In the present paper, the naturally occurring
glycosides digitoxin,
gitoxin,
16-acetyl-gitoxin,
digoxin,
cymarol,
ouabain, and
proscillaridin, and the semi-synthetic 16-epi-gitoxin and 16-acetyl-16-epi-gitoxin are investigated as to their inotropic action and their effects on rhythmicity at isolated spontaneously beating atria of the guinea-pig heart in dependence on the variation of the
potassium concentration of the nutritive fluid ([K+]0: 1.34, 2.68, and 5.36 mM resp.). The major results are as follows. 1. Effects of raising [K+]0 from 1.34 to 2.68 mM: The range of the inotropically effective concentrations as well as the size of the maximum inotropic action are more or less strongly improved with all
glycosides. The
glycoside concentrations required to get inotropic maximum had to be increased to a high degree with
proscillaridin and
digoxin. The mean
arrhythmia percentage occurring at the inotropic maximum is either decreased (
gitoxin, 16-epi-
gitoxin,
digoxin,
proscillaridin), unchanged (digitoxin, 16-acetyl-16-epi-gitoxin) or even increased (16-acetyl-gitoxin, cymarol, ouabain). The inotropic value is improved to a high extent with
gitoxin only. 2. Effect of raising [K+]0 from 2.68 to 5.36 mM: The range of the inotropically effective concentrations is extended (
digitoxin and
cymarol) or diminished (
proscillaridin), but remains essentially unchanged with most
glycosides. The size of the maximum inotropic effect is increased with
digoxin,
ouabain and 16-epi-gitoxin, but decreased significantly with
digitoxin and
proscillaridin. The
glycoside concentrations required to produce the inotropic maximum are essentially unchanged with the exception of 16-epi-gitoxin,
16-acetyl-gitoxin and
ouabain. The mean
arrhythmia percentage at the maximum inotropic effect is dramatically reduced with
digoxin,
cymarol and
proscillaridin. The inotropic value is improved with all
glycosides except
digitoxin. 3. Evaluation of the various
glycosides: When judged on the basis of the range of inotropically effective concentrations, the maximum inotropic effect, the mean
arrhythmia percentage at the inotropic maximum and the inotropic value, the best first three
glycosides include 16-epi-gitoxin and
digoxin. 16-Epi-gitoxin and its 16-acetate show that most favourable relationship between the effect on contractility and rhythmicity. The cause of the differential actions of the structurally-different
glycosides on contractility and rhythmicity is hypothesized to be due to divergences in structure and/or conformation of the receptor areas of (Na+ + K+)-
ATPase of contractile and excitable cells.