Mibefradil- and omega-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, omega-conotoxin (omega-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 0.3-3 microM reduced the electrically evoked tritium overflow in a reversible and concentration-dependent manner (IC50%: 1 microM), whereas 0.1-10 microM nifedipine (a selective blocker of L-type channels) was ineffective. The evoked tritium overflow was almost abolished by 0.2 microM omega-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.