Local Anesthetic Contracture and Relaxation of Airway Smooth Muscle

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Abstract
Local anesthetics administered as an aerosol may have clinical use as bronchodilators. To assess direct actions on airway smooth muscle the effects of 5 local anesthetics on intrinsic and agonist-induced tone of guinea-pig tracheal chains were studied. Drug effects were recorded with an isotonic transducer against a tension of either 300 mg or 4 g and were expressed as percentages of the maximal relaxation produced by isoproterenol (10-6 M) or the maximal contracture produced by acetylcholine (10-3 M). Bath solution was usually maintained at pH 7.5, but the effects of lidocaine were also studied at pH 7.0 and pH 8.0, produced by changing the concentrations of CO2 and bicarbonate ion. In lightly weighted tracheal chains, tricaine produced purely relaxant effects, whereas lidocaine, bupivacaine, procaine and tetracaine produced contracture at low concentrations and relaxation at higher concentrations. The transition from contracture to relaxation occurred at a breakpoint concentration characteristic for each anesthetic. Lidocaine produced dose-related contracture from 3 .times. 10-5 to 10-3, with greater effect (P < .05) at pH 7.0 than at pH 8.0; correlation coefficients for contracture as an exponential function of lidocaine concentration were significantly greater (P < .01) for ionized drug (r = 0.96) or total drug (r = 0.92) than for nonionized drug (r = 0.71). All local anesthetics produced predominantly relaxant effects when tested in heavily weighted chains that were partially contracted with carbamylcholine (3 .times. 10-7 M) or histamine (3 .times. 10-5 M). At low concentrations, 3 .times. 10-5 to 10-4 M, procaine (P < .001), tetracaine (P < .05) and bupivacaine (P < .05) were more effective against carbamylcholine than histamine; the low-dose anticholinergic effects of procaine and tetracaine were greater (P < .01) than those of other local anesthetics and at 10-4 M produced relaxation equivalent to 47 .+-. 3 (.+-. SE) and 40 .+-. 7%, respectively, of the maximal effect of isoproterenol. At high concentration, 10-3 M, tricaine, bupivacaine and tetracaine produced nearly complete relaxation of both carbamylcholine- and histamine-enhanced tone, but the relaxant effects of lidocaine and procaine were significantly less (P < .01). The results show that there are marked differences in the direct effects of local anesthetics on airway smooth muscle that could affect their clinical use as bronchodilators. These differences include extent of contracture, anticholinergic effects at low concentration and nonspecific relaxant effects at high concentration. The poor correlation of contracture with concentration of nonionized drug suggests a superficial site of action for the contractor effect.