Effect of calcium antagonists on adrenergic mechanisms in canine saphenous veins

Experiments were designed to investigate the effect of two calcium antagonists, diltiazem and nicardipine (concentration range: 10(-7)-10(-4) M), on the contractile responses to transmural nerve stimulation, exogenous noradrenaline and tyramine in isolated canine saphenous vein rings. Both diltiazem and nicardipine inhibited the contractile response to transmural nerve stimulation in a non-competitive, concentration-dependent manner. At a concentration of 10(-4) M, diltiazem and nicardipine inhibited the maximum contractile response to transmural nerve stimulation to 0.8 +/- 0.8% and 20 +/- 10% of control respectively. Effects of diltiazem and nicardipine (up to 10(-4)M) on the contractile response to exogenous noradrenaline were minimal. The only significant difference observed was a 30% depression of the maximum contractile response with a shift in ED50 at high concentrations of nicardipine. Diltiazem (up to 10(-4) M) had no significant effect on concentration-effect curves for tyramine. Nicardipine inhibited the response to tyramine in a non-competitive manner with the maximum response depressed to 46% of control at 10(-4) M-nicardipine. Release of [3H]noradrenaline during transmural nerve stimulation was reduced by both calcium antagonists in a concentration-dependent manner. However, release of [3H]noradrenaline produced by the indirect sympathomimetic agent tyramine was not significantly inhibited by nicardipine. These experiments suggest that the calcium antagonists diltiazem and nicardipine inhibit the contractile response to transmural nerve stimulation in the canine saphenous vein predominantly by inhibiting the release of endogenous noradrenaline. However, nicardipine appears to have an additional post-synaptic inhibitory effect on the responses to exogenous as well as endogenous noradrenaline.