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

Abstract

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 e ect of guanethidine. Therefore, we investigated the e ect of increasing concentrations of guanethidine (0.1 ± 100 mM) on nicotineinduced relaxations of longitudinal muscle strips of rat gastric fundus. 2 In the presence of 1 mM atropine and 3 mM guanethidine, nicotine (30 mM) induces a fast and sustained relaxation which is partly inhibited by the nitric oxide synthase inhibitors No-nitro-Larginine (L-NOARG) and No-nitro-L-arginine methyl ester (L-NAME) (both 30 and 100 mM). One mM tetrodotoxin (TTX) completely blocks this nicotine-induced relaxation. 3 High concentrations of guanethidine (510 mM), but not adrenoceptor blockade by the aadrenoceptor antagonist phentolamine in combination with the b-adrenoceptor antagonist nadolol (both 3 mM), inhibit the nicotine-induced relaxation. 4 Guanethidine (0.1 ± 100 mM) has no e ect on relaxations induced by electrical ®eld stimulation (EFS; 1 ± 8 Hz), nitric oxide (NO; 0.01 ± 1 mM), vasoactive intestinal polypeptide (VIP; 0.1 ± 10 nM) or isoprenaline (1 ± 10 nM). 5 We conclude that high concentrations of guanethidine (510 mM) block nicotine-induced NANC relaxations of longitudinal muscle strips of the rat gastric fundus most likely at the level of the nicotinic acetylcholine receptor.

Activation of an adrenergic and vagally‐mediated NANC pathway in surgery‐induced fundic relaxation in the rat

“…Alternatively, guanethidine may be more po-tent in inhibiting re¯ex pathways by its potential local anaesthetic effects or its possible nicotinic receptorblocking effect. 35,36 Interestingly, adrenergic receptor blockade and guanethidine slowed the onset of the relaxation evoked by M + R, which may indicate that adrenergic nerves provide a fast-onset component, whereas the NANC component is slower in onset. Comparable ®ndings were reported earlier in vitro where the nerve-mediated NANC relaxation of the rat gastric fundus is also composed of a fast nitrergic component and a slower peptidergic or vasoactive intestinal polypeptide-mediated component.…”

Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by α2‐adrenoceptors in the presence of experimental colitis

“…Therefore, when interpreting the present results from guanethidine‐treated animals, we took into account the possibility that nicotinic transmission might be implicated in the reduction of intestinal transit elicited by colitis. However, the putative antagonism of guanethidine on nicotinic receptors seems to occur only at high concentrations (>10 μ M ), and was not substantiated by radioligand binding experiments (Blommaart et al ., 1999). Furthermore, the colitis‐induced reduction of intestinal transit was fully reversed by rauwolscine, suggesting the presence of a sympathetic inhibitory tone on digestive motility, driven via activation of α 2 ‐adrenoceptors.…”

“…The use of guanethidine as an adrenergic neuron blocker deserves some comments. We are aware that guanethidine has been suggested to act also as a nicotinic receptor blocker at the level of enteric neurons (Blommaart et al ., 1999). Therefore, when interpreting the present results from guanethidine‐treated animals, we took into account the possibility that nicotinic transmission might be implicated in the reduction of intestinal transit elicited by colitis.…”