A comparison of the skeletal neuromuscular and autonomic ganglion-blocking potencies of five non-depolarizing relaxants.

1 Results from in vitro experiments on the phrenic nerve-diaphragm and the hypogastric nerve-vas deferens preparations of the guinea-pig have been used to plot log concentration-effect curves for skeletal neuromuscular and ganglion blockade, respectively, for (+)-tubocurarine, pancuronium, alcuronium, gallamine and fazadinium (AH 8165). 2 From the log concentration-effect curves, EC50S and equipotent ratios were calculated. The order of neuromuscular blocking potency was pancuronium = alcuronium > (+)-tubocurarine > fazadinium = gallamine. The ratio EC50 for ganglion blockade/EC50 for neuromuscular blockade was 2.3 for fazadinium, 6.7 for (+)-tubocurarine, 22.9 for alcuronium, 24.3 for gallamine and 200.0 for pancuronium. 3 For pancuronium and gallamine there was a range of concentrations below those producing ganglion blockade at which the response of the vas deferens to hypogastric nerve stimulation was augmented. 4 The results are compared with some of those available in the literature, measured on other species by other methods.

The response of the circular muscle layer of the guinea-pig isolated vas deferens to transmural electrical stimulation.

1 Four preparations are described for the isolation of the response of the circular muscle of the guinea-pig vas deferens. These are the ;Furchgott' strip, the ;Vane' strip, the chain preparation and the perfused preparation.2 The four preparations were stimulated transmurally with pulses of supramaximal voltage. The threshold pulse width to which the strips and the perfused preparation responded was 0.025 ms and the maximum responses occurred at 0.1 ms. The threshold frequency was 2 Hz for strip and perfused preparations, the maxima being 20 or 50 Hz for strip preparations and 100 Hz for perfused preparations. The effect of varying the number of pulses per train was also investigated on the perfused vas. Responses occurred to train lengths of 8, 16, 32, 128 pulses, the maximum response being given at 128 pulses at 100 Hz; 256 pulses per train did not produce a further increase in response. The perfused preparation exhibited an after-response at certain frequencies and train lengths.3 Tetrodotoxin and the local anaesthetics, procaine and lignocaine, reversibly abolished the responses of strip and perfused preparations to transmural stimulation.4 The response to intramural nerve fibre stimulation was abolished by guanethidine or bethanidine; this abolition was reversed by dexamphetamine. Noradrenaline contracted strip preparations of circular muscle and raised the pressure in perfused preparations; noradrenaline was competitively antagonized by thymoxamine. The major part of the motor innervation of the circular layer seems to be noradrenergic.

The isolated circular muscle layer of the vas deferens of the guinea-pig.

1 A method is described for the removal of the outer longitudinal layer of muscle from the guinea-pig isolated vas deferens. The remaining tube of circular muscle was perfused at constant flow for recording changes in pressure in response to transmural electrical stimulation or to drugs. 2 The response to transmural stimulation was a rise in perfusion pressure at frequencies of stimulation of 5 to 50 Hz for trains of 16 to 256 pulses. At some frequencies and train lengths a second rise in pressure (the after-response) occurred after the cessation of the stimulus train. 3 Perfused vasa stripped of their longitudinal muscle did not develop longitudinal tension on electrical stimulation nor on intraluminal or extraluminal exposure to agonists. 4 Stripped perfused vasa gave concentration-dependent pressure rises to noradrenaline but not to acetylcholine. 5 Responses to transmural stimulation and to noradrenaline were antagonized by thymoxamine. Cocaine or desmethylimipramine increased the duration of the after-response to transmural stimulation. Reserpine pretreatment almost abolished the response and after-response. The after-response, but not the response, was increased by physostigmine and antagonized by atropine. 6 The results are discussed in relation to the known histochemical and electronmicroscopical demonstrations of dense noradrenergic and cholinergic populations of nerve terminals in the circular layer. It is suggested that mechanisms may exist for the separate control of the longitudinal and circular layers as a basis for propulsive activity.

Antagonism of the response of human isolated arteries to noradrenaline.

1. Spirally-cut strips from human visceral arteries isolated in vitro were contracted by noradrenaline and this contraction was antagonized by the alpha-receptor blocking agent, thymoxamine.2. The cumulative log dose-response curves to noradrenaline in the presence of thymoxamine were moved to the right of and parallel to the curve for noradrenaline alone. The blockade was surmountable and reversible.3. The quantitative criteria for simple competitive antagonism were satisfied. When log (x - 1) was plotted against pA(x) the points fitted a straight line with a slope (-n) of 0.91. The pA(2) for thymoxamine was 7.54 and the mean value for log K(2) was 7.82. These values are in approximate agreement with those previously reported for animal isolated arterial strips.

A comparison of the sensitivities of innervated and denervated rat vasa deferentia to agonist drugs.

1. One vas deferens of a rat was denervated by stripping away the serous coat; the other vas was left intact as a control. One week later the sensitivity in vitro of both vasa deferentia to noradrenaline, adrenaline, dopamine, oxymetazoline or acetylcholine was measured.2. Log concentration response curves for the mean responses of both vasa from a group of four rats for each drug were plotted. Denervated vasa were more sensitive than control vasa to noradrenaline (16-fold), to adrenaline (8-fold), to dopamine (2-fold) and to oxymetazoline (2-fold). Denervated vasa were more sensitive to acetylcholine over the lower half of the concentration range only.3. It is concluded that these results support the theory that at least part of the increased sensitivity of denervated smooth muscle to catecholamines is due to an abolition or reduction of the neuronal uptake process. There is also a small non-specific increase in sensitivity.

Effects of a sedative and of a non-sedative H1-antihistamine on the event-related potential (ERP) in normal volunteers.

Measurements of the amplitude and latency of the P3b component of the event-related potential (ERP), simple reaction time (SRT) and four psychomotor tests (VAS, DSST, DSp and CFF) were made on 12 male subjects (aged 19-24 years) 1.0-1.5 and 4.0-4.5 h after single oral doses of triprolidine (7.5 mg), terfenadine (60 mg) and placebo. Neither triprolidine nor terfenadine changed P3b amplitude or latency although VAS, CFF and DSST scores were significantly altered by triprolidine at 1.0-1.5 h after dosage. These results suggest that the P3b is too robust to reflect the mild sedative properties of an H1-receptor antihistamine, or that H1-receptors are not involved in P3b generation.

A comparison of some psychological and physiological effects exerted by zetidoline (DL308) and by oxazepam.

In a double-blind, balanced crossover study, eight healthy male volunteers ingested either DL-308 (10 mg), DL-308 (20 mg), oxazepam (30 mg) or placebo. Subjective estimates of coordination and anxiety, objective performance measurements and cardiovascular measurements were taken at 1, 3, 5 and 8 h after ingestion. DL-308 (20 mg) exerted a strong sedative effect as judged by self-reported coordination scores and performance on logical reasoning and reaction time tests. The effect was evident almost immediately and, on the coordination and reasoning tests, lasted up to 8 h following ingestion. Attention is drawn to the need to extend performance testing in order to maximise test sensitivity. No drug had any consistent or strong influence on cardiovascular measures.

Intraocular pressure reduction in chronic simple glaucoma by continuous infusion of dilute pilocarpine solution.

Ten hospital outpatients with bilateral chronic simple glaucoma received a single drop of 2% pilocarpine to one eye and a continuous infusion of 0.1 % pilocarpine at a flow rate of 0.01 ml/min to the other eye (both solutions were at pH 7.2). On another occasion the treatments were reversed. Measurements of intraocular pressure (IOP) and pupil diameter were made at 30 min intervals for 2 hours. The continuous infusion of dilute solution was as effective as the single drop of more concentrated solution in reducing IOP and in constricting the pupil; the drop was somewhat faster in producing its effect.

A comparison of the pupilloconstrictor effect of pilocarpine solution administered to the conjunctival sac as a single drop or as a continuous infusion in normal subjects.

Pilocarpine was administered into the conjunctival sac of normal volunteers by single-drop administration or by continuous infusion of a solution to the inner canthus by means of a fine Silastic tube. Using pupilloconstriction as a measure of response it was shown that infusion with a 0-01 per cent solution of pilocarpine was as effective as a single drop of 0-5 per cent pilocarpine. The response to the single drop was faster at onset. It was demonstrated that at pH 7-2 pilocarpine was more effective than at acid pH. The infusion method is simple to use, comfortable for long periods, has potential for reducing the need for frequent drop administration and for reducing the total amount of drug administered, and could be used for drugs other than pilocarpine.