Investigation of endogenous neurotransmitters of guinea pig gallbladder using nicotinic agonist stimulation

Gallbladder motility is modulated by intrinsic nerves, the identities of which are not well established. The aim of this study was to determine the effect of nicotinic receptor stimulation of intrinsic nerves on gallbladder muscle contractility. Guinea pig gallbladder muscle strips were studied in vitro. Histamine 1 microM was used to increase baseline tone. The nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), produced a biphasic response characterized by an initial transient contraction followed by a sustained relaxation. The initial contraction was inhibited by the neural blocker tetrodotoxin, the nicotinic antagonist hexamethonium, and the muscarinic antagonist atropine, but not by a substance P receptor antagonist or a bombesin receptor antagonist. The relaxation response to DMPP was not affected by tetrodotoxin, but was reduced by hexamethonium and omega-conotoxin GVIA, an inhibitor of neurotransmitter release. The relaxation response was reduced by the nitric oxide synthase inhibitor L-NAME, but not by a vasoactive intestinal peptide antagonist or propranolol. DMPP produces a biphasic response in the guinea pig gallbladder. The initial contractile response is mediated by nicotinic receptors on the cell body or axon of cholinergic nerves. The relaxation response appears to result, in part, from activation of nicotinic receptors on nerve terminals of nitric oxide-releasing nerves. These results suggest nicotinic receptors have heterogeneity in location depending on excitatory or inhibitory neuronal function.