title: Inhibition of spontaneous activity of rabbit atrioventricular node cells by KB-R7943 and inhibitors of sarcoplasmic reticulum Ca(2+) ATPase.
abstract: The atrioventricular node (AVN) can act as a subsidiary cardiac pacemaker if the sinoatrial node fails. In this study, we investigated the effects of the Na-Ca exchange (NCX) inhibitor KB-R7943, and inhibition of the sarcoplasmic reticulum calcium ATPase (SERCA), using thapsigargin or cyclopiazonic acid (CPA), on spontaneous action potentials (APs) and [Ca(2+)](i) transients from cells isolated from the rabbit AVN. Spontaneous [Ca(2+)](i) transients were monitored from undialysed AVN cells at 37°C using Fluo-4. In separate experiments, spontaneous APs and ionic currents were recorded using the whole-cell patch clamp technique. Rapid application of 5 μM KB-R7943 slowed or stopped spontaneous APs and [Ca(2+)](i) transients. However, in voltage clamp experiments in addition to blocking NCX current (I(NCX)) KB-R7943 partially inhibited L-type calcium current (I(Ca,L)). Rapid reduction of external [Na(+)] also abolished spontaneous activity. Inhibition of SERCA (using 2.5 μM thapsigargin or 30 μM CPA) also slowed or stopped spontaneous APs and [Ca(2+)](i) transients. Our findings are consistent with the hypothesis that sarcoplasmic reticulum (SR) Ca(2+) release influences spontaneous activity in AVN cells, and that this occurs via [Ca(2+)](i)-activated I(NCX); however, the inhibitory action of KB-R7943 on I(Ca,L) means that care is required in the interpretation of data obtained using this compound.
authors.affiliation: School of Physiology and Pharmacology, Medical Sciences Building, University of Bristol, UK.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Clive H
authors.initials: CH
authors.lastname: Orchard
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001283:Atrioventricular Node / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D019831:Sodium-Calcium Exchanger; D019284:Thapsigargin; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013890:Thiourea