title: I(f)-dependent modulation of pacemaker rate mediated by cAMP in the presence of ryanodine in rabbit sino-atrial node cells.
abstract: I(f) contributes to generation and autonomic control of spontaneous activity of cardiac pacemaker cells through a cAMP-dependent, Ca(2+)-independent mechanism of rate regulation. However, disruption of Ca(2+) release from sarcoplasmic reticulum (SR) by ryanodine (Ry) has been recently shown to slow spontaneous rate and inhibit beta-adrenergic receptor (betaAR)-induced rate acceleration, leading to the suggestion that the target of betaAR modulation of pacemaking is the intracellular Ca(2+)-regulatory process. We have investigated whether the Ry-induced decrease of betaAR rate modulation alternatively involves disruption of the betaAR-adenylate-cyclase-cAMP-I(f) mechanism. Prolonged exposure to Ry (3 microM, >2 min) slowed spontaneous rate of pacemaker cells by 29.8% via a depolarizing shift of take-off potential (TOP) without significantly changing early diastolic depolarization rate. Ry depressed rate acceleration caused by isoproterenol (Iso) (1 microM, 23.6% in control vs. 8.0%), but did not modify that caused by two membrane-permeable cAMP analogs, CPT-cAMP (300 microM, 17.7% vs. 17.3%) and Rp-cAMPs (50 microM, 18.0% vs. 20.6%). Consistent with the rate effect, exposure to Ry decreased the shift induced by Iso, but not that induced by either cAMP analog on the I(f)-activation curve. We conclude that disruption of Ry receptor function and SR Ca(2+) release depresses betaAR-induced modulation of heart rate, but does not impair cAMP-dependent rate acceleration mediated by I(f). However, abolishment of normal Ca(2+) homeostasis may result in the failure of betaAR agonists to sufficiently elevate cAMP near f-channels. The molecular basis for Ca(2+)-dependent interference in beta-adrenergic signaling remains to be determined.
authors.affiliation: Department of General Physiology and Biochemistry, Laboratory of Molecular Physiology and Neurobiology, University of Milan, via Celoria 26, Milano 20133, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bucchi
authors.forename: Mirko
authors.initials: M
authors.lastname: Baruscotti
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.forename: Dario
authors.initials: D
authors.lastname: DiFrancesco
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003971:Diastole / Q000187:drug effects; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D007473:Ion Channels; D011943:Receptors, Adrenergic, beta; D012433:Ryanodine; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium