The physiological basis of allergy.
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If small doses of histamine are alternated with small doses of acetylcholine on the isolated guinea-pig ileum in Tyrode solution, the response to histamine tends to diminish and may disappear. When the response to the small doses of histamine has disappeared, a contraction may be elicited by larger doses. The diminution is reversible, the response returning if the preparation is left unstimulated by drugs for varying periods of time. This phenomenon also occurs when the loops are suspended in Tyrode solution containing cocaine or atropine.
The effects of histamine in the normal and H. pertussis vaccinated rat have been investigated. In the normal animal small doses of histamine (from 1 to 30 mg./kg., i.v.) produced significant, reversible alterations in the blood pressure, electrocardiogram and electroencephalogram. Doses of 100 mg./kg. or more caused bronchoconstriction and doses of 200 mg./kg. or more an effect on the muscular contractions after electrical stimulation of the nerve. Acute histamine intoxication resulted on rapid injection of 500 mg./kg. intravenously; death was probably due to cardiovascular collapse. In the vaccinated rat, a distinction could be made between the immediate and delayed effects of histamine. With a sublethal dose of histamine (5 mg./kg.) alterations in the blood pressure, electrocardiogram and electroencephalogram were noted. The neuromuscular system, which in the normal animal was the least reactive to histamine, showed the most marked increase in sensitivity in the vaccinated rat. The delayed effects of histamine observed after an interval of 5 to 30 min. were characteristic and irreversible, leading to death of the animal. The mechanism of death in the vaccinated rat after histamine appears to differ from that of the normal animal and has been discussed in the light of present knowledge.
In cats under chloralose anaesthesia the cerebral ventricles were perfused with Locke solution at a rate of 0.1 ml./min. from an indwelling cannula in the lateral ventricle. The effluent was collected from a cannula either inserted into the cisterna magna or pushed into the aqueduct. When collection was from the cisterna the perfusion included relatively large areas of the subarachnoidal spaces since in cats the foramina of Luschka form the only outlet from the fourth ventricle. Tubocurarine, histamine, and adrenaline injected intravenously caused great variations in outflow from the cisterna, but these changes did not occur when the collection was from the aqueduct. The changes in outflow from the cisterna were similar whether the injection produced a fall of arterial blood pressure as after tubocurarine and histamine, or a rise, as after adrenaline.
Carbonic acid inhibited the stimulating action of histamine on guinea-pig intestine and of oxytocin on the uterus of many animal species. This effect was relatively specific. Under the same conditions the actions of acetylcholine, KCl, adrenaline (on rabbit uterus), and ergot alkaloids were not inhibited. The electrical excitability of smooth muscle was similarly not affected. The inhibitory action of carbonic acid is directly proportional to its concentration in the medium in which the isolated organ is maintained. The study of the activity of histamine and oxytocin at different pH in a medium free of NaHCO(3) and buffered with a mixture of sodium maleate and maleic acid suggested that the inhibitory action exerted by carbonic acid was specific and independent of the simultaneous modifications of the hydrogen ion concentration. The mechanism of these phenomena is discussed.
Histamine has been shown to depress transmission through the perfused superior cervical ganglion of the cat when doses of 150 mug. or more were administered. The intensity of the ganglionic block was related to the dose of histamine employed. In one-third of the experiments, a slow contracture of the nictitating membrane occurred after histamine had been injected; the contracture lasted up to 10 min., and subsequent injections of histamine gave rise to progressively smaller responses. The blocking action of histamine was evident in all experiments and was the most prominent feature observed. Histamine in a sub-depressant dose enhanced the action of the competitive blocking agents tetraethylammonium and hexamethonium, and also the depolarizing blocking agents tetramethylammonium and nicotine. The possible physiological rôle of histamine in the autonomic nervous system is discussed.
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