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(Circulation. 2000;101:403.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

N-Type Calcium Channels Control Sympathetic Neurotransmission in Human Heart Atrium

G. J. Molderings, MD; J. Likungu, MD; M. Göthert, MD

From the Institute of Pharmacology and Toxicology, University of Bonn (G.J.M., M.G.) and the Clinic of Cardiovascular Surgery (J.L.), University of Bonn, Bonn, Germany.

Correspondence to G.J. Molderings, MD, Institute of Pharmacology and Toxicology, University of Bonn, Reuterstraße 2B, D-53113 Bonn, Germany. E-mail molderings{at}uni-bonn.de

Background—Because knowledge about the type of calcium channels involved in action potential–induced norepinephrine release from the human peripheral sympathetic nervous system is sparse, we investigated which types of calcium channels are functionally important in the sympathetic nerves of human cardiac tissue.

Methods and Results—In superfused segments of human right atrial appendages, the type of calcium channels that control [³H]norepinephrine release evoked by transmural electrical stimulation was determined. [³H]norepinephrine release was almost abolished by 0.2 µmol/L -conotoxin GVIA (a selective blocker of N-type channels) but was not modified by 0.1 µmol/L -agatoxin IVA (a selective blocker of P- and Q-type channels). Mibefradil (a T-type and N-type calcium channel blocker) at concentrations of 0.3 to 3 µmol/L reduced the evoked tritium overflow in a frequency- and calcium-dependent manner, whereas 0.1 to 10 µmol/L amlodipine, diltiazem, and verapamil (selective blockers of L-type channels) were ineffective.

Conclusions—Norepinephrine release from cardiac sympathetic nerves is triggered by Ca²⁺ influx via N-type but not L- and P/Q-type calcium channels. The inhibitory effect of mibefradil on norepinephrine release at clinically relevant concentrations is probably due to its blocking action on N-type Ca²⁺ channels. This property of mibefradil is unique among the calcium channel blockers that have been or still are therapeutically applied and may considerably contribute to its slight negative chronotropic effect in vivo.

Key Words: atrium • calcium channels • norepinephrine • mibefradil

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