Differential Effects of Verapamil, Nicardipine and Diltiazem on Ca2+-dependent and Ca2+-independent Noradrenaline Release and Contraction in Isolated Canine Saphenous Veins

We reported that verapamil, nicardipine and diltiazem inhibited both 3H overflow and contraction induced by transmural nerve stimulation (TNS) in the canine saphenous vein preloaded with 3H-noradrenaline. In the present study, the effects of these Ca channel antagonists in the presence of tetraethylammonium (TEA) were investigated to evaluate whether the antagonists act by inhibiting Ca2+ influx into the nerve endings. The effects of the drugs on both responses to tyramine were also studied. In the 1 mmol/l-TEA-pretreated veins, verapamil and nicardipine inhibited only the contraction. Diltiazem inhibited the two parameters, the effects being nearly equipotent to those in the absence of TEA. The L-cis isomer of diltiazem inhibited the TNS-evoked responses to a similar degree as diltiazem, which was unaffected by 1 mmol/l TEA. Verapamil, nicardipine and diltiazem inhibited the TNS-evoked 3H overflow in 0.25 mmol/l Ca2+ and 20 mmol/l TEA medium, the inhibitions by the two former antagonists being greater than those seen in normal Krebs solution. TEA (1 mmol/l) added after the Ca channel antagonists, overcame the inhibition of the evoked overflow by diltiazem more poorly than that by verapamil or nicardipine. Only verapamil inhibited both responses to tyramine. These data together with previous results suggest that unlike verapamil and nicardipine, diltiazem may inhibit the TNS-evoked neurotransmitter release via a mechanism being unrelated to its Ca2+ influx-inhibiting action, resulting in an inhibition of the contraction, and that only verapamil inhibits the tyramine-evoked neurotransmitter release.