Anual Review Physiol

PACEMAKER MECHANISMS

IN CARDIAC TISSUE

Dario DiFrancesco

Dipartimento di Fisiologia e Biochimica Generali, Elettrofisiologia, Universita di

Milano, via Celoria 26,20133 Milano, Italy

KEY WORDS: cardiac pacemaker, sinoatrial node, pacemaker current, if current, modulation

INTRODUCTION

The heartbeat is a sign of life, and not surprisingly it has attracted much

interest and curiosity since the early stages of scientific investigation. Even

Leonardo da Vinci, in his anatomical studies, realized that rhythmic, restless

activity was an intrinsic property of cardiac muscle (92), "As to the heart: it

moves itself, and doth never stop, except it be for eternity." In fact, a search

for the basis of spontaneous cardiac activity could only be undertaken several

centuries after these primitive observations with the development of techniques

that allowed the study of the electrical properties of excitable tissues and

particularly of cardiac muscle (18, 71,77,23).

Cardiac pacemaker activity originates in specialized myocytes located in

restricted areas of the heart that are characterized by the ability to beat

spontaneously even when separated from the rest of the cardiac muscle (24,

106, 103, 11, 81). Voltage-clamp investigation of pacemaker tissue opened

the way to a better understanding of the ionic mechanisms promoting

rhythmicity in pacemaker tissue (64, 6). In pacemaker cells of the mammalian

sino-atrial (SA) node, spontaneous activity results from a typical phase of

their action potential, the slow diastolic depolarization. The concept that a

slow depolarization is an inherent property of spontaneously active myocardium

is an old one that has been actively investigated since the first recordings

of cardiac electrical activity revealed the existence of a slow depolarizing

phase preceding the action potential onset in beating tissue (for a review, see

105). During this phase, corresponding to diastole of the cardiac contraction

cycle, the membrane slowly depolarizes following termination of an action

potential, until threshold for a new action potential is reached. Thus, the

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