PROLONGED D-TUBOCURARINE INFUSION AND OR IMMOBILIZATION CAUSE UP-REGULATION OF ACETYLCHOLINE-RECEPTORS AND HYPERKALEMIA TO SUCCINYLCHOLINE IN RATS/

Background: Hyperkalemic cardiac arrest after the administration of su ccinylcholine (SCh) to critically ill intensive care patients has been attributed to changes in the acetylcholine receptors (AChRs) at the m uscle membrane. The current study attempts to characterize the contrib utory roles of chronic administration of nondepolarizing muscle relaxa nts typified by d-tubocurarine (dTC) and/or of immobilization on AChR upregulation and the relationship of these AChR changes to SCh-induced hyperkalemia. Methods: Rats received chronic subparalytic infusion of saline or dTC for 28 days via subcutaneous osmotic pumps inserted whi le they were under anesthesia. Approximately half of the saline- or dT C-treated rats underwent bilateral hind-limb immobilization with plast er casts for the same duration as the infusion. After 4 weeks, the osm otic pumps were removed, and 24-48 h later, the blood potassium concen trations were measured at baseline and at 1, 3, 5, 7, and 10 min after SCh (3 mg/kg). At the end of this period, the gastrocnemius muscle wa s excised for quantitation of AChR number using I-125-alpha-bungarotox in. Results: At 28 days, the weight gain in mobile animals receiving s aline or dTC infusion did not differ, nor did that in immobilized anim als receiving saline or dTC infusion, confirming that infusion of dTC did not unduly affect the ability of the animals to feed. The maximal potassium change after SCh occurred at 5 min. Potassium responses to S Ch changed (mean +/- SE): (1) from 3.9 +/- 0.04 to 4.5 +/- 0.1 mEq/l i n the mobile saline-treated control group, where the AChR concentratio n was 18.4 +/- 2 fmol/mg protein; (2) from 3.9 +/- 0.03 to 5.1 +/- 0.1 in the mobile dTC-infused group (AChRs = 48.6 +/- 7); (3) from 3.8 +/ - 0.1 to 5.5 +/- 0.3 in the immobilized saline-treated group (AChRs = 107.4 +/- 14); and (4) from 3.8 +/- 0.1 to 6.3 +/- 0.2 in the immobili zed-dTC-treated group (AChRs = 183.5 +/- 23). There was a significant positive correlation between maximal change in blood potassium concent ration and the respective AChR concentration in the gastrocnemius of t he same animal (r = 0.81, P < 0.01). Conclusions: Subtherapeutic (subp aralytic) doses of chronic infusion of dTC (with no immobilization) or immobilization alone (with no dTC) independently increased number of AChRs. The infusion of (ITC with immobilization caused the greatest up regulation of AChRs. The magnitude of the increase in blood potassium to SCh was directly dependent on AChR number. This study shows direct evidence and confirms previous speculation that AChR number plays an i mportant role in the magnitude of the hyperkalemic response to SCh. Pr esuming this represents an appropriate model for patients who are immo bilized and/or receiving nondepolarizing muscle relaxants for prolonge d periods, exaggerated blood potassium responses to SCh are possible w hen either or both of these perturbations are present in patients.