Mibefradil- and ω-conotoxin GVIA-induced inhibition of noradrenaline release from the sympathetic nerves of the human heart

Segments of human right atrial appendages preincubated with 3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to determine the effects of mibefradil, ω-conotoxin (ω-CTx) GVIA and nifedipine on tritium overflow evoked by transmural electrical stimulation. Mibefradil (which predominantly blocks T-type, and at lower potency also N-type, Ca²⁺ channels) at concentrations of 0.3–3μM reduced the electrically evoked tritium overflow in a reversible and concentration-dependent manner (IC_50%: 1μM), whereas 0.1–10μM nifedipine (a selective blocker of L-type channels) was ineffective. The evoked tritium overflow was almost abolished by 0.2μM ω-CTx GVIA (a selective blocker of N-type channels). It is concluded that noradrenaline release from cardiac sympathetic nerves is triggered by Ca²⁺-influx via N-type, but not L-type, Ca²⁺ channels and that the inhibitory effect of mibefradil at clinically relevant concentrations on noradrenaline release is probably due to its blocking action on N-type Ca²⁺ channels. This property of mibefradil is unique among the therapeutically applied Ca²⁺ channel blockers and may contribute to the slight negative chronotropic effect of the drug in vivo. Received: 24 September 1997 / Accepted: 3 November 1997