Beyond Bowditch: the convergence of cardiac chronotropy and inotropy

Abstract

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 Ca 2+ cycling via SERCA2 and ryanodine receptors (RyR) has long been appreciated with respect to cardiac inotropy, recent evidence also implicates Ca 2+ cycling with respect to chronotropy. In spontaneously beating primary sinoatrial nodal pacemaker cells, RyR Ca 2+ releases occurring during diastolic depolarization activate the Na +–Ca 2+ 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 Ca 2+ 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 Ca 2+ channel activation following the action potential, and also synchronizes RyR Ca 2+ releases following depolarization, and in the absence of depolarization, both leading to the generation of a global cytosolic Ca i 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 Ca 2+ 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.