CALCIUM CONCENTRATION-DEPENDENT MECHANISMS THROUGH WHICH KETAMINE RELAXES CANINE AIRWAY SMOOTH-MUSCLE

Background: Ketamine is a potent bronchodilator that, in clinically us ed concentrations, relaxes airway smooth muscle in part by a direct ef fect. This study explored the role of calcium concentration (Ca2+) in this relaxation. Methods: Canine trachea smooth muscle strips were loa ded with the fluorescent probe fura-2 and mounted in a spectrophotomet ric system to measure force and intracellular calcium concentration ([ Ca2+](i)) simultaneously. Calcium influx was estimated using a mangane se quenching technique, Cyclic nucleotides in the airway smooth muscle strips were measured by radioimmunoassay. Results: In smooth muscle s trips stimulated with submaximal (0.1 mu M) and maximal (10 mu M) conc entrations of acetylcholine, ketamine caused a concentration-dependent decrease in force and [Ca2+](i). The sensitivity of the force respons e to ketamine significantly decreased as the intensity of muscarinic r eceptor stimulation increased; the median effective concentration for relaxation induced by ketamine was 59 mu M and 850 mu M for tissue con tracted by 0.1 mu M or 10 mu M acetylcholine, respectively (P < 0.05). In contrast, the sensitivity of the [Ca2+](i) response did not depend on the intensity of muscarinic receptor stimulation. Ketamine at 1 mM significantly inhibited calcium influx, Ketamine did not significantl y increase cyclic nucleotide concentrations. Conclusions: Ketamine-ind uced relaxation of canine ah-way smooth muscle is associated with a de crease in [Ca2+](i) and calcium influx, effects that are not mediated by an increase in cyclic nucleotides; and the sensitivity of the force response to ketamine decreases as the level of preexisting muscle ton e increases, an effect that is not explained by differential effects o n [Ca2+](i).