Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors.
Antagonists of the serotonergic 5-hydroxytryptamine 3A receptor (5-HT(3A)R) and muscle nicotinic acetylcholine receptors (nAChR) are widely used in anesthesia practice. Both 5-HT(3A)R and nAChR are ligand-gated ion channels with known pharmacological overlap between some of their agonists and antagonists. We studied the actions of clinically used 5-HT(3A)R antagonist antiemetics and nondepolarizing muscle blockers on ionic currents elicited by the activation of mammalian 5-HT(3A)R and muscle nAChR, expressed in Xenopus laevis oocytes. Currents were recorded using a whole-cell two-electrode voltage clamp technique. Dolasetron, ondansetron, and granisetron reversibly inhibited 5-HT(3A)R function at nanomolar concentrations with 50% inhibitory concentrations (IC(50)) of 11.8, 6.4, and 0.2 nM; the rank order of inhibition correlated well with their clinical antiemetic potencies. The principal metabolite of dolasetron, hydrodolasetron, was 40 times more potent than the parent compound on 5-HT(3A)R (IC(50) = 0.29 nM). The potency of the nondepolarizing muscle blocker d-tubocurarine in blocking 5-HT(3A)R was similar to that of the antiemetics and significantly more than vecuronium and rapacuronium (IC(50) = 11.4 nM, 18.9 microM, 60.5 microM). Conversely, ondansetron, dolasetron, and granisetron also reversibly inhibited nAChR currents in a dose-dependent manner with IC(50)s of 14.2, 7.8, and 4.4 microM for the adult nAChR and 16.0, 18.6, and 13.9 microM for the embryonic nAChR. Again, hydrodolasetron showed significantly (10 times) more inhibitory potency on the adult nAChR than the parent compound dolasetron. These results indicate that drugs that target specific ligand-gated ion channels may also affect other ion channel types.
Paul
Matthias
M
*Department of Anesthesia and Perioperative Care, University of Cologne, Cologne, Germany; †Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California; and ‡Department of Anesthesia, University Hospital, Basel, Switzerland.
Callahan
Robert
R
Au
John
J
Kindler
Christoph H
CH
Yost
C Spencer
CS
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018075:RNA, Complementary / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014403:Tubocurarine / Q000494:pharmacology; D014673:Vecuronium Bromide / Q000031:analogs & derivatives / Q000494:pharmacology
D000932:Antiemetics; D003473:Neuromuscular Nondepolarizing Agents; D018733:Nicotinic Antagonists; D018075:RNA, Complementary; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D012701:Serotonin; D014673:Vecuronium Bromide; C082938:rapacuronium; D014403:Tubocurarine