Nondepolarizing neuromuscular blockers inhibit the serotonin-type 3A receptor expressed in Xenopus oocytes

Molecular cloning and sequence comparison indicates a high degree of structural homology between muscle nicotinic acetylcholine (nACh) and serotonin-type 3 (5-HT3A) receptors, both members of the direct ligand-gated family of ion channels. Because of the structural similarities and common evolutionary origin of these receptors, neuromuscular blockers (competitive nACh antagonists) may demonstrate pharmacologic cross talk and exhibit attributes of 5-HT3A receptor antagonists. We examined six clinically-used neuromuscular blockers for their ability to antagonize currents flowing through the 5-HT3A receptors in voltage clamped Xenopus oocytes. The neuromuscular blockers reversibly inhibited the 5-HT3A receptor-gated current in the rank order potency of (IC50 mean +/- SEM): d-tubocurarine (0.046 +/- 0.003 mu M), atracurium (0.40 +/- 0.03 mu M), mivacurium (15.1 +/- 2.93 mu M), vecuronium (16.3 +/- 2.24 mu M), and rocuronium (19.5 +/- 2.31 mu M) Gallamine was essentially inactive as a 5-HT3A receptor antagonist with an extrapolated IC50 of 1170 mu M. We demonstrate that drugs classically known as competitive nACh receptor antagonists also block 5-HT3A receptors. It is likely that certain neuromuscular blockers share pharmacological properties with 5-HT3A receptor antagonists, such as a reduction in postoperative nausea and vomiting. With careful drug selection, pharmacological cross talk could potentially be used to minimize polypharmacy and optimize patient management. Implications: Muscle nicotinic acetylcholine and serotonin-type3A (5-HT3A) receptors are similar. Therefore neuromuscular relaxants may block 5-HT3A receptors. our pharmacological study demonstrates that neuromuscular relaxants, as with ondansetron, are 5-HT3A receptor antagonists. It is likely that certain neuromuscular relaxants exhibit ondansetron-like clinical properties, such as reduction in postoperative nausea and vomiting.