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 microM) and amitriptyline (0.3 microM) produced an approximately parallel shift to the right in the dose-response curve to NA. Protriptyline (> 0.3 microM), amitriptyline (> 0.3 microM) and xylamine (0.01-1 microM) significantly reduced the maximal contractile response to NA. The IC50 values for inhibition of the contractile response to 3 microM NA were 1.58 microM for xylamine, 1.70 microM for amitriptyline and 2.57 microM for protriptyline. 3 Protriptyline and amitriptyline dose-dependently inhibited the high K+ (60 mM)-induced contraction (IC50 = 0.69 microM for protriptyline and IC50 = 3.15 microM for amitriptyline). In contrast, xylamine did not affect the high K(+)-induced contraction. 4 Protriptyline and amitriptyline dose-dependently inhibited TPA (1 microM)-induced contraction in calcium-free solution; xylamine (up to 30 microM) was without effect. Staurosporine (10 nM) completely inhibited the TPA- and NA-induced contraction. 5. Protriptyline (3 microM) and amitriptyline (3 microM) caused about 54% and 60% inhibition, respectively, of aortic contractions caused by endothelin-1 (10 nM) in the absence of endothelium. Xylamine (10 microM) 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 microM). 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 alpha-adrenoceptors on rat aortic smooth muscle.