Baldi[260] found that caffein in small doses increases muscular excitability in dogs and frogs. The spinal and muscular hyperic excitability produced by caffein is, in his opinion, due to the methyl groups attached to the xanthin nucleus. Fredericq[261] states that caffein increases the irritability of the cardiac vagus and accelerates the appearance of pseudofatigue of the vagus which is produced by prolonged stimulation of the nerve. The action of caffein on the mammalian heart has also been investigated by Pilcher,[262] who found that, following the rapid intravenous injection of caffein, there is an acute fall of blood pressure; and with a maximal quantity of caffein, 10 milligrams per kilogram, the cardiac volume and the amplitude of the excursions are usually unchanged. With larger quantities, the volume progressively increases and the amplitude of the excursion decreases. Salant[263] found that the intravenous injection of 15 to 25 milligrams of caffein per kilogram in animals was followed by a fall of blood pressure amounting to 7 to 35 percent in most cases, which was transitory, although in some animals it remained unchanged. A moderate rise was rarely observed. Caffein aids the action of nitrates, acetanilid, ethyl alcohol and amyl alcohol, and increases the toxicity of barium chloride. In a very thorough study of the toxicity of caffein which he made with Reiger,[264] a greater toxicity of about 15 to 20 percent by subcutaneous injection than by mouth, and but about one-half this when injected peritoneally, was found. Intramuscularly the toxicity is 30 percent greater than subcutaneously. In making the tests on animals, they found that individuality, season, age, species, and certain pathological conditions caused variation in the toxic effect of the administered caffein. Low protein diet tends to decrease resistance to caffein in dogs, and a milk or meat diet does the same for growing dogs. Caffein is not cumulative for the rabbit or dog. As a result of experiments on the action of caffein on the bronchiospasm caused by peptone (Witte), silk peptone, B-imidoazolyl-ethylamin, curare, vasodilation, and mucarin, Pal[265] concluded that caffein stimulates certain branches of the peripheral sympathetic and is thus enabled to widen the bronchi or remove bronchiospasm. According to Lapicque[266], caffein produces a change in the excitability of the medulla of the frog similar to that produced by raising the temperature of the nerve centers. Schuerhoff[267] has pointed out that the continued use of large quantities of caffein will produce cardiac irregularity and sleeplessness.