How fast do cardioactive steroids act independently of diffusion in guinea‐pig myocardium?

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Abstract
1 The rate of onset of the inotropic effect of different cardioactive steroids (in order of increasing potency: dihydroouabain, digoxigenin, digoxin, ouabain, digitoxin) was studied in guinea-pig papillary muscles stimulated at 0.5 Hz. For an estimate of diffusion rate the time to defined levels of effect was evaluated in relation to the diameter of cylindrical muscles. 2 The dependence of onset rates on muscle diameter was more pronounced with a highly potent steroid, e.g., digitoxin, than with a less potent compound, e.g., dihydroouabain; that is, the apparent rate of diffusion was inversely correlated with the inotropic potency. Reduction of the ratio of receptor to steroid concentration with increase of ouabain or K+ concentration enhanced the apparent rate of diffusion. 3 Extrapolation to negligibly short diffusion distance indicated that the effects of the various steroids develop faster in the absence of diffusion. The effect of 50 μmol l−1 of dihydroouabain appeared more quickly than with ouabain in the perfused heart. The time courses of the inotropic effect in perfused hearts and in papillary muscles of diameters < 0.75 mm were superimposable, indicating that the onset of the dihydroouabain effect was not controlled by diffusion. 4 After the interference of diffusion had been excluded, the rates of onset of action correlated inversely with the inotropic potencies of the steroids. The dissociation rate of the drug-receptor complex appeared to be related to the different receptor affinities.