1. The ability of several groups of compounds, related to
caffeine, to induce
contractures in isolated frog auricular trabeculae has been tested.2. Of the methylxanthines,
theophylline,
theobromine and
paraxanthine are of similar potency to
caffeine. This applies to
contractures produced in either high-
potassium or in
sodium-free
solution, and to the twitch responses in normal Ringer.3.
Xanthines in which the 9-position
nitrogen is combined and is, therefore, without an
ethylene bond do not affect contraction.4. The hypothesis is put forward that a double-bonded
nitrogen, in an
imidazole ring, is required for activity of the
methylxanthine. This hypothesis is supported by the ability of
imidazole and several close derivatives (e.g.
histamine), as well as
imidazolines, to evoke
contractures. As predicted by the hypothesis,
imidazolidines and imidazolidones, in which all the
nitrogen atoms have single bonds, fail to initiate tension development.5. The activity of
histamine and
histidine is only demonstrable at high pH ( bumpy equals, equals 9.0).6. Raising the pH in
sodium-free
solution induces a transient
contracture.7. Several arguments suggest that
cyclic AMP is probably not an intermediate in the response to the methylxanthines. The activity of
cyclic AMP (and
adenosine) in eliciting
contractures is predicted by the hypothesis because they contain an
imidazole moiety as part of their molecular structure.