title: N-methyl-D-aspartate (NMDA) antagonists--S(+)-ketamine, dextrorphan, and dextromethorphan--act as calcium antagonists on bovine cerebral arteries.
abstract: Ketamine, an intravenous anesthetic and a major drug of abuse, is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine's enantiomer, S(+)-ketamine, acts stereoselectively on neuronal NMDA receptors. The purpose of this in vitro study was to compare the direct effects of S(+)-ketamine, 2 other noncompetitive NMDA receptor antagonists (dextrorphan and dextromethorphan), and the calcium entry blocker nimodipine on the cerebral vasculature, using bovine middle cerebral arteries as an experimental model. Arterial rings were mounted in isolated tissue chambers equipped with isometric tension transducers to obtain pharmacologic dose-response curves. In the absence of exogenous vasoconstrictors, the NMDA antagonists or nimodipine had negligible effects on cerebral arterial tone. When rings were preconstricted with either potassium or the stable thromboxane A2 mimetic U46619, the NMDA antagonists and nimodipine each produced dose-dependent relaxation. Prior endothelial stripping had no effect on subsequent drug-induced relaxation of K+-constricted rings. In Ca2+-deficient media containing either potassium or U46619, the NMDA antagonists and nimodipine each produced competitive inhibition of subsequent Cainduced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using 45calcium (45Ca) as a radioactive tracer. The NMDA antagonists and nimodipine each blocked potassium-stimulated or U46619-stimulated Ca2+ uptake into arterial strips. These results indicate that S(+)-ketamine, dextrorphan, and dextromethorphan, like nimodipine, directly dilate cerebral arteries by acting as calcium antagonists; they all inhibit 45Ca uptake through both potential-operated (potassium) and receptor-operated (U46619) channels in cerebrovascular smooth muscle.
authors.affiliation: Department of Anesthesiology, Temple University Hospital, Philadelphia, PA 19140, USA.
authors.forename: Ihab R
authors.initials: IR
authors.lastname: Kamel
authors.forename: Woodrow W
authors.initials: WW
authors.lastname: Wendling
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wendling
authors.forename: Concetta
authors.initials: C
authors.lastname: Harakal
authors.forename: Christer
authors.initials: C
authors.lastname: Carlsson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D002417:Cattle; D003915:Dextromethorphan / Q000494:pharmacology*; D003917:Dextrorphan / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D020768:Middle Cerebral Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009553:Nimodipine / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D018690:Excitatory Amino Acid Agonists; D014662:Vasoconstrictor Agents; D003917:Dextrorphan; D009553:Nimodipine; D016202:N-Methylaspartate; D007649:Ketamine; D003915:Dextromethorphan; D002118:Calcium