e lower
animals show that caffein acts as a diuretic not only by
influencing the circulation, but also by directly affecting the
secreting cells, the probabilities being in favor of the first of
these theories of action. According to Schroeder, not only the
water but also the solids of the urine are increased.

The question whether caffein has an influence upon tissue changes
and the consequent nitrogenous elimination can not be considered as
distinctly answered, though the most probable conclusion is that
the action of caffein upon urea elimination and upon general
nutrition is not direct or pronounced. While the therapeutic dose
of caffein is broken up in the body with the formation of
methylxanthin, which escapes with the urine, the toxic dose is at
least in part eliminated by the kidney unchanged.

The metabolism of the methyl purins, of which group caffein is a member,
appears to vary with the quantity ingested. The manner in which the
methyl group is liberated by the cell protoplasm is said[259] to
determine the amount of stimulus which the tissues receive from these
substances. The xanthin group is almost without any excitatory action,
and its metabolic end products are constant. Perhaps the variation in
the excretions of unchanged methylpurins is dependent upon the amount of
total reactive energy they invoke.

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