title: BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo.
abstract: Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels play prominent roles in shaping muscle and neuronal excitability. In the cardiovascular system, BK channels promote vascular relaxation and protect against ischemic injury. Recently, inhibition of BK channels has been shown to lower heart rate in intact rodents and isolated hearts, suggesting a novel role in heart function. However, the underlying mechanism is unclear. In the present study, we recorded ECGs from mice injected with paxilline (PAX), a membrane-permeable BK channel antagonist, and examined changes in cardiac conduction. ECGs revealed a 19 ± 4% PAX-induced reduction in heart rate in wild-type but not BK channel knockout (Kcnma1(-/-)) mice. The heart rate decrease was associated with slowed cardiac pacing due to elongation of the sinus interval. Action potential firing recorded from isolated sinoatrial node cells (SANCs) was reduced by 55 ± 15% and 28 ± 9% by application of PAX (3 μM) and iberiotoxin (230 nM), respectively. Furthermore, baseline firing rates from Kcnma1(-/-) SANCs were 33% lower than wild-type SANCs. The slowed firing upon BK current inhibition or genetic deletion was due to lengthening of the diastolic depolarization phase of the SANC action potential. Finally, BK channel immunoreactivity and PAX-sensitive currents were identified in SANCs with HCN4 expression and pacemaker current, respectively, and BK channels cloned from SANCs recapitulated similar activation as the PAX-sensitive current. Together, these data localize BK channels to SANCs and demonstrate that loss of BK current decreases SANC automaticity, consistent with slowed sinus pacing after PAX injection in vivo. Furthermore, these findings suggest BK channels are potential therapeutic targets for disorders of heart rate.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Fischell Department of Bioengineering, University of Maryland, College Park, Maryland;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine and the François M. Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa;
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine and the François M. Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa;
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine and the François M. Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa; Department of Physiology and Molecular Biophysics, University of Iowa, Iowa City, Iowa; and.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: AgResearch, Grasslands Research Centre, Palmerston North, New Zealand.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Dalziel
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Fischell Department of Bioengineering, University of Maryland, College Park, Maryland; ameredith@som.umaryland.edu.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Meredith
mesh_terms: D000200:Action Potentials; D000818:Animals; D006339:Heart Rate; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012849:Sinoatrial Node / Q000378:metabolism* / Q000502:physiology
chemical_list: C578706:Hcn4 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007211:Indoles; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D010455:Peptides; D026902:Potassium Channel Blockers; C048220:paxilline; C064719:iberiotoxin
keywords: calcium-activated potassium channel; heart rate; large-conductance channel; potassium channels; sinoatrial node