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ANESTHETIC PHARMACOLOGY

Antiemetics of the 5-Hydroxytryptamine 3A Antagonist Class Inhibit Muscle Nicotinic Acetylcholine Receptors

Matthias Paul, MD, DEAA^*, Robert Callahan, BS, John Au, BS, Christoph H. Kindler, MD, DEAA, and C. Spencer Yost, MD

*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

Address correspondence and reprint requests to C. Spencer Yost, MD, Department of Anesthesia and Perioperative Care, University of California, 513 Parnassus Ave., Room S-261, Box 0542, San Francisco, CA 94143-0542. Address e-mail to spyost{at}itsa.ucsf.edu.

Antagonists of the serotonergic 5-hydroxytryptamine 3A receptor (5-HT_3AR) and muscle nicotinic acetylcholine receptors (nAChR) are widely used in anesthesia practice. Both 5-HT_3AR 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_3AR antagonist antiemetics and nondepolarizing muscle blockers on ionic currents elicited by the activation of mammalian 5-HT_3AR 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_3AR function at nanomolar concentrations with 50% inhibitory concentrations (IC₅₀) 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_3AR (IC₅₀ = 0.29 nM). The potency of the nondepolarizing muscle blocker d-tubocurarine in blocking 5-HT_3AR was similar to that of the antiemetics and significantly more than vecuronium and rapacuronium (IC₅₀ = 11.4 nM, 18.9 µM, 60.5 µM). Conversely, ondansetron, dolasetron, and granisetron also reversibly inhibited nAChR currents in a dose-dependent manner with IC₅₀s of 14.2, 7.8, and 4.4 µM for the adult nAChR and 16.0, 18.6, and 13.9 µM 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.