Chapter

Adenosine Receptors in Health and Disease

Volume 193 of the series Handbook of Experimental Pharmacology pp 161-188

Date:

Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology

  • S. Jamal  MustafaAffiliated withDepartment of Physiology and Pharmacology, School of Medicine, West Virginia University Email author 
  • , R. Ray  MorrisonAffiliated withDivision of Critical Care Medicine, St. Jude Children’s Research Hospital
  • , Bunyen TengAffiliated withDepartment of Physiology and Pharmacology, School of Medicine, West Virginia University
  • , Amir PellegAffiliated withDepartment of Medicine, College of Medicine, Drexel University

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Abstract

Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A1, A2A, A2B, and A3. All four subtypes are known to regulate coronary flow. In general, A2AAR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and -independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A1AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-β-adrenergic effects). In supraventricular tissues (atrial myocytes, sinuatrial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A1R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.

Keywords

A1 adenosine receptor A2A adenosine receptor A2B adenosine receptor A3 adenosine receptor Endothelium Coronary artery Smooth muscle Adenosine receptor knockout Phospholipase C MAPK Adenosine receptor agonist Adenosine receptor antagonist Sinus node AV node Cardiac electrophysiology PSVT Anti-beta adrenergic action