N-Type calcium channels control sympathetic neurotransmission in human heart atrium.
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.


RESULTS
In superfused segments of human right atrial appendages, the type of calcium channels that control [(3)H]norepinephrine release evoked by transmural electrical stimulation was determined. [(3)H]norepinephrine release was almost abolished by 0.2 micromol/L omega-conotoxin GVIA (a selective blocker of N-type channels) but was not modified by 0.1 micromol/L omega-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 micromol/L reduced the evoked tritium overflow in a frequency- and calcium-dependent manner, whereas 0.1 to 10 micromol/L amlodipine, diltiazem, and verapamil (selective blockers of L-type channels) were ineffective.


CONCLUSIONS
Norepinephrine release from cardiac sympathetic nerves is triggered by Ca(2+) 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 Ca(2+) 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.
Molderings
G J
GJ
Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. molderings@uni-bonn.de
Likungu
J
J
Göthert
M
M
D000328:Adult; D000368:Aged; D017311:Amlodipine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000502:physiology*; D004110:Diltiazem / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000294:innervation*; D006325:Heart Atria; D006801:Humans; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020867:omega-Agatoxin IVA; D017311:Amlodipine; D020748:Mibefradil; D020866:omega-Conotoxin GVIA; D014700:Verapamil; D004110:Diltiazem; D009638:Norepinephrine