Tolerance and upregulation of acetylcholine receptors follow chronic infusion of d-tubocurarine

Abstract

The hypothesis that chronic competitive antagonism of nicotinic acetylcholine receptors (nAChR), even in the absence of immobilization or paralysis, induces proliferation of the receptor and tolerance to the competitive antagonist was tested. Chronic antagonism of the nAChR was achieved in rats by an infusion of d-tubocurarine (dTC) via subcutaneously placed osmotic pumps. After 2 wk of dTC or saline, the neuromuscular pharmacodynamics and nAChR number were examined. No differences in weight gain or mobility were observed between groups. Chronic dTC infusion at 2 wk resulted in a baseline concentration of 0.41 +/- 0.07 (SE) micrograms/ml, which, if achieved acutely, would cause a depression of the twitch tension to 60% of control twitch height. Moreover the experimental group was able to develop a baseline twitch tension of 50 g, similar to that of controls. Despite the baseline dTC concentration in the experimental group, the effective doses of dTC for twitch depression were similar to those of controls. The plasma dTC concentration required for steady-state twitch inhibition was significantly (P less than 0.05) higher in the experimental group (0.83 +/- 0.04 vs. 0.50 +/- 0.15 micrograms/ml) as were the extrajunctional nAChR (19.76 +/- 1.77 vs. 13.37 +/- 1.82 fmol/mg protein). The diaphragmatic nAChR were unaltered. This study confirms that chronic doses of dTC cause tolerance to its effects and proliferation of nAChR even in the absence of immobilization. The absence of nAChR changes in the diaphragm may be due to the higher margin of safety of the diaphragm for muscle relaxants than for peripheral muscles. Intensive Care Unit patients receiving chronic infusions of dTC to facilitate mechanical ventilation will require increased doses with time.