{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:12:14Z","timestamp":1791209534836,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2002,1,11]]},"abstract":"<jats:p>\n            It has long been recognized that activation of sympathetic \u03b2-adrenoceptors (\u03b2-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of \u03b2-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of \u03b2-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca\n            <jats:sup>2+<\/jats:sup>\n            releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO; 0.1 \u03bcmol\/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 2.00\u00b10.04 to 2.17\u00b10.03 F\/F\n            <jats:sub>0<\/jats:sub>\n            ;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05 [F and F\n            <jats:sub>0<\/jats:sub>\n            refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80\u00b10.44 to 5.45\u00b10.47 \u03bcm;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca\n            <jats:sup>2+<\/jats:sup>\n            transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, \u03b2-AR stimulation fails to amplify subsarcolemmal Ca\n            <jats:sup>2+<\/jats:sup>\n            releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved \u03b2-AR stimulation-induced augmentation of L-type Ca\n            <jats:sup>2+<\/jats:sup>\n            current amplitude. Thus, the RyR Ca\n            <jats:sup>2+<\/jats:sup>\n            release acts as a switchboard to link \u03b2-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by \u03b2-AR stimulation lead to an increase in the heart rate.\n          <\/jats:p>","DOI":"10.1161\/hh0102.102271","type":"journal-article","created":{"date-parts":[[2002,7,28]],"date-time":"2002-07-28T23:16:07Z","timestamp":1027898167000},"page":"73-79","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":183,"title":["\u03b2-Adrenergic Stimulation Modulates Ryanodine Receptor Ca\n            <sup>2+<\/sup>\n            Release During Diastolic Depolarization to Accelerate Pacemaker Activity in Rabbit Sinoatrial Nodal Cells"],"prefix":"10.1161","volume":"90","author":[{"given":"Tatiana M.","family":"Vinogradova","sequence":"first","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin Yu.","family":"Bogdanov","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward G.","family":"Lakatta","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences, National Institute on Aging, Gerontology Research Center, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1993.73.1.197"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1994.sp020038"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1997.273.5.H2481"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1996.sp003983"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01746203"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-3623(96)00182-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00415.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.88.12.1254"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.0793u.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00153-X"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.87.9.760"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/PL00008086"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77229-2"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.88.8.794"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.153br.x"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bb.18.060189.002001"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8235594"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.665ba.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.81.4.462"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.54.030192.001431"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0696fje"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a122945"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.385bb.x"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1997.sp022020"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90446-4"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1984.tb10735.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1997.272.4.H1625"},{"key":"e_1_3_3_28_2","first-page":"H604","volume":"265","year":"1993","unstructured":"DuBell WH, Lewartowski B, Spurgeon HA, Silverman HS, Lakatta EG. 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