Speed of action of various muscle relaxants at the neuromuscular junction binding vs. buffering hypothesis.
The speed of action of several nondepolarizing muscle relaxants (gallamine, rocuronium, D-tubocurarine, atracurium, vecuronium, pancuronium and doxacurium) was tested iontophoretically at the frog cutaneous pectoris neuromuscular junction at various temperatures. If differences in rate of onset and offset are due to different molecular rates of binding (and unbinding), and of resulting conformational changes, they should be strongly temperature dependent. In contrast, if differences are due to differences in buffered diffusion, temperature dependence should be low to moderate. The onset and recovery time constants of inhibition of brief acetylcholine pulses, caused by long pulses of relaxants for all of the muscle relaxants, were inversely related to apparent dissociation constants (KD values), that ranged from 4.56 microM (gallamine) to 0.11 microM (doxacurium). The kinetics showed only modest temperature dependence (Q10 values of 1/time constant of offset were typically < 1.4). Because KD values of all muscle relaxants were even less temperature dependent (Q10 < 1.3), this suggests that the kinetics of inhibition is probably determined by the extent of buffering in the synaptic cleft, and not by binding and unbinding. Diffusion of relaxants from the synaptic cleft is expected to be strongly buffered, because the nerve terminal presents a physical barrier to diffusion, and because of extremely high density of acetylcholine receptors. The density of acetylcholine receptors can be calculated from the time constant of offset and KD values of various relaxants, assuming that buffer diffusion is determining the kinetics of action of muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)
Glavinovic
M I
MI
Department of Anesthesia Research, McGill University, Montreal, Canada.
Law Min
J C
JC
Kapural
L
L
Donati
F
F
Bevan
D R
DR
D000818:Animals; D001665:Binding Sites; D002021:Buffers; D004058:Diffusion; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D003473:Neuromuscular Nondepolarizing Agents / Q000378:metabolism / Q000494:pharmacology*; D011894:Rana pipiens; D011950:Receptors, Cholinergic / Q000378:metabolism; D013696:Temperature
D002021:Buffers; D003473:Neuromuscular Nondepolarizing Agents; D011950:Receptors, Cholinergic