currents in cardiac cells. The cellular electrophysiological ...

Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes.

Reactive oxygen species (ROS), including H2O2, cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H2O2-induced arrhythmic activity and contractile dysfunction are the results of an effect of H2O2 to increase the magnitude of the late sodium current (late INa). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 microM H2O2. Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. [Na+]i and [Ca2+]i were determined by fluorescence measurements. H2O2 caused a persistent late INa that was almost completely inhibited by 10 microM tetrodotoxin (TTX). H2O2 prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and aftercontractions. H2O2 also caused increases of [Na+]i and [Ca2+]i. Ranolazine (10 microM), a novel inhibitor of late INa, attenuated H2O2-induced late INa by 51+/-9%. TTX (2 microM) or 10 microM ranolazine attenuated H2O2-induced APD prolongation and suppressed EADs. Ranolazine accelerated the twitch relaxation rate in the presence of H2O2 and abolished H2O2-induced aftercontractions. Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na+]i, and [Ca2+]i caused by H2O2. In conclusion, the results confirm the hypothesis that an increase in late INa during exposure of ventricular myocytes to H2O2 contributes to electrical and contractile dysfunction and suggest that inhibition of late INa may offer protection against ROS-induced Na+ and Ca2+ overload.

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

The new anti-anginal drug ranolazine causes a slight ( 1 seconds, and caused early afterdepolarizations; both actions were attenuated by ranolazine (0.1-30 micromol/L). Ranolazine (10 micromol/L) reduced by 89% the 13.6-fold increase in variability of APD caused by 10 nmol/L ATX-II. The effects of ATX-II (3 nmol/L) in combinations with either the IKr blocker E-4031 or the IKs blocker chromanol 293B to increase APD were attenuated 76 +/- 5% and 71 +/- 4%, respectively, by 10 micromol/L ranolazine. The results demonstrate that ranolazine reduces late INa and has an anti-arrhythmic effect when late INa is increased.

Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes.

Prolongation of the QT interval of the ECG is associated with increased risk of torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal agent, is reported to decrease the delayed rectifier potassium current, I(Kr), and to increase action potential duration (APD) and the QT interval. However, ranolazine is also reported to reduce late sodium current (late I(Na)), a depolarizing current that contributes to prolongation of the plateau of the ventricular action potential. We hypothesized that ranolazine would decrease APD and the occurrence of arrhythmias when late I(Na) is increased. Therefore, we measured the effects of ranolazine alone and in the presence of anemone toxin (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3 syndrome, on epicardial monophasic action potentials and ECGs recorded from guinea pig isolated hearts. Ranolazine (0.1-50 microM) prolonged monophasic APD at 90% repolarization (MAPD(90)) by up to 22% but did not cause either early afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1-20 nM) markedly increased APD and caused EADs and VT. Ranolazine (5-30 microM) significantly attenuated increases in MAPD(90) and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD(90) increase caused by combinations of ATX-II and blockers of I(K) [E-4031; 1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)piperidine]. Thus, although ranolazine alone prolonged APD, it reduced APD and ventricular arrhythmias caused by agents that increased late I(Na) and decreased I(K).

Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome.

This study determined the role of a slowly inactivating component of sodium current (INa), late INa, to induce delayed afterdepolarizations (DADs) and triggered activity. We hypothesized that an in...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.01357.2007

Yejia Song

Papers

Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes.

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes.

Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome.

An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes