title: beta-Adrenergic stimulation modulates ryanodine receptor Ca(2+) release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells.
abstract: It has long been recognized that activation of sympathetic beta-adrenoceptors (beta-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of beta-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of beta-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca(2+) releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO; 0.1 micromol/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/F(0); P<0.05 [F and F(0) refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80+/-0.44 to 5.45+/-0.47 microm; P<0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca(2+) transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, beta-AR stimulation fails to amplify subsarcolemmal Ca(2+) releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved beta-AR stimulation-induced augmentation of L-type Ca(2+) current amplitude. Thus, the RyR Ca(2+) release acts as a switchboard to link beta-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by beta-AR stimulation lead to an increase in the heart rate.
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, MD 21224, USA. vinogradovat@grc.nia.nih.gov
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Vinogradova
authors.forename: Konstantin Yu
authors.initials: KY
authors.lastname: Bogdanov
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D010138:Pacemaker, Artificial; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012849:Sinoatrial Node / Q000378:metabolism / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D007545:Isoproterenol; D002118:Calcium