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(Circulation Research. 2002;90:73.)
© 2002 American Heart Association, Inc.

Cellular Biology

ß-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

From the Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, Md.

Correspondence to Tatiana M. Vinogradova, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. 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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