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

  • S. Jamal  Mustafa
  • R. Ray  Morrison
  • Bunyen Teng
  • Amir Pelleg
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 193)

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 

Abbreviations

AC

Adenylate cyclase

AH

Atrial to His bundle activation time (representative of AV-nodalconduction time)

AR

Adenosine receptor

ATP

Adenosine 5 -triphosphate

AV

Atrioventricular

AVN

AV-nodal

CCPA

2-Chloro-N 6-cyclopentyl-adenosine

CF

Coronary flow

CGS-21680

2-[p-(2-carboxyethyl)]-phenylethyl-amino-5 -N-ethylcarboxamidoadenosine

CGS-22492

2-[(2-Cyclohexylethyl)amino]-adenosine

Cox-I

Cyclooxygenase I

CPA

N 6-Cyclopentyladenosine

DAD

Delayed afterdepolarizations

DPCPX

1,3-Dipropyl-8-cyclopentylxanthine

DPMA

N 6-[2-(3,5-Dimethoxyphenyl)-2-(2-methoxyphenyl] ethyladenosine

ECG

Electrocardiogram

ERK

Extracellular regulated kinase

HV

His bundle to ventricular activation time

HUT

Head-up tilt table test

ICa

Inward calcium current

ICaL

Inward L-type Ca2 + current

ICl

Chloride current

If

Hyperpolarization-activated current (“funny” current)

IKAdo,Ach

Outward potassium current

IK,ATP

ATP-dependent outward potassium current

ITi

Transient inward current

JNK

Jun N-terminal kinase

KO

Knockout

L-NMA

N G-Methyl-l-arginine

LAD

Left anterior descending artery

LQTS

Long QT interval syndrome

MAPK

Mitogen-activated protein kinase

NECA

Adenosine-5 -N-ethylcarboxamide

NO

Nitric oxide

PDBu

Phorbol 12,13-dibutyrate

PI3-kinase

Phosphatidylinositol 3-kinase

PLC

Phospholipase C

PKA

Protein kinase A

PKB (Akt)

Protein kinase B

PKC

Protein kinase C

PR

P wave to R wave interval on the ECG

PSVT

Paroxysmal supraventricular tachycardia

QT

Q wave–T wave interval in the ECG

QTc

Corrected QT interval

RR

R wave–R wave interval in the ECG

SN

Sinus node

SR

Sarcoplasmic reticulum

SSS

Sick sinus syndrome

SVT

Supraventricular tachycardia

VF

Ventricular fibrillation

VT

Ventricular tachycardia

Notes

Acknowledgements

We thank would like to Luiz Belardinelli, M.D. for critical reading of the manuscript and his helpful comments. Also, we would like to acknowledge the support of NIH (HL-027339-SJM; HL-074001-RRM).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • S. Jamal  Mustafa
    • 1
  • R. Ray  Morrison
    • 2
  • Bunyen Teng
    • 1
  • Amir Pelleg
    • 3
  1. 1.Department of Physiology and Pharmacology, School of MedicineWest Virginia UniversityMorgantownUSA
  2. 2.Division of Critical Care MedicineSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of Medicine, College of MedicineDrexel UniversityPhiladelphiaUSA

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