期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 307, 期 9, 页码 H1327-H1338出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00354.2014
关键词
large-conductance channel; calcium-activated potassium channel; heart rate; potassium channels; sinoatrial node
资金
- American Heart Association [0930292N]
- National Institutes of Health (NIH) [R01-HL-102758]
- American Physiological Society's Ryuji Ueno award - S R Foundation
- Marsden Fund Royal Society of New Zealand [AGR302]
- NIH [R01-HL-079031, R01-HL-096652, R01-HL-070250, R01-HL-071140, T32-AA-R07592, T32-HL-72751]
Large-conductance Ca2+ - 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 mu M) 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.
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