Nicotinic acetylcholine receptor blocking effect of guanethidine in the rat gastric fundus

1 Guanethidine is commonly used as a drug to investigate adrenergic neurotransmission and, in combination with atropine, to realize non-adrenergic non-cholinergic (NANC) conditions. Previous studies suggested a nicotinic acetylcholine receptor blocking effect of guanethidine. Therefore, we investigated the effect of increasing concentrations of guanethidine (0.1-100 mu M) on nicotine-induced relaxations of longitudinal muscle strips of rat gastric fundus. 2 In the presence of 1 mu M atropine and 3 mu M guanethidine, nicotine (30 mu M) induces a fast and sustained relaxation which is partly inhibited by the nitric oxide synthase inhibitors N omega-nitro-L-arginine (L-NOARG) and N omega-nitro-L-arginine methyl ester (L-NAME) (both 30 and 100 mu M). One mu M tetrodotoxin (TTX) completely blocks this nicotine-induced relaxation. 3 High concentrations of guanethidine (greater than or equal to 10 mu M), but not adrenoceptor blockade by the alpha-adrenoceptor antagonist phentolamine in combination with the beta-adrenoceptor antagonist nadolol (both 3 mu M), inhibit the nicotine-induced relaxation. 4 Guanethidine (0.1-100 mu M) has no effect on relaxations induced by electrical field stimulation (EFS; 1-8 Hz), nitric oxide (NO; 0.01-1 mu M), vasoactive intestinal polypeptide (VIP; 0.1-10 nM) or isoprenaline (1-10 nM). 5 We conclude that high concentrations of guanethidine (greater than or equal to 10 mu M) block nicotine-induced NANC relaxations of longitudinal muscle strips of the rat gastric fundus most likely at the level of the nicotinic acetylcholine receptor.