β-adrenergic stimulation modulates ryanodine receptor Ca2+ release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells

Tatiana M. Vinogradova, Konstantin Yu Bogdanov, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

Abstract

It has long been recognized that activation of sympathetic β-adrenoceptors (β-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of β-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of β-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca2+ releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO; 0.1 μmol/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 2.00±0.04 to 2.17±0.03 F/F0; P<0.05 [F and F0 refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80±0.44 to 5.45±0.47 μm; P<0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca2+ transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, β-AR stimulation fails to amplify subsarcolemmal Ca2+ releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved β-AR stimulation-induced augmentation of L-type Ca2+ current amplitude. Thus, the RyR Ca2+ release acts as a switchboard to link β-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by β-AR stimulation lead to an increase in the heart rate.

Original languageEnglish (US)
Pages (from-to)73-79
Number of pages7
JournalCirculation research
Volume90
Issue number1
DOIs
StatePublished - Jan 11 2002

Keywords

  • Local Ca release
  • Ryanodine receptor
  • Sinoatrial node
  • β-adrenergic stimulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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