Circulation Research. 2001
Published online before print November 15, 2001, doi: 10.1161/hh0102.102271
Published online before print November 15, 2001, doi: 10.1161/hh0102.102271
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Submitted on June 28, 2001
Revised on November 6, 2001
Accepted on November 6, 2001
ß-Adrenergic Stimulation Modulates Ryanodine Receptor Ca2+ Release During Diastolic Depolarization to Accelerate Pacemaker Activity in Rabbit Sinoatrial Nodal Cells
From the Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: vinogradovat{at}grc.nia.nih.gov.
It has long been recognized that activation of sympathetic ß-adrenoceptors (ß-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of ß-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of ß-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, ß-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 ß-AR stimulation-induced augmentation of L-type Ca2+ current amplitude. Thus, the RyR Ca2+ release acts as a switchboard to link ß-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by ß-AR stimulation lead to an increase in the heart rate.
Key words: sinoatrial node • ß-adrenergic stimulation • ryanodine receptor • local Ca2+ release
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