Inhibitory effect of noradrenaline uptake inhibitors on contractions of rat aortic smooth muscle

1 The effects of noradrenaline (NA) uptake inhibitors on contractions induced by NA, high K + , and 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) in rat isolated aorta were investigated. 2 Protriptyline (0.3 μ m ) and amitriptyline (0.3 μ m ) produced an approximately parallel shift to the right in the dose‐response curve to NA. Protriptyline (>0.3 μ m ), amitriptyline (>0.3 μ m ) and xylamine (0.01‐1 μ m ) significantly reduced the maximal contractile response to NA. The IC 50 values for inhibition of the contractile response to 3 μ m NA were 1.58 μ m for xylamine, 1.70 μ m for amitriptyline and 2.57 μ m for protriptyline. 3 Protriptyline and amitriptyline dose‐dependently inhibited the high K + (60 mM)‐induced contraction (IC 50 = 0.69 μ m for protriptyline and IC 50 = 3.15 μ m for amitriptyline). In contrast, xylamine did not affect the high K( + ‐induced contraction. 4 Protriptyline and amitriptyline dose‐dependently inhibited TPA (1 μ m )‐induced contraction in calcium‐free solution; xylamine (up to 30 μ m ) was without effect. Staurosporine (10 nM) completely inhibited the TPA‐ and NA‐induced contraction. 5 Protriptyline (3 μ m ) and amitriptyline (3 μ m ) caused about 54% and 60% inhibition, respectively, of aortic contractions caused by endothelin‐1 (10 nM) in the absence of endothelium. Xylamine (10 μ m ) was without effect. 6 Inhibitory effects of NA uptake inhibitors on contractions were independent of the presence of endothelium and were unaffected by the K + channel blockers, tetraethylammonium ions (up to 3 mM) and glibenclamide (up to 30 μ m ). 7 These results indicate that tricyclic antidepressant drugs such as protriptyline and amitriptyline could act as both postsynaptic adrenoceptor antagonists and direct inhibitors of muscle contraction; whereas, xylamine, a structurally distinct NA uptake blocker might principally exert its action only at α‐adrenoceptors on rat aortic smooth muscle.