Different magnitude of resistance to nondepolarizing muscle relaxants in the denervated mouse skeletal muscle
Abstract
Aim: To test the hypothesis that different magnitude of resistance of denervated skeletal muscle to nondepolarizing muscle relaxants (NDMRs) is related to their varying potencies at ε-AChR and γ-AChR.
Methods: Both innervated and denervated mouse muscle cells, and human embryonic kidney 293 (HEK293) cells expressing ε-AChR or γ-AChR were used. The effects of NDMRs on nAChR were explored using whole-cell patch clamp technique.
Results: NDMRs vecuronium (VEC), atracurium (ATR) and rocuronium (ROC) produced reversible, dose-dependent inhibition on the currents induced by 30 μmol/L acetylcholine both in innervated and denervated skeletal muscle cells. Compared to those obtained in innervated skeletal muscle cells, denervation shifted the concentration-response curves rightward and significantly increased the 50% inhibitory concentration (IC50) values (VEC: from 11.2 to 39.2 nmol/L, P<0.01; ATR: from 24.4 to 129.0 nmol/L, P<0.01; ROC: from 37.9 to 101.4 nmol/L, P<0.01). In HEK293 cell expression system, ATR was less potent at γ-AChR than ε-AChR (IC50 values: 35.9 vs 22.3 nmol/L, P<0.01), VEC was equipotent at both receptor subtypes (IC50 values: 9.9 vs 10.2 nmol/L, P>0.05), while ROC was more potent at γ-AChR than ε-AChR (IC50 values: 22.3 vs 33.5 nmol/L, P <0.05).
Conclusion: Magnitude differences of resistance to different NDMRs caused by denervation are associated with distinct potencies of NDMRs at nAChR subtypes.
Keywords:
Methods: Both innervated and denervated mouse muscle cells, and human embryonic kidney 293 (HEK293) cells expressing ε-AChR or γ-AChR were used. The effects of NDMRs on nAChR were explored using whole-cell patch clamp technique.
Results: NDMRs vecuronium (VEC), atracurium (ATR) and rocuronium (ROC) produced reversible, dose-dependent inhibition on the currents induced by 30 μmol/L acetylcholine both in innervated and denervated skeletal muscle cells. Compared to those obtained in innervated skeletal muscle cells, denervation shifted the concentration-response curves rightward and significantly increased the 50% inhibitory concentration (IC50) values (VEC: from 11.2 to 39.2 nmol/L, P<0.01; ATR: from 24.4 to 129.0 nmol/L, P<0.01; ROC: from 37.9 to 101.4 nmol/L, P<0.01). In HEK293 cell expression system, ATR was less potent at γ-AChR than ε-AChR (IC50 values: 35.9 vs 22.3 nmol/L, P<0.01), VEC was equipotent at both receptor subtypes (IC50 values: 9.9 vs 10.2 nmol/L, P>0.05), while ROC was more potent at γ-AChR than ε-AChR (IC50 values: 22.3 vs 33.5 nmol/L, P <0.05).
Conclusion: Magnitude differences of resistance to different NDMRs caused by denervation are associated with distinct potencies of NDMRs at nAChR subtypes.