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1. Using a guinea-pig model of allergic asthma, in which the animals display early (0-5 h) and late phase (8-23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2. Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3. After the early response, there was no change in cardiac muscarinic M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 autoreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine-induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Neuromuscular blockade studies often use the thumb adductor twitch response to ulna nerve stimulation. Two factors that may influence the results are the resting muscle tension (initial fiber length) and the pattern of the stimulus wave form. This study was undertaken to improve understanding of the effect of these factors and lead to better controlled study conditions and more consistent data. During nitrous oxide-barbiturate-narcotic anesthesia in 10 normal adult patients, as the resting thumb tension was increased from 50 to 200 g, the evoked thumb adductor twitch response (Grass stimulator, 0.25 Hz) was augmented by 28%. There was only a 2.5% increase in the evoked (developed) tension when the resting tension was further increased from 200 to 300 g. Developed tension at 50 g was significantly (p less than 0.001) less than at the other resting tensions. The developed tension at 100 g was also significantly (p less than 0.05) less than at resting tensions of 200 or 300 g. Cumulative dose-response curves for gallamine in nine patients were not significantly altered by increasing resting tension from 50 to 200 g. Biphasic (Block-Aide monitor) or single square wave (Grass stimulator) stimuli wave forms in nine normal adult patients yielded gallamine dose-response curves that were not statistically different. The muscle response to biphasic stimulation during a non-depolarizing blockade was not affected by the average muscle refractory period. Because of the significantly lower developed tension at resting tension settings of 50 to 100 g, a practical consideration during neuromuscular function studies would be to have the resting thumb tension adjusted and rechecked for each patient and kept within the 200-300-g range to ensure maximum uniform developed tension. The type of stimulus wave form selected will not affect results as long as it is used consistently throughout the study.

Gallamine, metocurine, pancuronium, and d-tubocurarine were compared when given alone and in combination with isolated guinea pig nerve-lumbrical preparations stimulated via the nerve. The experimental design was set up to control the effects of variation among preparations, order of administration, and time of administration (i.e., fresh vs. older preparation). The result was an assay able to measure potentiation with a coefficient of variation of 3%. A format for a graphic presentation to summarize such results is presented and discussed. Two combinations, gallamine plus d-tubocurarine and gallamine plus pancuronium, showed no sign of an interaction beyond that to be expected from a simple competitive interaction. Two others, metocurine plus pancuronium and gallamine plus metocurine, showed about a twofold greater potency when combined than would have been expected. The last two sets, pancuronium plus d-tubocurarine and metocurine plus d-tubocurarine, showed a slight degree of potentiation. These studies demonstrate that the deviation from simple additivity seen in vivo persists when examined in a system free from artifacts associated with uptake and distribution in the whole organism.

Fifty patients were pretreated with either suxamethonium 10 mg or gallamine 20 mg before an injection of suxamethonium 1 mg kg-1. The effect of the pretreatment upon neuromuscular transmission was monitored by recording the mechanical response of the adductor pollicis muscle to indirect stimulation, using a 2-Hz train-of-four stimulus repeated every 12 s. The pretreatment injection of suxamethonium caused fasciculation in one-quarter of the patients studied. Significant neuromuscular blockade occurred during pretreatment in 16 of the 25 patients investigated. Pretreatment with gallamine 20 mg predictably decreased the efficacy of the intubating injection of suxamethonium, making intubation more difficult. The frequency of muscle pain was similar in both groups.

Supramaximal paired stimuli were applied to the ulnar nerve, and the amplitude of the muscle action potential evoked in the abductor digiti minimi by the second member of the stimulus pair (test response) was compared with that evoked by the first component (conditioning response). The interval between the two components of the stimulus pair (the pair interval) was increased stepwise from 7 to 100 msec and a curve (recovery curve) was obtained by relating the changes in pair interval to the difference in amplitude of the test and conditioning responses. Alterations of the recovery curve (RC) during partial paralysis by muscle relaxants were investigated in healthy adult patients under the lightest plane of general anaesthesia. The control curve obtained in 32 subjects before the administration of a muscle relaxant drug was characterized by slight depressions at very short intervals of paired stimuli, followed by a slight potentiation at 20-100 msec. With non-depolarizing relaxants, RC altered to the characteristic pattern of potentiation at very short intervals of stimuli, followed by a notable depression at longer intervals. In depolarizing blocks with small doses of suxamethonium, the depression of RC at short intervals in the control was enhanced and the pattern of RC was different from that of non-depolarizing agents. When desensitization blocks were instigated by the i.v. administration of suxamethonium, the RC patterns were similar to those of competitive agents.

A technique combining an intravenous bolus and intravenous infusion regimen of gallamine based on its pharmacokinetics was developed to produce continuous relaxation during surgery. The combination of a bolus dose of gallamine, 2.5 mg/kg, and infusion, 0.8 mg/kg/hr, was tested in 11 patients. In 10 patients, surgery continued long enough to allow demonstration of an apparent plateau in the serum gallamine concentrations. At the cessation of the infusion, the mean gallamine concentration of 11.8 microgram/ml was associated with an average paralysis intensity of 92%. Pharmacokinetic analysis of the gallamine serum concentration-time data was fitted to a three-compartment model. In this study of 50- to 76-year-old patients, the most striking difference from other studies was that the elimination halflife averaged 247 minutes in this study whereas 128 to 141 minutes has been reported previously.