Effects of Bay K 8644 on spontaneous and evoked transmitter release at the mouse neuromuscular junction.
The dihydropyridine, Bay K 8644, was applied in vitro to mouse phrenic nerve-diaphragm muscle preparations. The drug increased both spontaneous and evoked release of acetylcholine from the motor nerve terminal in a concentration- and time-dependent manner. The rise in miniature endplate potential frequency, however, was the result of an increased intraterminal mobilization of free calcium, rather than well-established activation of voltage-dependent calcium channels. This view is supported by the following observations: (1) an increase in frequency was apparent in Ca2+-free medium; (2) Bay K 8644 is known to require a moderate depolarization to affect Ca2+ channels, but no membrane depolarization was detected; and (3) exposure to low Ca2+ and high Mg2+ medium did not diminish the effect on miniature endplate potential frequency. In a medium containing low Ca2+ and high Mg2+, Bay K 8644 increased quantal content of the evoked endplate potentials to a greater degree and with a faster time course than the frequency of miniature endplate potentials. This enhancement in evoked release did not appear to be caused solely by an increase in cytoplasmic Ca2+, but rather reflected at least in part the Bay K 8644-induced activation of voltage-gated Ca2+ channels, perhaps L-type, at the presynaptic nerve terminal. Thus, we propose that Bay K 8644 exerts dual effects on the motor nerve endings, characterized by a primary action on the presynaptic Ca2+ channels and a secondary action associated with the elevation of intracellular Ca2+ concentration.
Pancrazio
J J
JJ
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville 22908.
Viglione
M P
MP
Kim
Y I
YI
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000109:Acetylcholine / Q000378:metabolism* / Q000502:physiology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004095:Dihydropyridines / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D004095:Dihydropyridines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000109:Acetylcholine