INHIBITION BY ADRENERGIC-NEURON BLOCKING-AGENTS OF THE RELAXATION INDUCED BY BRL-38227 IN VASCULAR, INTESTINAL AND UTERINE SMOOTH-MUSCLE

1 The adrenergic neurone blocking agents, guanethidine and bretylium, have been tested for inhibitory activity against the actions of some relaxant drugs (BRL 38227, noradrenaline, sodium nitroprusside, theophylline) in vascular, intestinal and uterine smooth muscle. 2 In guinea-pig isolated taenia caeci pre-contracted with KCl (25 mM), BRL 38227 (0.1 - 10 muM) and noradrenaline (10 nM - 100 muM) each caused concentration-dependent relaxation. Guanethidine and bretylium (50 muM) each antagonized the relaxation to BRL 38227 but not that to noradrenaline. At high concentration (500 muM), the adrenergic neurone blocking agents antagonized the action of BRL 38227 and, to some extent, that of noradrenaline. 3 In rat isolated aorta pre-contracted with noradrenaline (300 nM), BRL 38227 (0.0125 - 3.2 muM) and sodium nitroprusside (0.3 - 100 nM) each produced concentration-dependent smooth muscle relaxation. Guanethidine and bretylium (5 - 500 muM) each antagonized the action of BRL 38227 without antagonizing that of sodium nitroprusside. 4 Rats were pretreated with 17-beta oestradiol benzoate. Tension waves were then induced from segments of isolated, oestrogen-dominated uterus by transmural electrical stimulation or by oxytocin (0.2 nM). These tension waves were inhibited by BRL 38227 (0.025-3.2 muM) or theophylline (0.05-0.8 mM) in a concentration-dependent manner. Guanethidine (50 muM) antagonized the action of BRL 38227 in both the electrically- and oxytocin-driven tissues. In the electrically-driven tissues, guanethidine (50 muM) did not antagonize the inhibition to theophylline. 5 In KCl (25 mM)-treated guinea-pig taenia caeci, guanethidine (50 muM) inhibited the efflux of Rb-86+ evoked by BRL 38227 (10 muM) but not that evoked by noradrenaline (10 muM). In contrast, apamin (100 nM) reduced the efflux of Rb-86+ which was promoted by noradrenaline, but did not affect efflux induced by BRL 38227. 6 It is concluded that the adrenergic neurone blocking agents, guanethidine and bretylium (each at 50 muM), selectively inhibit the relaxant action of BRL 38227 in vascular, intestinal and uterine smooth muscle. If this inhibition reflects direct blockade of the K+-channel (K(KCO)) which is opened by BRL 38227, then the adrenergic neurone blocking agents act as inhibitors selective for K(KCO) as opposed to the small, apamin-sensitive (SK(Ca)) and large (BK(Ca)) conductance, Ca2+-dependent K+-channels.