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

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Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((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.

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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

I Ca :

Inward calcium current

I CaL :

Inward L-type Ca2 + current

I Cl :

Chloride current

I f :

Hyperpolarization-activated current (“funny” current)

I KAdo,Ach :

Outward potassium current

I K,ATP :

ATP-dependent outward potassium current

I Ti :

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

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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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Authors and Affiliations

  1. Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, 26505-9229, USA

    S. Jamal Mustafa & Bunyen Teng

  2. Division of Critical Care Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

    R. Ray Morrison

  3. Department of Medicine, College of Medicine, Drexel University, Philadelphia, PA, USA

    Amir Pelleg

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  1. S. Jamal Mustafa
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Correspondence to S. Jamal Mustafa .

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  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

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Mustafa, S.J., Morrison, R.R., Teng, B., Pelleg, A. (2009). Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_6

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