Abstract
The Delphinium alkaloids methyllycaconitine (MLA), nudicauline, 14-deacetylnudicauline (14-DN), barbinine, and deltaline were investigated for their effects on neuromuscular transmission in lizards. The substituent at C14 provides the only structural difference among the alkaloids MLA, nudicauline, 14-DN, and barbinine. Deltaline lacks the N-(methylsuccinyl)anthranilic acid at C18 common to the other four alkaloids. Each alkaloid reversibly reduced extracellularly recorded compound muscle action potential (CMAP) amplitudes in a concentration-dependent manner. The IC50values for CMAP blockade were between 0.32 and 13.2 μM for theN-(methylsuccinimido)anthranoyllycacotonine-type alkaloids and varied with the C14 moiety; the IC50 value for deltaline was 156 μM. The slopes of the concentration-response curves for CMAP blockade were similar for each alkaloid except barbinine, whose shallower curve suggested alternative or additional mechanisms of action. Each alkaloid reversibly reduced intracellularly recorded spontaneous, miniature end-plate potential (MEPP) amplitudes. Alkaloid concentrations producing similar reductions in MEPP amplitude were 0.05 μM for 14-DN, 0.10 μM for MLA, 0.50 μM for barbinine, and 20 μM for deltaline. Only barbinine altered the time constant for MEPP decay, further suggesting additional or alternative effects for this alkaloid. MLA and 14-DN blocked muscle contractions induced by exogenously added acetylcholine. All five alkaloids are likely nicotinic receptor antagonists that reduce synaptic efficacy and block neuromuscular transmission. The substituent at C14 determines the potency and possibly the mechanism of nicotinic acetylcholine receptor blockade for MLA, nudicauline, 14-DN, and barbinine at neuromuscular synapses. The lower potency of deltaline indicates that theN-(methylsuccinyl)anthranilic acid at C18 affects alkaloid interactions with nicotinic acetylcholine receptors at neuromuscular junctions.
Footnotes
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Send reprint requests to: Dr. John P. Walrond, Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523. E-mail:jwalrond{at}cvmbs.colostate.edu
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↵1 This work represents a portion of a thesis submitted to the Academic Faculty of Colorado State University in partial fulfillment of the requirements for the degree of Ph.D. (to P.D.). This work was supported by U.S. Department of Agriculture Contract 58-82HW-0-54 and U.S. Department of Agriculture Grant 94-37204-0495 to J.P.W.
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↵2 Current address: Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, CO 80309-0447.
- Abbreviations:
- MLA
- methyllycaconitine
- 14-DN
- 14-deacetylnudicauline
- nAChR
- nicotinic acetylcholine receptor
- CMAP
- compound muscle action potential
- MEPP
- miniature end-plate potential
- MDL
- 7,8-methylenedioxylycoctonine-type
- MSAL
- N-(methylsuccinimido)anthranoyllycacotonine
- EDL
- m. extensor digitorum longus
- PSS
- physiological saline solution
- Rm
- membrane resistance
- τMEPP
- miniature end-plate potential time constant
- τch
- acetylcholine receptor time constant
- τMEPC
- miniature end-plate current time constant
- Received March 10, 1999.
- Accepted July 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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