Beyond Bowditch: The convergence of cardiac chronotropy and inotropy

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The ability of the heart to acutely beat faster and stronger is central to the vertebrate survival instinct. Released neurotransmitters, norepinephrine and epinephrine, bind to β-adrenergic receptors (β-AR) on pacemaker cells comprising the sinoatrial node, and to β-AR on ventricular myocytes to modulate cellular mechanisms that govern the frequency and amplitude, respectively, of the duty cycles of these cells. While a role for sarcoplasmic reticulum Ca2+ cycling via SERCA2 and ryanodine receptors (RyR) has long been appreciated with respect to cardiac inotropy, recent evidence also implicates Ca2+ cycling with respect to chronotropy. In spontaneously beating primary sinoatrial nodal pacemaker cells, RyR Ca2+ releases occurring during diastolic depolarization activate the Na+-Ca2+ exchanger (NCX) to produce an inward current that enhances their diastolic depolarization rate, and thus increases their beating rate. β-AR stimulation synchronizes RyR activation and Ca2+ release to effect an increased beating rate in pacemaker cells and contraction amplitude in myocytes: in pacemaker cells, the β-AR stimulation synchronization of RyR activation occurs during the diastolic depolarization, and augments the NCX inward current; in ventricular myocytes, β-AR stimulation synchronizes the openings of unitary L-type Ca2+ channel activation following the action potential, and also synchronizes RyR Ca2+ releases following depolarization, and in the absence of depolarization, both leading to the generation of a global cytosolic Cai transient of increased amplitude and accelerated kinetics. Thus, β-AR stimulation induced synchronization of RyR activation (recruitment of additional RyRs to fire) and of the ensuing Ca2+ release cause the heart to beat both stronger and faster, and is thus, a common mechanism that links both the maximum achievable cardiac inotropy and chronotropy.

Original languageEnglish (US)
Pages (from-to)629-642
Number of pages14
JournalCell Calcium
Issue number6
StatePublished - Jun 2004
Externally publishedYes


  • Ca cycling
  • Cardiac myocytes
  • Cardiac pacemaker cells
  • Ryanodine receptors
  • Sarcoplasmic reticulum
  • β-Adrenergic receptor signalling

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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