title: Contributions of cardiac "funny" (f) channels and sarcoplasmic reticulum Ca2+ in regulating beating rate of mouse and guinea pig sinoatrial node.
abstract: The aim of this study was to investigate the effects on spontaneous beating rate of mouse atrial preparations following selective block of cardiac "funny" (f) channels, I(f), and/or suppression of sarcoplasmic reticulum (SR) function in the absence and presence of β-adrenoceptor stimulation. ZD7288 [to block I(f)] caused a substantial reduction (222 ± 13 bpm) in beating rate from 431 ± 14 to 209 ± 14 bpm, ryanodine alone (to block SR Ca(2+) release) reduced beating rate by 105 ± 11 bpm, with subsequent addition of ZD7288 further reducing rate by 57 ± 9 bpm. Cyclopiazonic acid (CPA) alone (to inhibit Ca(2+) reuptake by the SR) reduced beating rate by 148 ± 13 bpm with subsequent addition of ZD7288 further reducing rate by 79 ± 12 bpm. In additional experiments measuring Ca(2+) transients in the SA node region using Rhod-2, effects of ivabradine and ZD7288 on rate were again substantially reduced after CPA. Effects of CPA alone on rate developed much more slowly than effects on Ca(2+) transient amplitude. ZD7288, ivabradine, and CPA reduced the slope and maximum response of the log(concentration)-response curves for effects of isoprenaline on beating rate. Very little response to isoprenaline remained after treatment with CPA followed by ZD7288. Similar changes in isoprenaline log(concentration)-response curves were seen in guinea pig preparations. These observations are consistent with a role for Ca(2+) released from the SR in regulating I(f) and therefore beating rate of SA node preparations; there appear to be additional contributions of SR-derived Ca(2+) to effects of β-adrenoceptor stimulation on beating rate that are independent of I(f).
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
authors.forename: Islom B
authors.initials: IB
authors.lastname: Nazarov
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK derek.terrar@pharm.ox.ac.uk.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Terrar
keywords: Calcium; HCN; I(f); cardiac; pacemaker; sarcoplasmic reticulum; sino‐atrial node