Relationship between the uptake, binding and pharmacological action of procaine in the isolated heart.

1. The uptake, efflux and pharmacological actions of procaine hydrochloride were studied on isolated hearts of female guinea-pigs. The hearts were perfused with Krebs solution containing (14)C-procaine (0.1-500 mug/ml.) by the Langendorff technique at 37 degrees C, using a constant flow pump. Hearts and cardiac effluent were assayed for procaine by liquid scintillation spectrometry.2. Accumulation of procaine did not appear to involve active transport mechanisms for the following reasons. The rate of procaine uptake was most rapid at the highest perfusion concentration (500 mug/ml.), when it was three times faster than at the lowest concentration (0.1 mug/ml.); it was not affected by lowering the temperature to 3 degrees C. The ratio of the concentration of procaine in the heart to the concentration in the perfusing fluid decreased with increasing concentration in the perfusion fluid.3. When the efflux of (14)C-procaine from hearts previously perfused with procaine-containing Krebs solution for 10 min was compared with the efflux of (14)C-inulin, the patterns of efflux of both compounds were similar, and showed at least two exponential components. At the highest concentration of procaine (500 mug/ml.) the efflux of procaine was more rapid than that of inulin.4. A relationship was found between the pharmacological action of procaine, the rate of uptake and the level of procaine in the heart. When the procaine-containing perfusion fluid was changed to a procaine-free solution, the heart rate increased rapidly, and there was a rapid decline in the levels of procaine in the hearts.5. It is concluded that guinea-pig hearts accumulate procaine by a passive diffusion process, and that the pattern and rate of efflux indicate that the drug is loosely bound. If it is permissible to extrapolate from these findings to the antiarrhythmic effect in man, the short duration of its action may be due to loose binding rather than to rapid metabolic inactivation.